1. 脱发病理基础与关键调控靶点概述
1.1 主要脱发类型的病理特征
脱发，特别是雄激素性脱发（Androgenetic Alopecia, AGA），是全球范围内最常见的毛发缺失疾病，影响着男性和女性，并对患者的心理健康和生活质量产生显著影响 12。AGA的发生发展是一个复杂的过程，涉及多种病理生理机制，包括激素失衡、遗传易感性、炎症微环境和氧化应激等。
激素失衡 是AGA病理学中的核心因素。二氢睾酮（Dihydrotestosterone, DHT）被认为是男性AGA的关键雄激素，它由睾酮在5α-还原酶（5α-reductase）的作用下转化而来 123。DHT对毛囊上皮细胞具有显著影响，尤其是在遗传易感个体的毛囊中，DHT会与毛囊中的雄激素受体结合，导致毛囊进行性微型化（follicular miniaturization） 245。这一过程表现为毛囊体积逐渐缩小，生长期缩短，毛发变细、变短，最终可能完全丧失生发能力，形成“空毛孔” 6。在女性AGA中，激素作用机制更为复杂，可能涉及雄激素水平升高或毛囊对雄激素敏感性增加，但DHT同样扮演了重要角色 3。
遗传易感性 在AGA的发生中起着决定性作用。AGA被认为是一种多基因遗传性疾病，其发病与遗传因素高度相关，遗传 predisposition 约占80% 46。多个基因位点与AGA风险相关，其中X染色体上的AR/EDA2R位点和20p11染色体上的位点已被明确鉴定为主要的遗传风险区域 4。对AGA的基因组关联研究（GWAS）揭示了多个单核苷酸多态性（SNPs）与疾病发展相关 4。除了AGA，其他类型的脱发，如斑秃（Alopecia Areata, AA），也具有显著的遗传倾向，涉及与免疫系统相关的基因，如HLA、CTLA4、IL-2/IL-21等 78910。
炎症微环境 也被认为是脱发，特别是AGA和AA的重要病理特征。尽管AGA传统上被认为是非炎症性脱发，但越来越多的研究表明，毛囊周围的慢性微炎症在AGA的进展中发挥作用 11。这种微炎症可能导致毛囊损伤，加速毛囊微型化进程。在AA中，毛囊周围的自身免疫性炎症攻击是导致毛发脱落的直接原因，表现为免疫细胞浸润和毛囊免疫豁免的崩溃 7。
氧化应激 是近年来越来越受到关注的脱发病理机制之一。毛囊的正常发育和毛发生长受到多种因素和信号通路的调控，而氧化应激能够破坏毛囊内环境的稳态，导致毛囊损伤和功能障碍，从而引发或加重脱发 12。研究表明，在AGA患者中，毛囊乳头细胞（Dermal Papilla Cells, DPCs）的氧化应激水平升高，这可能导致细胞衰老和毛囊微型化 1314。氧化应激通过影响多种信号通路，如p38途径，导致线粒体功能障碍和细胞衰老，从而抑制毛发生长 1214。清除衰老细胞和减少衰老相关分泌表型（SASP）被认为是改善AGA的潜在治疗策略 13。
这些病理机制往往相互关联，共同驱动着脱发疾病的发生和发展。深入理解这些机制对于开发更有效、更具针对性的生发药物至关重要。
1.2 毛囊周期调控的关键分子靶点
毛囊是一个复杂的迷你器官，其生长具有周期性，可分为生长期（anagen）、退行期（catagen）和休止期（telogen）三个主要阶段，并受到一系列复杂分子信号网络的精确调控。毛囊干细胞（Hair Follicle Stem Cells, HFSCs）在毛囊周期的启动和再生中起着核心作用 15。多种信号通路和生长因子协同作用，维持毛囊的稳态并促进毛发生长。
WNT/β-catenin 信号通路 被认为是毛囊诱导和毛发生长周期（特别是生长期启动）的“主调节器” 1617。Wnt/β-catenin通路的激活能刺激干细胞增殖和毛囊形成 18。在毛囊乳头细胞（DPCs）中，Wnt信号的激活被认为是刺激毛发生长的关键因素 19。例如，褪黑素（Melatonin）能够通过上调Wnt/β-catenin信号通路相关基因来促进毛发再生 20。此外，KY19382等新型Wnt/β-catenin信号激活剂，通过抑制CXXC5与Dvl的相互作用，可有效促进毛发再生和新毛囊的形成 21。雄激素性脱发（AGA）与雄激素介导的Wnt抑制有关，因此靶向这一失调网络是治疗AGA的一个有前景的途径 18。维甲酸（Retinoic acid, RA）也通过刺激Wnt/β-catenin信号通路来促进休眠期HFSCs的活化，加速毛发生长，并有望作为AGA的早期干预治疗策略 22。
Sonic Hedgehog (SHH) 信号通路 在毛囊形态发生和后期分化中扮演重要角色 17。它支持毛囊增殖和形态发生 18。肥胖会导致毛囊干细胞中的SHH信号转导显著受抑制，从而导致毛囊小型化和脱发；相反，通过转基因或药物激活SHH可以挽救高脂饮食诱导的脱发 23。SHH信号传导还通过其主要信号微环境中的真皮乳头成纤维细胞来调节毛囊功能 24。SHH信号通路与Wnt/β-catenin信号通路之间存在相互作用，共同调控毛囊的发育和再生 17。
TGF-β/BMP 信号通路 对毛囊周期具有抑制作用，主要参与毛囊的静止期维持和退行期启动 18。骨形态发生蛋白（BMP）通路负责维持毛囊干细胞的静止状态，并启动退行期 18。TGF-β信号的激活也与AGA中雄激素介导的毛囊微型化有关 18。研究表明，一些植物提取物可通过抑制TGF-β或BMP信号通路来促进毛发生长 25。TGF-β信号通路还会导致β-catenin的抑制，而Noggin等BMP抑制剂可以抵消这种抑制作用，促进SHH信号的放大 17。
除了上述信号通路，一些重要的生长因子也对毛囊周期发挥关键作用：
胰岛素样生长因子-1 (IGF-1)：IGF-1主要由生发皮肤上的真皮乳头细胞分泌，通过激活PI3K/Akt和MAPK/ERK等关键通路，刺激毛囊增殖和血管生成，并促进毛囊向生长期过渡 26。IGF-1还能抑制细胞凋亡，延长毛囊生长期，并促进血管内皮生长因子（VEGF）的表达，从而改善毛囊的微循环和营养供应 26。胶原蛋白XVII与IGF-1联合应用，已被证明在AGA小鼠模型中能有效促进血管新生、减轻炎症反应和刺激毛发再生 27。一些植物提取物也能通过上调IGF-1的表达来促进毛发生长 2528。
血管内皮生长因子 (VEGF)：VEGF对毛囊的生长和发育至关重要，因为它能促进血管生成，从而确保毛囊获得充足的血液供应和营养物质 26。RWE（一种植物水提物）通过增加VEGF、EGF和IGF-1的蛋白表达来促进毛发生长 28。
肝细胞生长因子 (HGF) 和 角质细胞生长因子 (KGF, 也称为FGF-7)：这些生长因子也与毛囊细胞的增殖、分化和毛囊周期调控密切相关 1925。它们能够促进毛囊细胞增殖，延长毛囊生长期 19。
此外，Notch信号通路在调节毛囊干细胞命运中发挥作用 1718。Wnt和Notch信号通路之间的相互作用，以及上皮和间充质细胞之间的信号串扰，对于毛囊的正常发育至关重要 17。
这些信号通路和生长因子并非独立作用，而是通过复杂的交叉对话和反馈机制，共同构成了调控毛囊生长周期的精细网络 18。对这些关键靶点的深入理解，为开发新型生发药物提供了理论基础和方向。
2. 经典生发药物的作用机制与临床应用
2.1 米诺地尔：从降压药到生发剂的转化与机制探索
米诺地尔（Minoxidil）作为一种广泛使用的生发药物，其最初的用途却与头发无关。在20世纪70年代，米诺地尔作为一种强效外周血管扩张剂被开发用于治疗严重的顽固性高血压 2930。然而，临床应用中意外发现其一个重要的副作用是增加细毛的生长或使体毛颜色变深，这一发现促使科学家们将其研发为局部生发制剂 29。
米诺地尔促进毛发生长的确切机制至今尚未完全阐明，但目前普遍认为其通过多种途径发挥作用 313233：
首先，钾通道开放剂的作用是米诺地尔最被广泛接受的机制之一。米诺地尔本身是一种前药，其活性代谢产物米诺地尔硫酸盐（Minoxidil Sulphate）被认为是一种三磷酸腺苷（ATP）敏感性钾通道（KATP）开放剂 29303134。通过开放细胞膜上的钾通道，米诺地尔能够引起细胞膜超极化，进而可能对毛囊细胞的活动产生影响。虽然直接在毛囊中证明KATP通道的表达和米诺地尔对其作用仍有难度，但这一机制被认为延长了毛囊的生长期并可能增加毛囊的大小 31。
其次，米诺地尔的血管扩张作用和促进血管生成的能力也被认为是其生发机制的重要组成部分 293536。通过扩张血管，米诺地尔能够增加毛囊区域的血流量，从而为毛囊提供更多的氧气、血液和营养物质 29。此外，有研究表明口服米诺地尔能够显著提高血清血管内皮生长因子（VEGF）水平，而VEGF是促进血管生成和支持毛囊生长的关键因子 36。这种血管生成作用有助于改善毛囊周围的微循环，为毛发生长创造有利条件 3637。
第三，米诺地尔还可能通过延长毛囊生长期（anagen phase）来促进毛发生长，同时缩短休止期（telogen phase），促使休止期毛囊提前进入生长期 293132。在动物研究中，局部米诺地尔已被观察到能缩短休止期，使静止的毛囊过早进入生长期，在人体中可能也存在类似作用 31。米诺地尔还可能直接刺激毛乳头细胞的增殖，并抑制胶原合成，这些体外效应也可能与毛发生长有关 31。此外，米诺地尔还被认为是一种抗炎剂，并能诱导Wnt/β-catenin信号通路，这两种作用也可能协同促进毛发生长 3233。
在临床应用方面，局部米诺地尔（2%或5%溶液，以及5%泡沫剂）是美国食品药品监督管理局（FDA）批准用于治疗男性和女性雄激素性脱发（AGA）的一线药物 63238。对于男性AGA，5%的米诺地尔溶液和泡沫剂的疗效相似，且优于2%溶液 32。临床试验显示，米诺地尔能够有效促进额颞部和头顶区域的毛发再生 32。在一项为期五年的研究中，2%米诺地尔在男性患者中表现出在第一年达到毛发生长高峰，随后几年有所下降的趋势 32。
尽管米诺地尔在临床上取得了显著疗效，但其也存在一定的局限性。首先是起效较慢，通常需要持续使用数月才能观察到明显的生发效果，并且需要长期规律使用以维持疗效，一旦停药，新生的毛发会在数月内脱落 629。其次是个体差异，患者对米诺地尔的反应存在个体差异，部分患者可能对治疗反应不佳，这可能与毛囊磺基转移酶（sulfotransferase）的活性有关，因为该酶负责将米诺地尔转化为活性形式米诺地尔硫酸盐 32。此外，局部米诺地尔常见的不良反应包括头皮瘙痒、刺激性或过敏性接触性皮炎（可能与非活性成分丙二醇有关）以及头皮屑等 629。在治疗初期，部分患者可能会经历暂时性脱发加剧，这被认为是米诺地尔诱导毛囊周期同步化所致，旧的休止期毛发脱落以便新的生长期毛发生长 629。口服米诺地尔则可能引起多毛症和心血管系统症状，且这些副作用呈剂量依赖性 33。
2.2 非那雄胺：从口服到局部给药的优化升级
非那雄胺（Finasteride）是另一种被广泛用于治疗雄激素性脱发（AGA）的经典药物，其作用机制与米诺地尔截然不同。非那雄胺的核心作用机制在于特异性抑制5α-还原酶（5α-reductase）。5α-还原酶是一种关键酶，负责将睾酮（testosterone）转化为更具活性的二氢睾酮（dihydrotestosterone, DHT）3940。DHT被认为是男性AGA发生发展的主要雄激素，它与毛囊中的雄激素受体结合，导致毛囊微型化，最终引起脱发40。非那雄胺通过竞争性抑制5α-还原酶，尤其是II型5α-还原酶（部分研究也指出其对I型有一定抑制作用），从而有效降低血清和头皮组织中的DHT水平，阻断DHT对毛囊的有害作用，逆转毛囊微型化进程，促进毛发生长3941。
非那雄胺最初被开发为口服制剂，用于治疗良性前列腺增生症（BPH），后发现其在AGA治疗中的潜力。口服非那雄胺（1 mg/天）被FDA批准用于男性AGA的治疗，并在一系列临床试验中证实了其显著疗效。例如，每天口服1 mg非那雄胺在24周（平均增加12.4根头发/平方厘米）和48周（平均增加16.4根头发/平方厘米）后，均能显著增加总毛发数量，优于安慰剂39。然而，口服非那雄胺也存在一些局限性，最主要的是可能引起全身性不良反应，特别是性功能障碍（如勃起功能障碍、性欲减退和射精障碍）394243。此外，还可能伴随情绪问题如抑郁39，甚至一些患者在停药后仍持续出现这些副作用，被称为“非那雄胺后综合征”（Post-finasteride syndrome, PFS）3944。这些系统性副作用限制了部分患者的依从性，促使研究人员探索局部给药途径。
局部外用非那雄胺的研发旨在最大限度地发挥其在头皮的局部疗效，同时最小化全身暴露和系统性副作用。口服和外用非那雄胺在药代动力学上存在显著差异：
- 口服非那雄胺：口服后吸收迅速，血药浓度较高。一项研究显示，健康志愿者口服38.1 mg [14C]非那雄胺后，芬那雄胺及其代谢产物在约2小时达到峰值血浆浓度，其终末半衰期约为5.9小时45。另有研究表明，口服非那雄胺1 mg/天，血浆非那雄胺的最大浓度（Cmax）和曲线下面积（AUC0-t）分别为6.86 ± 1.78 ng/mL和57.93 ± 29.38 ng/mL·h46。口服芬那雄胺能有效抑制血浆DHT水平达62%至72%46。
- 局部外用非那雄胺：相比之下，局部外用非那雄胺的全身吸收量显著降低，血药浓度远低于口服制剂。一项针对AGA中国男性志愿者的I期研究显示，每天一次头皮局部喷洒0.25%非那雄胺溶液7天后，其Cmax为29.7 ± 12.9 pg/mL，AUC为530 ± 251 h·pg/mL，显著低于口服制剂的暴露量47。多项研究证实，局部外用非那雄胺的血浆非那雄胺浓度比口服途径低100倍以上4648。这意味着局部外用可在局部发挥疗效的同时，大幅减少全身性药物暴露，从而降低系统性副作用的风险。例如，外用非那雄胺对血清DHT水平的抑制作用（约34.5%）明显低于口服制剂（约55.6%），但在头皮DHT水平的降低方面与口服制剂相似，甚至可以达到与口服制剂相当的头皮DHT抑制效果4648。
Ⅲ期临床试验数据进一步证实了局部外用非那雄胺在疗效和安全性方面的优势。一项随机、双盲、安慰剂对照的Ⅲ期临床试验评估了局部外用非那雄胺喷雾溶液（0.25%）与安慰剂以及口服非那雄胺的效果。结果显示，与安慰剂相比，局部外用非那雄胺在24周时目标区域毛发数量（Target Area Hair Count, TAHC）显著增加（调整后的平均变化分别为20.2根对6.7根；P < 0.001），且其疗效与口服非那雄胺在数值上相似48。在安全性方面，局部外用非那雄胺与安慰剂之间的不良事件发生率和类型没有显著差异，也未出现与治疗相关的严重不良事件48。由于局部外用非那雄胺的血浆浓度极低，且对血清DHT的降低程度较小，因此与口服非那雄胺相比，发生与DHT降低相关的性功能不良反应的可能性更低48。
此外，非那雄胺的剂型优化也在持续进行中。例如，有研究探索了通过纳米载体技术（如植物纳米囊泡）递送非那雄胺，以进一步增强透皮吸收、局部药物滞留，并减少氧化应激，从而在AGA小鼠模型中有效逆转毛囊微型化并刺激毛发再生，且效果优于米诺地尔49。纳米颗粒的应用还可以改善非那雄胺的溶解度和生物利用度，但其在全身药代动力学和组织分布方面的影响还需要进一步研究50。
尽管局部外用非那雄胺在改善疗效和降低系统性副作用方面显示出巨大潜力，但仍需注意的是，其长期疗效和安全性数据仍在积累中，且尚未获得FDA的正式批准4151。然而，其作为一种避免全身治疗的有用选择，在近年来受到了越来越多的关注51。口服非那雄胺的局限性，特别是其性副作用和“非那雄胺后综合征”的潜在风险3944，使得局部制剂成为一个重要的优化方向。
3. 植物提取物的生发潜力与作用靶点解析
随着对化学合成药物副作用关注的增加，天然植物提取物因其多组分、多靶点的作用特点和相对较低的毒副作用，在生发领域展现出巨大的潜力。许多传统草药在民间被用于治疗脱发，现代科学研究正逐步揭示其背后的活性成分和作用机制。
3.1 活性成分与促毛发生长效能
植物提取物中含有多种具有生物活性的化合物，这些成分通过不同的机制影响毛囊周期和毛发生长。常见的活性成分包括酚类、萜类、含硫化合物等。
酚类化合物，如类黄酮、酚酸等，广泛存在于植物中，以其抗氧化、抗炎特性而闻名。例如，姜黄（Curcumin）中的主要活性成分姜黄素（curcumin）是一种酚类化合物，其在生发方面表现出多重功效。研究表明，姜黄素锌框架纳米颗粒（ZnMOF）能显著提高小鼠真皮乳头细胞（DPCs）的活力，抵抗过量的活性氧（ROS），抑制锌缺乏引起的细胞凋亡，并逆转二氢睾酮（DHT）渗透的抑制作用 52。此外，姜黄素还能通过激活Wnt/β-catenin信号通路、下调TGF-β1表达以及减轻毛囊周围炎症来重塑毛囊微环境，促进毛发再生 53。
萜类化合物，如人参皂苷、锯叶棕提取物中的植物甾醇等，在植物生发研究中也备受关注。人参（Ginseng）及其提取物，特别是红参，已被证实具有促进毛发生长的作用。一项研究发现，红参的70%甲醇提取物在体外小鼠触须毛囊培养实验中表现出优于白参的促毛发生长活性。其主要活性成分人参皂苷-Rb1 (G-Rb1) 和20(S)-人参皂苷-Rg3 (20(S)-G-Rg3) 也显示出促毛发活性 54。此外，一项研究比较了3%米诺地尔与3%米诺地尔联合韩国红参在治疗女性型脱发中的应用 55。锯叶棕（Saw Palmetto）提取物是局部生发产品中活性成分之一，其作用机制有待进一步研究 56。
含硫化合物，如洋葱汁，也被认为具有促进毛发生长的潜力，是局部生发产品中活性成分之一 56。此外，其他植物提取物，如落新妇叶提取物（PO-ex），在体外研究中显示能通过清除活性氧自由基，改善毛囊细胞增殖环境。当其与透明质酸微针（PO-ex MN）结合使用时，还能通过机械刺激激活Wnt/β-catenin通路，进一步促进毛囊生长 57。
多种植物提取物在不同实验模型中展现出促毛发生长效能：
体外实验（毛乳头细胞增殖）：
离体实验（毛囊培养）：
体内实验（动物模型）：
这些研究结果表明，多种植物提取物通过激活不同的细胞信号通路、调节生长因子表达、抑制氧化应激和炎症反应等机制，展现出显著的生发潜力。然而，对于许多植物提取物，其活性成分的标准化、作用机制的深入解析以及临床疗效的进一步验证仍然是未来研究的重点。
3.2 多靶点协同作用机制
植物提取物在促进毛发生长方面的独特优势在于其通常包含多种活性成分，能够通过多靶点协同作用，而非单一靶点干预，来调节毛囊的生长周期和微环境。这种多维度干预对于复杂病因的脱发类型（如雄激素性脱发）尤为重要。主要作用机制包括调节生长因子、抑制氧化应激与炎症、激活信号通路以及拮抗雄激素受体等。
1. 调节生长因子
许多植物提取物能够上调促毛发生长因子，下调抑制性生长因子，从而协同促进毛囊从休止期向生长期转化，并延长生长期。
促进 IGF-1 和 VEGF 表达：
- 多种植物提取物被证实能显著提高毛乳头细胞（DPCs）中胰岛素样生长因子-1 (IGF-1) 和血管内皮生长因子 (VEGF) 的表达。例如，紫茉莉水提物（RWE）在二氢睾酮（DHT）诱导的脱发小鼠模型中，显著增加了VEGF、表皮生长因子（EGF）和IGF-1的蛋白表达 28。红豆杉树皮提取物（Pinus densiflora bark extract）也能提高毛囊中IGF-I和VEGF的水平，从而促进毛发生长 60。此外，桃仁（Persicae Semen, TR）中的活性成分苦杏仁苷（amygdalin, Am）通过调节Wnt/β-catenin和VEGF通路，促进毛发再生 61。
- IGF-1 通过激活PI3K/Akt和MAPK/ERK等通路，促进毛囊细胞增殖和分化，并延长毛囊生长期。VEGF则通过促进血管生成，改善毛囊的血液供应和营养状况 62。
促进 HGF 和 KGF 表达：
抑制 DKK1 和 TGF-β1 等抑制因子：
2. 抑制氧化应激与炎症
氧化应激和炎症是导致毛囊损伤和脱发的重要因素。许多植物提取物富含抗氧化剂和抗炎成分，能够减轻毛囊微环境中的不良影响。
抗氧化作用：
- 植物提取物中的酚类、类黄酮等成分具有强大的自由基清除能力，能对抗活性氧（ROS）对毛囊的损伤。
- 醉浆草提取物（Oxyresveratrol, ORV）具有显著的抗氧化特性，能降低H2O2诱导的活性氧水平，从而保护人毛乳头细胞 65。
- 茶叶籽粕提取物能有效对抗氧化应激，防止毛乳头细胞衰老 63。
- 摩洛哥坚果饼粕提取物（Argan press cake extract, APC）也能有效对抗H2O2诱导的氧化应激，保护真皮乳头细胞免受损伤 66。
- “参营养真方”（Shen-Ying-Yang-Zhen formula, SYF）通过改善毛囊周围的氧化应激和血管生成，促进毛发生长，并通过调节VEGF/Akt/Caspase-9信号通路，减少DHT处理的HDPC细胞凋亡 67。
抗炎作用：
3. 激活 AKT/ERK 信号通路
AKT 和 ERK 信号通路是细胞增殖、存活和分化的关键通路。植物提取物通过激活这些通路，促进毛乳头细胞增殖，从而延长毛囊生长期。
- RWE能激活ERK、AKT和GSK-3β等毛发生长调节通路相关因子 28。
- 茶叶籽粕提取物能促进毛乳头细胞增殖，并通过ERK和AKT信号通路的磷酸化激活，同时上调HGF、VEGF和IGF-1的mRNA水平，下调TGF-β1的mRNA水平 63。
- 鱼腥草提取物（Houttuynia cordata extract, HC）能够诱导ERK和AKT的磷酸化，并增加Bcl-2的表达，从而刺激人毛乳头细胞的增殖，延长生长期 68。
- 积雪草提取物（Centipedegrass extract, CGE）能上调hDPCs中CTNNB1、ALP、SOX2、IGF1和VEGFA基因的表达，并增加ALP、β-catenin、磷酸化GSK3β和磷酸化AKT的蛋白表达 69。
4. 拮抗雄激素受体和抑制 5α-还原酶
对于雄激素性脱发，直接干预雄激素通路是有效的治疗策略。一些植物提取物被发现具有类似非那雄胺的作用，通过抑制5α-还原酶活性或拮抗雄激素受体，从而降低DHT对毛囊的有害影响。
- 锯叶棕（Saw Palmetto）被广泛研究，被认为通过抑制5α-还原酶来降低DHT水平，进而改善AGA 7071。
- 胡枝子提取物（Lespedeza capitata extract, LCE）能减少DKK1的分泌并降低5α-还原酶活性（二氢睾酮/睾酮比率降低60%） 58。
- 某些天然产品被发现具有5α-还原酶抑制活性，有助于治疗AGA 71。
综上所述，植物提取物通过多靶点协同作用，包括调节生长因子、抑制氧化应激和炎症、激活关键信号通路以及拮抗雄激素作用，共同干预毛囊微型化进程，展现出巨大的生发潜力。然而，要实现其临床应用，仍需进一步研究其活性成分的标准化、作用机制的深入阐明以及临床疗效和安全性的严格验证。
4. 新型生发靶点与药物研发前沿
随着对毛发生长调控机制理解的不断深入，研究人员发现了许多新的分子靶点，并据此开发出了一系列新型生发药物。这些药物致力于更精准地干预毛囊周期，激活休眠毛囊，或对抗导致脱发的病理过程。
4.1 基于信号通路的靶向药物开发
毛囊的生长周期和再生过程受到多种复杂信号通路的精密调控。针对这些关键信号通路的靶向药物开发，为脱发治疗带来了新的希望。
1. Wnt/β-catenin 信号通路激活剂
Wnt/β-catenin 信号通路被认为是毛囊发生、生长期启动和维持的核心调控因子 7273。激活该通路能够有效促进毛囊再生和毛发生长。
- 小分子激活剂的研发进展：
- KY19382 是一种小分子Wnt/β-catenin信号通路激活剂，通过抑制CXXC5与Dvl之间的相互作用来发挥作用。研究表明，KY19382能够显著促进小鼠模型中的毛发再生和新毛囊的形成 72。此外，糖尿病小鼠模型中，Wnt/β-catenin信号通路受到抑制，导致毛发再生能力下降。KY19382能够恢复糖尿病小鼠的毛发再生能力，并增加高糖培养条件下人毛囊的长度，提示其在治疗糖尿病引起的脱发方面具有潜力 72。
- Deoxyshikonin (Ds)，来源于中药紫草（Arnebiae Radix），被鉴定为一种具有促毛发生长潜力的活性成分。网络药理学和分子对接研究表明，Ds主要通过靶向糖原合成酶激酶3β (GSK3β) 促进Wnt/β-catenin信号通路，从而促进人真皮乳头细胞（HDPCs）的增殖并诱导脱发小鼠的毛发再生 74。
- CHIR99021 是一种GSK3α/β抑制剂，通过抑制GSK3β的活性来激活Wnt信号通路。在体外研究中，CHIR99021与TGF-β受体抑制剂SB431542和PDGF-AA联合使用，能够有效维持高传代真皮乳头细胞（DPCs）的毛发诱导能力，促进其增殖和关键基因（如Sox2、Versican、ALP）的表达，表明其在重建新毛囊中的应用潜力 75。
- 其他Wnt/β-catenin激活剂，如通过刺激毛囊乳头细胞分泌Wnt3a和Wnt7b的巨噬细胞来源的细胞外囊泡（MAC-EVs），能够显著增强DPCs的增殖、迁移以及毛发诱导标记物的表达，并在小鼠和人毛囊模型中促进毛发生长 76。
- 桃仁（Persicae Semen, TR）中的活性成分苦杏仁苷（amygdalin, Am）也被发现通过调节Wnt/β-catenin信号通路促进毛发再生 61。
2. JAK-STAT 信号通路抑制剂
JAK-STAT（Janus激酶-信号转导和转录激活因子）信号通路在免疫反应和细胞分化中发挥关键作用，其异常激活与多种自身免疫性疾病相关，包括斑秃（Alopecia Areata, AA）77。针对JAK-STAT通路的抑制剂在AA的治疗中取得了突破性进展。
- JAK抑制剂在斑秃治疗中的应用：
- 巴瑞替尼 (Baricitinib) 是一种口服、选择性、可逆的Janus激酶1和2 (JAK1/JAK2) 抑制剂，能够阻断斑秃发病机制中涉及的细胞因子信号传导 78。两项关键的III期临床试验（BRAVE-AA1和BRAVE-AA2）证实，对于重度斑秃患者（SALT评分≥50），每日口服4mg巴瑞替尼在第36周时能显著提高达到SALT评分≤20（头皮毛发损失≤20%）的患者比例，效果远优于安慰剂。即使是每日2mg剂量也显示出显著疗效 78。长期随访结果显示，巴瑞替尼在104周内保持了较高的疗效，且安全性良好，未发现新的安全信号 79。
- 托法替尼 (Tofacitinib) 是另一种JAK抑制剂，主要抑制JAK1和JAK3。它在斑秃治疗中也显示出积极效果。一项网络Meta分析显示，口服托法替尼和鲁索替尼（ruxolitinib）相比安慰剂，能显著提高斑秃患者的完全缓解率 80。
- 鲁索替尼 (Ruxolitinib) 是一种JAK1/JAK2抑制剂，也被用于斑秃的治疗研究，并显示出良好的疗效和安全性 80。
- 伊伐昔替尼 (Ivarmacitinib) 和 利特昔替尼 (Ritlecitinib) 等新型JAK抑制剂也在斑秃治疗中表现出潜力。例如，一项比较口服JAK抑制剂疗效的系统评价和贝叶斯网络Meta分析显示，4mg巴瑞替尼最有可能是最有效的治疗方案，其次是利特昔替尼200/50mg和伊伐昔替尼4mg，且部分药物表现出剂量依赖性效应 81。
- JAK抑制剂的共同不良事件包括感染、血脂异常和血细胞计数异常等，但总体可控 7778。
3. 其他信号通路靶点
PGE2 信号通路：前列腺素E (PGE) 在组织再生中发挥作用，其类似物比马前列素已被FDA批准用于睫毛生长。近期研究发现，15-羟基前列腺素脱氢酶（15-PGDH）抑制剂，如二氢异喹啉酮哌啶基羧基吡唑并吡啶 (DPP)，通过抑制15-PGDH来提高PGE水平。DPP在体外实验中增强了DHT损伤的人毛囊真皮乳头细胞 (HFDPCs) 的伤口愈合和碱性磷酸酶表达，减少活性氧生成，恢复线粒体膜电位，并激活AKT/ERK和Wnt信号通路。在离体人毛囊器官培养中，DPP也显著促进了毛发生长，提示其在改善脱发方面具有前景 82。
MLKL 介导的坏死性凋亡通路：混合谱系激酶结构域样假激酶（MLKL）介导的坏死性凋亡在多种皮肤疾病中发挥作用，但其对毛发生长的影响尚不明确。研究发现，雄激素性脱发（AGA）患者脱发区域的MLKL表达升高，小鼠皮肤中MLKL在毛囊退行期达到峰值。抑制MLKL表达或使用其靶向抑制剂奈硫磺酰胺（NSA）可促进毛发生长并阻止毛囊退行。NSA通过抑制ORS细胞中的MLKL激活，促进DPCs中的Wnt信号激活，并改善DHT诱导的毛发生长抑制，为脱发治疗提供了新的靶点和药物开发方向 83。
这些针对特定信号通路的靶向药物为脱发治疗提供了精准干预的可能性，有望克服传统药物的局限性，并为不同类型的脱发患者提供更有效的治疗方案。
4.2 抗衰老与细胞保护类药物探索
毛囊作为一个快速周转的组织，其衰老过程是导致脱发的重要因素之一。毛囊干细胞（HFSCs）的衰老、DNA损伤积累、自噬功能障碍以及氧化应激等细胞保护机制的失衡，都会影响毛囊的正常周期和再生能力，导致毛发稀疏乃至脱落。因此，针对这些衰老相关靶点和细胞保护机制的药物探索，为生发治疗开辟了新的途径 1384。
1. 毛囊干细胞衰老与再生能力下降
毛囊干细胞的衰竭是与年龄相关的脱发，特别是雄激素性脱发（AGA）的关键特征 138485。随着年龄增长，毛囊干细胞的功能下降，表现为静止状态被破坏、分化能力受损、增殖潜力降低，并最终导致毛囊小型化和毛发损失 8486。
- 衰老细胞的积累：衰老细胞在皮肤和毛囊中积累，释放衰老相关分泌表型（SASP）因子，这些因子会诱导炎症并影响周围组织的正常功能，从而加剧毛囊干细胞的衰老和功能障碍 13。
- 毛囊干细胞流失：在衰老过程中，毛囊干细胞会从毛囊生态位中“逃逸”到真皮层，导致毛囊小型化。单细胞RNA测序显示，衰老毛囊干细胞的细胞黏附和细胞外基质基因表达降低，这与FOXC1和NFATC1基因调控相关。敲除这些基因会重现毛囊小型化和脱发，提示细胞黏附机制在维持毛囊干细胞稳态中的重要性 85。
- Piezo1-钙-TNF-α 轴介导的干细胞损耗：毛干小型化导致物理生态位缩小，对毛囊干细胞产生机械压迫，激活机械敏感通道Piezo1，引发钙内流，进而导致HFSCs对肿瘤坏死因子-α (TNF-α) 的敏感性增加，诱导异位细胞凋亡，从而加速HFSCs的耗竭 87。
2. DNA损伤修复与端粒酶激活
DNA损伤的积累是细胞衰老的重要驱动因素，也影响毛囊的正常功能。毛囊细胞的端粒长度维持对于其无限增殖和再生能力至关重要。
- 端粒酶激活剂：
- 端粒酶（Telomerase）是一种核糖核蛋白逆转录酶，负责维持端粒（染色体末端保护结构）的长度。端粒的缩短是细胞衰老和功能丧失的关键标志 8889。
- 研究表明，端粒酶在毛发生长中发挥重要作用，其活性的改变与多种毛发疾病相关 89。毛囊（特别是毛囊干细胞）具有较高的端粒酶活性，这有助于其持续再生 90。
- 在角化不良性先天性再生障碍性贫血（Dyskeratosis congenita, DC）患者中，由于端粒酶复合体基因突变，导致端粒缩短，表现出皮肤萎缩、毛发缺陷等症状。体外实验证实，通过表达端粒酶逆转录酶（TERT）或端粒酶RNA组分（TERC）可以部分恢复DC患者皮肤角质形成细胞的增殖能力，并延长其寿命 88。
- 虽然端粒酶激活剂在延缓毛囊衰老和促进毛发生长方面显示出潜力，但需谨慎权衡其在癌症发生发展中的潜在作用 89。
3. 自噬调控与细胞保护
自噬（Autophagy）是细胞内重要的自我消化和回收机制，对于维持细胞稳态、清除损伤细胞器和蛋白质聚集物至关重要。自噬功能障碍与多种衰老相关疾病和组织功能下降有关。
- 自噬激活促进毛囊干细胞活化：
- 自噬在毛囊干细胞的代谢和功能中扮演重要角色。研究发现，毛囊干细胞在从休止期向生长期过渡时，自噬水平达到高峰 91。
- 抑制自噬（例如使用3-甲基腺嘌呤，3-MA）会导致毛囊提早进入退行期并延长休止期。相反，通过雷帕霉素（Rapamycin）激活自噬，能够促进毛发生长 91。
- 自噬通过增加毛囊干细胞乳酸脱氢酶（Ldha）的表达和活性，将毛囊干细胞的代谢模式转换为糖酵解，从而激活毛囊干细胞，启动毛囊周期并促进毛发生长 91。
- 异槲皮苷（Isoquercitrin, IQ），一种来源于中药的天然小分子，被发现能通过激活AMPK/mTOR/ULK1信号通路诱导自噬。IQ通过直接作用于AMPK和IGF-1R，促进毛囊进入生长期并促进毛发再生。此外，它还能通过IGF-1R/PI3K/AKT和VEGF/VEGFR/ANG通路促进血管生成 92。
- 维生素D也被发现能通过DDIT4-mTOR信号通路增强细胞自噬，这可能与其抗癌效应和细胞保护作用相关 93。虽然这并未直接在毛囊中进行研究，但提示维生素D可能在毛囊自噬调控中发挥作用。
4. SIRT1激动剂与抗衰老
SIRT1（Sirtuin 1）是一种NAD+-依赖性去乙酰化酶，在细胞代谢、DNA修复、炎症和衰老等多种生物过程中发挥关键作用，被认为是重要的抗衰老蛋白。
- SIRT1在毛囊中的作用：
- SIRT1激动剂在延缓衰老方面具有潜力。例如，棕榈酰四肽-20（PTP20）是一种α-MSH激动剂，被开发用于促进毛发色素沉着，减少毛发灰白。研究显示，PTP20能够增强催化酶活性，减少H2O2生成，并激活黑素生成过程。此外，PTP20还能调节SIRT1的酶活性，提示SIRT1可能参与其毛发色素沉着和抗衰老作用 94。
- 虽然直接在毛发生长中SIRT1激动剂的研究较少，但鉴于SIRT1在细胞抗衰老和维持细胞功能中的核心作用，SIRT1激动剂有望成为靶向毛囊衰老的潜在治疗策略。
综上所述，通过针对毛囊干细胞衰老、DNA损伤修复、自噬调控以及激活SIRT1等抗衰老机制，可以开发出新型的生发药物。这些药物旨在从细胞层面改善毛囊的健康状况和再生能力，为不同类型的脱发提供更全面和持久的治疗方案。例如，通过纳米载体递送的共轭亚油酸（CLA）纳米囊泡（Arg-CLAVs）被发现能通过减轻氧化应激、减少SASP和调节MAPK-ERK信号通路来“逆转”DHT诱导的毛囊衰老，同时促进血管生成和真皮乳头细胞增殖，为治疗AGA提供了新的抗衰老策略 95。此外，来自禽类MSC的生物脉冲细胞外囊泡（AMSC-sEVs）富含具有抗炎和抗衰老作用的miRNA（如miR-21-5p和miR-199a-5p），局部应用能显著改善毛发再生和皮肤年轻化 96。这些研究方向强调了从分子和细胞层面干预毛囊衰老，以期实现毛发再生的重要性。
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参考文献
1Treatment options for androgenetic alopecia: Efficacy, side effects, compliance, financial considerations, and ethics.PubMed
Mark S Nestor, Glynis Ablon, Anita Gade, et al.
J Cosmet Dermatol. 2021 Dec;20(12):3759-3781. doi: 10.1111/jocd.14537. Epub 2021 Nov 6.
BACKGROUND: Androgenetic alopecia (AGA) is the most common form of hair loss consisting of a characteristic receding frontal hairline in men and diffuse hair thinning in women, with frontal hairline retention, and can impact an individual's quality of life. The condition is primarily mediated by 5-alpha-reductase and dihydrotestosterone (DHT) which causes hair follicles to undergo miniaturization and shortening of successive anagen cycles. Although a variety of medical, surgical, light-based and nutraceutical treatment options are available to slow or reverse the progression of AGA, it can be challenging to select appropriate therapies for this chronic condition. AIMS: To highlight treatment options for androgenetic alopecia taking into consideration the efficacy, side effect profiles, practicality of treatment (compliance), and costs to help clinicians offer ethically appropriate treatment regimens to their patients. MATERIALS AND METHODS: A literature search was conducted using electronic databases (Medline, PubMed, Embase, CINAHL, EBSCO) and textbooks, in addition to the authors' and other practitioners' clinical experiences in treating androgenetic alopecia, and the findings are presented here. RESULTS: Although topical minoxidil, oral finasteride, and low-level light therapy are the only FDA-approved therapies to treat AGA, they are just a fraction of the treatment options available, including other oral and topical modalities, hormonal therapies, nutraceuticals, PRP and exosome treatments, and hair transplantation. DISCUSSION: Androgenetic alopecia therapy remains challenging as treatment selection involves ethical, evidence-based decision-making and consideration of each individual patient's needs, compliance, budget, extent of hair loss, and aesthetic goals, independent of potential financial benefits to the practitioners.
2Updates in Treatment for Androgenetic Alopecia.PubMed
Jung-Won Shin, Chang-Hun Huh
Ann Dermatol. 2025 Dec;37(6):327-335. doi: 10.5021/ad.25.042.
Androgenetic alopecia (AGA) is a common nonscarring hair loss condition that affects both men and women, often resulting in psychological distress and reduced quality of life. AGA pathogenesis involves genetic predisposition and androgen influence, primarily dihydrotestosterone (DHT), which leads to hair follicle miniaturization and progressive hair thinning. AGA remains challenging to manage due to its chronic progression and the combined influence of genetic and environmental factors. Topical minoxidil and oral finasteride are the most widely used treatments for AGA, addressing follicular miniaturization. However, their reliance on long-term use and potential for side effects or inconvenience has prompted increasing interest in alternative therapies. The mainstream of current AGA treatment can be categorized into androgen-targeting and non-androgen-targeting approaches. Finasteride and dutasteride, both 5-α-reductase inhibitors that reduce DHT levels in hair follicles, are key androgen-targeting treatments, with newer formulations like topical and injectable options emerging alongside traditional oral forms. Topical minoxidil remains central to non-androgen-targeted AGA treatments, though growing evidence supports the efficacy and safety of its low-dose oral form. Additionally, therapies like low-level light therapy, platelet-rich plasma, and exosome treatments are being explored. Recently, therapies targeting the androgen receptor, including small interfering RNA-based approaches, have been developed and are currently in clinical trial stages, offering innovative potential for AGA treatment. This review explores current and emerging treatments for AGA, addressing both androgen-targeted and non-androgen-targeted approaches with an emphasis on their mechanisms, efficacy, and safety. It ultimately aims to provide a comprehensive update on the latest advancements in AGA management.
3Androgens and alopecia.PubMed
Keith D Kaufman
Mol Cell Endocrinol. 2002 Dec 30;198(1-2):89-95. doi: 10.1016/s0303-7207(02)00372-6.
Androgens have profound effects on scalp and body hair in humans. Scalp hair grows constitutively in the absence of androgens, while body hair growth is dependent on the action of androgens. Androgenetic alopecia, referred to as male pattern hair loss (MPHL) in men and female pattern hair loss (FPHL) in women, is due to the progressive miniaturization of scalp hair. Observations in both eunuchs, who have low levels of testicular androgens, and males with genetic 5alpha-reductase (5alphaR) deficiency, who have low levels of dihydrotestosterone (DHT), implicate DHT as a key androgen in the pathogenesis of MPHL in men. The development of finasteride, a type 2-selective 5alphaR inhibitor, further advanced our understanding of the role of DHT in the pathophysiology of scalp alopecia. Controlled clinical trials with finasteride demonstrated improvements in scalp hair growth in treated men associated with reductions in scalp DHT content, and a trend towards reversal of scalp hair miniaturization was evident by histopathologic evaluation of scalp biopsies. In contrast to its beneficial effects in men, finasteride did not improve hair growth in postmenopausal women with FPHL. Histopathological evaluation of scalp biopsies confirmed that finasteride treatment produced no benefit on scalp hair in these women. These findings suggest that MPHL and FPHL are distinct clinical entities, with disparate pathophysiologies. Studies that elucidate the molecular mechanisms by which androgens regulate hair growth would provide greater understanding of these differences.
4Androgenetic alopecia: a review.PubMed
Francesca Lolli, Francesco Pallotti, Alfredo Rossi, et al.
Endocrine. 2017 Jul;57(1):9-17. doi: 10.1007/s12020-017-1280-y. Epub 2017 Mar 28.
PURPOSE: Androgenetic alopecia, commonly known as male pattern baldness, is the most common type of progressive hair loss disorder in men. The aim of this paper is to review recent advances in understanding the pathophysiology and molecular mechanism of androgenetic alopecia. METHODS: Using the PubMed database, we conducted a systematic review of the literature, selecting studies published from 1916 to 2016. RESULTS: The occurrence and development of androgenetic alopecia depends on the interaction of endocrine factors and genetic predisposition. Androgenetic alopecia is characterized by progressive hair follicular miniaturization, caused by the actions of androgens on the epithelial cells of genetically susceptible hair follicles in androgen-dependent areas. Although the exact pathogenesis of androgenetic alopecia remains to be clarified, research has shown that it is a polygenetic condition. Numerous studies have unequivocally identified two major genetic risk loci for androgenetic alopecia, on the X-chromosome AR⁄EDA2R locus and the chromosome 20p11 locus. CONCLUSIONS: Candidate gene and genome-wide association studies have reported that single-nucleotide polymorphisms at different genomic loci are associated with androgenetic alopecia development. A number of genes determine the predisposition for androgenetic alopecia in a polygenic fashion. However, further studies are needed before the specific genetic factors of this polygenic condition can be fully explained.
5Dihydrotestosterone-induced hair regrowth inhibition by activating androgen receptor in C57BL6 mice simulates androgenetic alopecia.PubMed
Danlan Fu, Junfei Huang, Kaitao Li, et al.
Biomed Pharmacother. 2021 May;137:111247. doi: 10.1016/j.biopha.2021.111247. Epub 2021 Jan 29.
Androgenic alopecia (AGA), also known as male pattern baldness, is one of the most common hair loss diseases worldwide. The main treatments of AGA include hair transplant surgery, oral medicines, and LDL laser irradiation, although no treatment to date can fully cure this disease. Animal models play important roles in the exploration of potential mechanisms of disease development and in assessing novel treatments. The present study describes androgen receptor (AR) in C57BL/6 mouse hair follicles that can be activated by dihydrotestosterone (DHT) and translocate to the nucleus. This led to the design of a mouse model of androgen-induced AGA in vivo and in vitro. DHT was found to induce early hair regression, hair miniaturization, hair density loss, and changes in hair morphology in male C57BL/6 mice. These effects of DHT could be partly reversed by the AR antagonist bicalutamide. DHT had similar effects in an ex vivo model of hair loss. Evaluation of histology, organ culture, and protein expression could explain the mechanism by which DHT delayed hair regrowth.
6Male Androgenetic AlopeciaPubMed
Leila Asfour, William Cranwell, Rodney Sinclair
Male androgenetic alopecia (MAA) is the most common form of hair loss in men, affecting 30-50% of men by age 50. MAA occurs in a highly reproducible pattern, preferentially affecting the temples, vertex and mid frontal scalp. Although MAA is often regarded as a relatively minor dermatological condition, hair loss impacts self-image and is a great cause of anxiety and depression in some men. MAA is increasingly identified as a risk factor for arterial stiffness and cardiovascular disease. A familial tendency to MAA and racial variation in the prevalence is well recognized, with heredity accounting for approximately 80% of predisposition. Normal levels of androgens are sufficient to cause hair loss in genetically susceptible individuals. The key pathophysiological features of MAA are alteration in hair cycle development, follicular miniaturization, and inflammation. In MAA, the anagen phase decreases with each cycle, while the length of telogen remains constant or is prolonged. Ultimately, anagen duration becomes so short that the growing hair fails to achieve sufficient length to reach the surface of the skin, leaving an empty follicular pore. Hair follicle miniaturization is the histological hallmark of androgenetic alopecia. Once the arrector pili muscle, that attaches circumferentially around the primary follicle, has detached from all secondary follicles and primary follicles have undergone miniaturization and detachment, hair loss is likely irreversible. While many men choose not to undergo treatment, topical minoxidil and oral finasteride are approved by the Food and Drug Administration (USA) for the treatment of MAA. Both medications prevent further hair loss, but only partially reverse baldness, and require continuous use to maintain the effect. Topical minoxidil is well tolerated as a 2% or 5% solution or 5% foam. There is initially accelerated hair loss for several weeks due to telogen hairs falling out. Minor adverse effects include itching of the scalp, dandruff, and erythema. Finasteride is a potent and selective antagonist of the type II 5 alpha reductase, and is not an anti-androgen. 5 alpha reductase converts testosterone into dihydrotestosterone (DHT). DHT binding to the scalp hair follicle androgen receptors produces MAA. A daily oral finasteride dose of one milligram reduces scalp dihydrotestosterone by 64% and serum dihydrotestosterone by 68%. Adverse effects, including sexual dysfunction (erectile dysfunction, low libido, anorgasmia) are uncommon, and most often resolve without discontinuing treatment. Permanent sexual adverse effects have been reported on social media and internet forums; however, the true incidence is unknown. Dutasteride inhibits type I and type II 5 alpha reductase, and it might be superior to finasteride in improving hair growth in young males. However, adverse sexual side effects are more common with dutasteride than with finasteride. Combining medications with different mechanisms of action enhances the efficacy. Topical antiandrogens, prostaglandin analogues, topical antifungals, growth factors, and laser treatment are all emerging medical treatments for MAA, yet lack the necessary research to confirm efficacy and safety. Hair transplantation involves removal of hair from the occipital scalp and re-implantation into the bald vertex and frontal scalp. With modern techniques, graft survival in excess of 90% can be reliably achieved. A combination of these therapeutic options is now available for men experiencing MAA, with favorable cosmetic outcomes possible. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.
7Genome-wide association study in alopecia areata implicates both innate and adaptive immunity.PubMed
Lynn Petukhova, Madeleine Duvic, Maria Hordinsky, et al.
Nature. 2010 Jul 1;466(7302):113-7. doi: 10.1038/nature09114.
Alopecia areata (AA) is among the most highly prevalent human autoimmune diseases, leading to disfiguring hair loss due to the collapse of immune privilege of the hair follicle and subsequent autoimmune attack. The genetic basis of AA is largely unknown. We undertook a genome-wide association study (GWAS) in a sample of 1,054 cases and 3,278 controls and identified 139 single nucleotide polymorphisms that are significantly associated with AA (P <or= 5 x 10(-7)). Here we show an association with genomic regions containing several genes controlling the activation and proliferation of regulatory T cells (T(reg) cells), cytotoxic T lymphocyte-associated antigen 4 (CTLA4), interleukin (IL)-2/IL-21, IL-2 receptor A (IL-2RA; CD25) and Eos (also known as Ikaros family zinc finger 4; IKZF4), as well as the human leukocyte antigen (HLA) region. We also find association evidence for regions containing genes expressed in the hair follicle itself (PRDX5 and STX17). A region of strong association resides within the ULBP (cytomegalovirus UL16-binding protein) gene cluster on chromosome 6q25.1, encoding activating ligands of the natural killer cell receptor NKG2D that have not previously been implicated in an autoimmune disease. By probing the role of ULBP3 in disease pathogenesis, we also show that its expression in lesional scalp from patients with AA is markedly upregulated in the hair follicle dermal sheath during active disease. This study provides evidence for the involvement of both innate and acquired immunity in the pathogenesis of AA. We have defined the genetic underpinnings of AA, placing it within the context of shared pathways among autoimmune diseases, and implicating a novel disease mechanism, the upregulation of ULBP ligands, in triggering autoimmunity.
8Genetics of alopecia areata.PubMed
J Green, R D Sinclair
Australas J Dermatol. 2000 Nov;41(4):213-8. doi: 10.1046/j.1440-0960.2000.00439.x.
Alopecia areata is a common disorder with a genetic predisposition where interaction with environmental factors leads to episodes of terminal hair loss. In this review article, we examine the evidence for a genetic basis to this disorder and discuss the prospects for future research into genetic susceptibility areas and the problems that are likely to be encountered in such research.
9Clinical and Genetic Aspects of Alopecia Areata: A Cutting Edge Review.PubMed
Chih-Yi Ho, Chiu-Yen Wu, Jeff Yi-Fu Chen, et al.
Genes (Basel). 2023 Jun 28;14(7):1362. doi: 10.3390/genes14071362.
Alopecia areata (AA) is a chronic, non-scarring, immune-mediated skin disease that affects approximately 0.5-2% of the global population. The etiology of AA is complex and involves genetic and environmental factors, with significant advancements in genetic research occurring in recent years. In addition to well-known genes such as , , and , which have been widely supported as being associated with AA, an increasing number of specific gene-related loci have been discovered through advances in genetic research. For instance, gene analysis of microRNAs can reveal the critical role of miRNAs in regulating gene expression, aiding in the understanding of cellular and organismal functional regulatory mechanisms. Furthermore, numerous studies have confirmed the existence of correlations between AA and other immune-related diseases. Examples include hyperthyroidism and rheumatoid arthritis. By understanding the interrelationships between AA and other immune diseases, we can further comprehend potential shared genetic foundations or pathogenic mechanisms among different diseases. Genetic research plays a crucial role in unraveling the pathogenesis of AA, as the identification of genetic variations associated with AA can assist in formulating more effective and targeted treatment strategies.
10Genetic linkage studies in alopecia areata.PubMed
Amalia Martinez-Mir, Abraham Zlotogorski, Jurg Ott, et al.
J Investig Dermatol Symp Proc. 2003 Oct;8(2):199-203. doi: 10.1046/j.1087-0024.2003.00809.x.
Alopecia areata affects approximately 4.6 million individuals in the United States alone. It is typified by patchy hair loss on the scalp that can progress to cover the entire scalp (alopecia totalis) and eventually the entire body (alopecia universalis). Despite the high incidence of this condition, its genetic basis is largely unknown. It is now generally accepted, however, that it fits the paradigm of a complex trait, in which a combination of genetic and environmental factors results in the final phenotype. Genetic studies have been limited thus far to association analyses, which suggest that a permissive HLA status may potentiate the development of alopecia areata. A systematic screen for identifying the primary genetic mechanisms underlying this disorder has never before been undertaken, however. Here we discuss our approach to the identification of susceptibility genes for alopecia areata. In particular, we recently initiated a comprehensive genetic analysis by performing a genome-wide scan in a collection of alopecia families with multiple affected family members. There are currently a number of examples of complex diseases of the skin, such as psoriasis and atopic dermatitis, in which genetic studies are being undertaken that substantiate the timeliness of this approach. We anticipate that these studies will lead to the identification of the susceptibility genes and provide a foundation for understanding how they interact with each other and with other variables, such as the immune system and environmental factors.
12Oxidative stress in hair follicle development and hair growth: Signalling pathways, intervening mechanisms and potential of natural antioxidants.PubMed
Fanpan Du, Jingjie Li, Shiqian Zhang, et al.
J Cell Mol Med. 2024 Jun;28(12):e18486. doi: 10.1111/jcmm.18486.
Hair follicle development and hair growth are regulated by multiple factors and multiple signalling pathways. The hair follicle, as an important skin appendage, is the basis for hair growth, and it has the functions of safeguarding the body, perceiving the environment and regulating body temperature. Hair growth undergoes a regular hair cycle, including anagen, catagen and telogen. A small amount of physiological shedding of hair occurs under normal conditions, always in a dynamic equilibrium. Hair loss occurs when the skin or hair follicles are stimulated by oxidative stress, inflammation or hormonal disorders that disrupt the homeostasis of the hair follicles. Numerous researches have indicated that oxidative stress is an important factor causing hair loss. Here, we summarize the signalling pathways and intervention mechanisms by which oxidative stress affects hair follicle development and hair growth, discuss existing treatments for hair loss via the antioxidant pathway and provide our own insights. In addition, we collate antioxidant natural products promoting hair growth in recent years and discuss the limitations and perspectives of current hair loss prevention and treatment.
13Cellular Senescence: Ageing and Androgenetic Alopecia.PubMed
Yongqiong Deng, Mengxue Wang, Yuxin He, et al.
Dermatology. 2023;239(4):533-541. doi: 10.1159/000530681. Epub 2023 Apr 22.
Androgenetic alopecia (AGA) is the most common type of hair loss and features progressive miniaturization of hair follicles. Generally, the occurrence of AGA has long been thought to be driven by genetic and androgen predisposition. However, increasingly, data proposed ageing and AGA are intimately linked. Elevated senescent cell burden and androgen and oxidative stress-induced senescence mechanisms in ageing may be initial targets to improve AGA. This review summarizes the biological links between ageing and AGA, with special focus on cellular senescence. In addition, we discuss the potential therapeutic strategies for improving cellular senescence in AGA, such as inhibiting dermal papilla cells and hair follicle stem cells senescence driven by androgen and reactive oxygen species, removing senescent cell, and reducing senescence-associated secretory phenotype (SASP).
14Cyanidin 3-O-arabinoside suppresses DHT-induced dermal papilla cell senescence by modulating p38-dependent ER-mitochondria contacts.PubMed
Young Hyun Jung, Chang Woo Chae, Gee Euhn Choi, et al.
J Biomed Sci. 2022 Mar 7;29(1):17. doi: 10.1186/s12929-022-00800-7.
BACKGROUND: Androgenetic alopecia (AGA) is a genetic disorder caused by dihydrotestosterone (DHT), accompanied by the senescence of androgen-sensitive dermal papilla cells (DPCs) located in the base of hair follicles. DHT causes DPC senescence in AGA through mitochondrial dysfunction. However, the mechanism of this pathogenesis remains unknown. In this study, we investigated the protective role of cyanidins on DHT-induced mitochondrial dysfunction and DPC senescence and the regulatory mechanism involved. METHODS: DPCs were used to investigate the effect of DHT on mitochondrial dysfunction with MitoSOX and Rhod-2 staining. Senescence-associated β-galactosidase activity assay was performed to examine the involvement of membrane AR-mediated signaling in DHT-induced DPC senescence. AGA mice model was used to study the cyanidins on DHT-induced hair growth deceleration. RESULTS: Cyanidin 3-O-arabinoside (C3A) effectively decreased DHT-induced mtROS accumulation in DPCs, and C3A reversed the DHT-induced DPC senescence. Excessive mitochondrial calcium accumulation was blocked by C3A. C3A inhibited p38-mediated voltage-dependent anion channel 1 (VDAC1) expression that contributes to mitochondria-associated ER membrane (MAM) formation and transfer of calcium via VDAC1-IP3R1 interactions. DHT-induced MAM formation resulted in increase of DPC senescence. In AGA mice models, C3A restored DHT-induced hair growth deceleration, which activated hair follicle stem cell proliferation. CONCLUSIONS: C3A is a promising natural compound for AGA treatments against DHT-induced DPC senescence through reduction of MAM formation and mitochondrial dysfunction.
15A systematic summary of survival and death signalling during the life of hair follicle stem cells.PubMed
Xi-Min Hu, Zhi-Xin Li, Dan-Yi Zhang, et al.
Stem Cell Res Ther. 2021 Aug 11;12(1):453. doi: 10.1186/s13287-021-02527-y.
Hair follicle stem cells (HFSCs) are among the most widely available resources and most frequently approved model systems used for studying adult stem cells. HFSCs are particularly useful because of their self-renewal and differentiation properties. Additionally, the cyclic growth of hair follicles is driven by HFSCs. There are high expectations for the use of HFSCs as favourable systems for studying the molecular mechanisms that contribute to HFSC identification and can be applied to hair loss therapy, such as the activation or regeneration of hair follicles, and to the generation of hair using a tissue-engineering strategy. A variety of molecules are involved in the networks that critically regulate the fate of HFSCs, such as factors in hair follicle growth and development (in the Wnt pathway, Sonic hedgehog pathway, Notch pathway, and BMP pathway), and that suppress apoptotic cues (the apoptosis pathway). Here, we review the life cycle, biomarkers and functions of HFSCs, concluding with a summary of the signalling pathways involved in HFSC fate for promoting better understanding of the pathophysiological changes in the HFSC niche. Importantly, we highlight the potential mechanisms underlying the therapeutic targets involved in pathways associated with the treatment of hair loss and other disorders of skin and hair, including alopecia, skin cancer, skin inflammation, and skin wound healing.
16Targeting Wnt/β-Catenin Pathway for Developing Therapies for Hair Loss.PubMed
Bu Young Choi
Int J Mol Sci. 2020 Jul 12;21(14):4915. doi: 10.3390/ijms21144915.
Persistent hair loss is a major cause of psychological distress and compromised quality of life in millions of people worldwide. Remarkable progress has been made in understanding the molecular basis of hair loss and identifying valid intracellular targets for designing effective therapies for hair loss treatment. Whereas a variety of growth factors and signaling pathways have been implicated in hair cycling process, the activation of Wnt/β-catenin signaling plays a central role in hair follicle regeneration. Several plant-derived chemicals have been reported to promote hair growth by activating Wnt/β-catenin signaling in various in vitro and in vivo studies. This mini-review sheds light on the role of Wnt/β-catenin in promoting hair growth and the current progress in designing hair loss therapies by targeting this signaling pathway.
17Signaling involved in hair follicle morphogenesis and development.PubMed
Pisal Rishikaysh, Kapil Dev, Daniel Diaz, et al.
Int J Mol Sci. 2014 Jan 22;15(1):1647-70. doi: 10.3390/ijms15011647.
Hair follicle morphogenesis depends on Wnt, Shh, Notch, BMP and other signaling pathways interplay between epithelial and mesenchymal cells. The Wnt pathway plays an essential role during hair follicle induction, Shh is involved in morphogenesis and late stage differentiation, Notch signaling determines stem cell fate while BMP is involved in cellular differentiation. The Wnt pathway is considered to be the master regulator during hair follicle morphogenesis. Wnt signaling proceeds through EDA/EDAR/NF-κB signaling. NF-κB regulates the Wnt pathway and acts as a signal mediator by upregulating the expression of Shh ligand. Signal crosstalk between epithelial and mesenchymal cells takes place mainly through primary cilia. Primary cilia formation is initiated with epithelial laminin-511 interaction with dermal β-1 integrin, which also upregulates expression of downstream effectors of Shh pathway in dermal lineage. PDGF signal transduction essential for crosstalk is mediated through epithelial PDGF-A and PDGFRα expressed on the primary cilia. Dermal Shh and PDGF signaling up-regulates dermal noggin expression; noggin is a potent inhibitor of BMP signaling which helps in counteracting BMP mediated β-catenin inhibition. This interplay of signaling between the epithelial and dermal lineage helps in epithelial Shh signal amplification. The dermal Wnt pathway helps in upregulation of epithelial Notch expression. Dysregulation of these pathways leads to certain abnormalities and in some cases even tumor outgrowth.
18Pathophysiological mechanisms of hair follicle regeneration and potential therapeutic strategies.PubMed
Depti Bellani, Raji Patil, Ashwin Prabhughate, et al.
Stem Cell Res Ther. 2025 Jun 15;16(1):302. doi: 10.1186/s13287-025-04420-4.
Androgenetic alopecia (AGA) is a chronic and progressive hair loss disorder marked by follicular miniaturization and a shortened anagen phase. While androgenic and genetic factors contribute to its pathogenesis, increasing evidence highlights the importance of dysregulated molecular signaling in impaired hair follicle (HF) regeneration.This review explores the interconnected signaling pathways that govern HF cycling and regeneration-Wnt/β-catenin, Sonic Hedgehog (Shh), Bone Morphogenetic Protein (BMP), and Notch. Wnt/β-catenin activation initiates anagen by stimulating stem cell proliferation and follicle formation, while Shh supports follicular proliferation and morphogenesis. Notch regulates HF stem cell (HFSC) fate, and BMP enforces quiescence and catagen onset. Crucially, crosstalk between Wnt-BMP and Shh-Notch pathways ensures follicular homeostasis, highlighting the need to view these pathways as an integrated regulatory network.Recent therapeutic innovations focus on modulating these signaling cascades. Small molecules such as valproic acid and CHIR99021 activate Wnt signaling; smoothened agonists target Shh; and Noggin mimetics or BMP-neutralizing antibodies inhibit BMP activity. These approaches have shown promising outcomes in preclinical models, including mouse studies, in vitro HFSC systems, etc. Additionally, emerging gene editing technologies (e.g., CRISPR-Cas9) and stem cell-biomaterial integration offer regenerative strategies that move beyond symptomatic treatments like minoxidil or hair transplantation.Given that AGA is associated with androgen-mediated Wnt suppression and TGF-β activation, targeting these dysregulated networks presents a promising route for long-term management. A deeper understanding of pathway interactions lays the groundwork for precise, durable, and disease-modifying therapies in the evolving landscape of alopecia treatment.
19Advances in Regenerative Stem Cell Therapy in Androgenic Alopecia and Hair Loss: Wnt pathway, Growth-Factor, and Mesenchymal Stem Cell Signaling Impact Analysis on Cell Growth and Hair Follicle Development.PubMed
Pietro Gentile, Simone Garcovich
Cells. 2019 May 16;8(5):466. doi: 10.3390/cells8050466.
The use of stem cells has been reported to improve hair regrowth in several therapeutic strategies, including reversing the pathological mechanisms, that contribute to hair loss, regeneration of hair follicles, or creating hair using the tissue-engineering approach. Although various promising stem cell approaches are progressing via pre-clinical models to clinical trials, intraoperative stem cell treatments with a one-step procedure offer a quicker result by incorporating an autologous cell source without manipulation, which may be injected by surgeons through a well-established clinical practice. Many authors have concentrated on adipose-derived stromal vascular cells due to their ability to separate into numerous cell genealogies, platelet-rich plasma for its ability to enhance cell multiplication and neo-angiogenesis, as well as human follicle mesenchymal stem cells. In this paper, the significant improvements in intraoperative stem cell approaches, from in vivo models to clinical investigations, are reviewed. The potential regenerative instruments and functions of various cell populaces in the hair regrowth process are discussed. The addition of Wnt signaling in dermal papilla cells is considered a key factor in stimulating hair growth. Mesenchymal stem cell-derived signaling and growth factors obtained by platelets influence hair growth through cellular proliferation to prolong the anagen phase (FGF-7), induce cell growth (ERK activation), stimulate hair follicle development (β-catenin), and suppress apoptotic cues (Bcl-2 release and Akt activation).
20Melatonin promotes hair regeneration by modulating the Wnt/β-catenin signalling pathway.PubMed
Yi-Lin Niu, Yu-Kang Li, Chen-Xi Gao, et al.
Cell Prolif. 2024 Sep;57(9):e13656. doi: 10.1111/cpr.13656. Epub 2024 May 21.
Melatonin (MLT) is a circadian hormone that reportedly influences the development and cyclic growth of secondary hair follicles; however, the mechanism of regulation remains unknown. Here, we systematically investigated the role of MLT in hair regeneration using a hair depilation mouse model. We found that MLT supplementation significantly promoted hair regeneration in the hair depilation mouse model, whereas supplementation of MLT receptor antagonist luzindole significantly suppressed hair regeneration. By analysing gene expression dynamics between the MLT group and luzindole-treated groups, we revealed that MLT supplementation significantly up-regulated Wnt/β-catenin signalling pathway-related genes. In-depth analysis of the expression of key molecules in the Wnt/β-catenin signalling pathway revealed that MLT up-regulated the Wnt/β-catenin signalling pathway in dermal papillae (DP), whereas these effects were facilitated through mediating Wnt ligand expression levels in the hair follicle stem cells (HFSCs). Using a DP-HFSCs co-culture system, we verified that MLT activated Wnt/β-catenin signalling in DPs when co-cultured with HFSCs, whereas supplementation of DP cells with MLT alone failed to activate Wnt/β-catenin signalling. In summary, our work identified a critical role for MLT in promoting hair regeneration and will have potential implications for future hair loss treatment in humans.
21KY19382, a novel activator of Wnt/β-catenin signalling, promotes hair regrowth and hair follicle neogenesis.PubMed
Yeong Chan Ryu, Dong-Hwan Lee, Jiyong Shim, et al.
Br J Pharmacol. 2021 Jun;178(12):2533-2546. doi: 10.1111/bph.15438. Epub 2021 May 5.
BACKGROUND AND PURPOSE: The promotion of hair regeneration and growth heavily depends on the activation of Wnt/β-catenin signalling in the hair follicle, including dermal papilla (DP). KY19382, one of the newly synthesized analogues of indirubin-3'-monoxime (I3O), was identified as a Wnt/β-catenin signalling activator via inhibition of the interaction between CXXC-type zinc finger protein 5 (CXXC5) and dishevelled (Dvl). Given the close relationship between the Wnt/β-catenin signalling and hair regeneration, we investigated the effect of KY19382 on hair regrowth and hair follicle neogenesis. EXPERIMENTAL APPROACH: In vitro hair induction effects of KY19382 were performed in human DP cells. The hair elongation effects of KY19382 were confirmed through the human hair follicle and vibrissa culture system. In vivo hair regeneration abilities of KY19382 were identified in three models: hair regrowth, wound-induced hair follicle neogenesis (WIHN) and hair patch assays using C57BL/6 mice. The hair regeneration abilities were analysed by immunoblotting, alkaline phosphatase (ALP) and immunohistochemical staining. KEY RESULTS: KY19382 activated Wnt/β-catenin signalling and elevated expression of ALP and the proliferation marker PCNA in DP cells. KY19382 also increased hair length in ex vivo-cultured mouse vibrissa and human hair follicles and induced hair regrowth in mice. Moreover, KY19382 significantly promoted the generation of de novo hair follicles as shown by WIHN and hair patch assays. CONCLUSION AND IMPLICATIONS: These results indicate that KY19382 is a potential therapeutic drug that exhibits effective hair regeneration ability via activation of the Wnt/β-catenin signalling for alopecia treatments.
22Retinoic acid drives hair follicle stem cell activation via Wnt/β-catenin signalling in androgenetic alopecia.PubMed
Lihong Wen, Zhexiang Fan, Weichang Huang, et al.
J Eur Acad Dermatol Venereol. 2025 Jan;39(1):189-201. doi: 10.1111/jdv.20000. Epub 2024 Apr 17.
BACKGROUND: Depletion or permanent quiescence of the hair follicle stem cell (HFSC) pool underlies pathogenesis in androgenetic alopecia (AGA). Reactivation of quiescent HFSCs is considered an efficient treatment strategy for hair loss. The retinoic acid (RA) is critical to ensure stem cell homeostasis and function. However, little is known about whether RA regulates HFSC homeostasis. We aimed to investigate the impact of RA on HFSC homeostasis and the underlying mechanisms, in order to provide new potential targets for medical therapies of AGA. METHODS: Microdissected hair follicles from the occipital and frontal scalp in AGA were obtained for RNA sequencing analysis and test. The C57BL/6 mice model in telogen was established to investigate the effect of exogenous RA. Miniaturized hair follicles from frontal scalp were incubated with or without RA in hair follicle organ culture to test the effects on hair shaft elongation, hair cycling and HFSC activities. A strategy to characterize the effect of RA on HFSC in primary culture was developed to identify novel mechanisms that control HFSC activation. A clinical study was performed to test the efficacy of RA treatment in AGA patients. RESULTS: RA signalling was inhibited in the course of AGA pathogenesis along with HFSC dysfunction. Hair regeneration was retarded in AGA miniaturized hair follicles with RA deficiency, but they tended to recover after treatment with RA. In addition, RA treatment during the telogen phase facilitated HFSC anagen entry and accelerated hair growth. Mechanistically, RA promoted hair growth by stimulating stem cells via Wnt/β-catenin signalling and accelerating the transition from a dormant to an activated state. Furthermore, a clinical study suggested that RA has obvious advantages in the early intervention of AGA by reactivating HFSCs. CONCLUSIONS: Our study provides insights into the reactivation of HFSCs in AGA and provides potential targets for medical therapies.
23Obesity accelerates hair thinning by stem cell-centric converging mechanisms.PubMed
Hironobu Morinaga, Yasuaki Mohri, Marina Grachtchouk, et al.
Nature. 2021 Jul;595(7866):266-271. doi: 10.1038/s41586-021-03624-x. Epub 2021 Jun 23.
Obesity is a worldwide epidemic that predisposes individuals to many age-associated diseases, but its exact effects on organ dysfunction are largely unknown. Hair follicles-mini-epithelial organs that grow hair-are miniaturized by ageing to cause hair loss through the depletion of hair follicle stem cells (HFSCs). Here we report that obesity-induced stress, such as that induced by a high-fat diet (HFD), targets HFSCs to accelerate hair thinning. Chronological gene expression analysis revealed that HFD feeding for four consecutive days in young mice directed activated HFSCs towards epidermal keratinization by generating excess reactive oxygen species, but did not reduce the pool of HFSCs. Integrative analysis using stem cell fate tracing, epigenetics and reverse genetics showed that further feeding with an HFD subsequently induced lipid droplets and NF-κB activation within HFSCs via autocrine and/or paracrine IL-1R signalling. These integrated factors converge on the marked inhibition of Sonic hedgehog (SHH) signal transduction in HFSCs, thereby further depleting lipid-laden HFSCs through their aberrant differentiation and inducing hair follicle miniaturization and eventual hair loss. Conversely, transgenic or pharmacological activation of SHH rescued HFD-induced hair loss. These data collectively demonstrate that stem cell inflammatory signals induced by obesity robustly represses organ regeneration signals to accelerate the miniaturization of mini-organs, and suggests the importance of daily prevention of organ dysfunction.
24Hedgehog signaling reprograms hair follicle niche fibroblasts to a hyper-activated state.PubMed
Yingzi Liu, Christian F Guerrero-Juarez, Fei Xiao, et al.
Dev Cell. 2022 Jul 25;57(14):1758-1775.e7. doi: 10.1016/j.devcel.2022.06.005. Epub 2022 Jun 30.
Hair follicle stem cells are regulated by dermal papilla fibroblasts, their principal signaling niche. Overactivation of Hedgehog signaling in the niche dramatically accelerates hair growth and induces follicle multiplication in mice. On single-cell RNA sequencing, dermal papilla fibroblasts increase heterogeneity to include new Wnt5a states. Transcriptionally, mutant fibroblasts activate regulatory networks for Gli1, Alx3, Ebf1, Hoxc8, Sox18, and Zfp239. These networks jointly upregulate secreted factors for multiple hair morphogenesis and hair-growth-related pathways. Among these is non-conventional TGF-β ligand Scube3. We show that in normal mouse skin, Scube3 is expressed only in dermal papillae of growing, but not in resting follicles. SCUBE3 protein microinjection is sufficient to induce new hair growth, and pharmacological TGF-β inhibition rescues mutant hair hyper-activation phenotype. Moreover, dermal-papilla-enriched expression of SCUBE3 and its growth-activating effect are partially conserved in human scalp hair follicles. Thus, Hedgehog regulates mesenchymal niche function in the hair follicle via SCUBE3/TGF-β mechanism.
25Can Plant Extracts Help Prevent Hair Loss or Promote Hair Growth? A Review Comparing Their Therapeutic Efficacies, Phytochemical Components, and Modulatory Targets.PubMed
Joon Yong Choi, Min Young Boo, Yong Chool Boo
Molecules. 2024 May 13;29(10):2288. doi: 10.3390/molecules29102288.
This narrative review aims to examine the therapeutic potential and mechanism of action of plant extracts in preventing and treating alopecia (baldness). We searched and selected research papers on plant extracts related to hair loss, hair growth, or hair regrowth, and comprehensively compared the therapeutic efficacies, phytochemical components, and modulatory targets of plant extracts. These studies showed that various plant extracts increased the survival and proliferation of dermal papilla cells in vitro, enhanced cell proliferation and hair growth in hair follicles ex vivo, and promoted hair growth or regrowth in animal models in vivo. The hair growth-promoting efficacy of several plant extracts was verified in clinical trials. Some phenolic compounds, terpenes and terpenoids, sulfur-containing compounds, and fatty acids were identified as active compounds contained in plant extracts. The pharmacological effects of plant extracts and their active compounds were associated with the promotion of cell survival, cell proliferation, or cell cycle progression, and the upregulation of several growth factors, such as IGF-1, VEGF, HGF, and KGF (FGF-7), leading to the induction and extension of the anagen phase in the hair cycle. Those effects were also associated with the alleviation of oxidative stress, inflammatory response, cellular senescence, or apoptosis, and the downregulation of male hormones and their receptors, preventing the entry into the telogen phase in the hair cycle. Several active plant extracts and phytochemicals stimulated the signaling pathways mediated by protein kinase B (PKB, also called AKT), extracellular signal-regulated kinases (ERK), Wingless and Int-1 (WNT), or sonic hedgehog (SHH), while suppressing other cell signaling pathways mediated by transforming growth factor (TGF)-β or bone morphogenetic protein (BMP). Thus, well-selected plant extracts and their active compounds can have beneficial effects on hair health. It is proposed that the discovery of phytochemicals targeting the aforementioned cellular events and cell signaling pathways will facilitate the development of new targeted therapies for alopecia.
26Insulin-like Growth Factor 1 (IGF-1) in Hair Regeneration: Mechanistic Pathways and Therapeutic Potential.PubMed
Wang-Ju Hsieh, Wei-Yin Qiu, Ivona Percec, et al.
Curr Issues Mol Biol. 2025 Sep 18;47(9):773. doi: 10.3390/cimb47090773.
IGF-1 (insulin-like growth factor 1) is a growth factor primarily secreted by dermal papilla cells on hair-bearing skin that stimulates hair follicle proliferation and vascularization, and promotes the transition to the anagen growth phase of the hair follicle by activating key pathways such as PI3K/Akt and MAPK/ERK. IGF-1 also inhibits apoptosis, prolongs the follicular growth phase, and boosts VEGF expression, which supports microcirculation and nutrient delivery to hair follicles. The combined effects of IGF-1 and other growth factors, including VEGF, KGF (FGF-7), and PDGF, further amplify its effects on follicular cell proliferation and tissue repair. IGF-1's ability to regulate the hair growth cycle and its interactions with other signaling pathways make it a compelling therapeutic target for hair loss disorders. Both preclinical models and clinical evidence highlight IGF-1 as a promising therapeutic option for conditions like androgenetic alopecia (AGA), where IGF-1 levels are typically diminished. While topical IGF-1 treatments have shown efficacy and safety with minimal systemic absorption, additional research is needed to improve delivery methods, such as liposomal gels and exosome-based carriers, and to evaluate long-term effects.
27Microenvironment-responsive recombinant collagen XVII-based composite microneedles for the treatment of androgenetic alopecia.PubMed
Zheng Xing, Xiaoxiao Zhang, Chen Zhao, et al.
Acta Biomater. 2025 Jun 15;200:400-415. doi: 10.1016/j.actbio.2025.05.039. Epub 2025 May 17.
Androgenetic alopecia (AGA) is the most prevalent form of hair loss worldwide. Growth factors have been used to treat hair loss, but their intradermal delivery remains challenging. Type XVII collagen (COL17) has been reported to regulate the aging process of hair follicles (HFs). We reason that combining the therapeutic efficacy of growth factors and collagen biomaterials will provide maximal hair regeneration. Here, we design a microenvironment-responsive recombinant human COL17 microneedle (MRrhCOL17 MN) system for the transdermal delivery of the insulin-like growth factor-1 (IGF-1) to stimulate hair growth. We load IGF-1 into mesoporous polydopamine nanoparticles (MPDAs) to allow for continuous release of the growth factor. When applied to the skin, the composite MNs penetrate the skin, release IGF-1 and rhCOL17 in response to the alteration of the microenvironment and photothermal effect, and stimulate hair growth in a mouse model of AGA. Compared with the clinical drug minoxidil, our MN system more effectively enhances neovascularization, alleviates tissue inflammatory responses, and promotes hair regeneration in AGA mice. These therapeutic effects have been linked to the activation of the VEGF/VEGFR and Src/p38 MAPK signaling pathways. Taken together, the composite MRrhCOL17 MN thereby offers a new option for intractable AGA patients. STATEMENT OF SIGNIFICANCE: Growth factors hold the potential to effectively stimulate the growth of hair follicles; however, their transdermal delivery remains a formidable challenge. In this study, recombinant human type XVII collagen (rhCOL17) is employed as the primary scaffolding material to fabricate microneedles (MNs) for the delivery of insulin-like growth factor 1 (IGF-1), with the aim of promoting hair follicle regeneration. Additionally, the concept of microenvironmental responsiveness is integrated to enable the controlled release of IGF-1 from the MNs. Moreover, the low-temperature photothermal effect of nanoparticles is harnessed to optimize the process of hair regeneration, thereby maximizing the outcome of hair follicle rejuvenation.
28Hair Growth Effect and the Mechanisms of Extract in DHT-Induced Alopecia Mice Model.PubMed
Ha-Rim Kim, Jung Up Park, Seung-Hyeon Lee, et al.
Int J Mol Sci. 2024 Oct 22;25(21):11362. doi: 10.3390/ijms252111362.
is a medicinal plant known for its potential anti-inflammatory, antioxidant, anti-cancer, and antimicrobial benefits. The pharmacological effects of extract on hair loss have not yet been documented. This research sought to assess the inhibitory effects and mechanisms of action of water extract (RWE) in a mouse model of dihydrotestosterone (DHT)-induced alopecia. The study was conducted using C57BL/6 mice, which were assigned to five groups: control, DHT-treated, water extract (RWE) at doses of 25 mg/kg and 100 mg/kg body weight, and bicalutamide-treated. To induce hair loss, dihydrotestosterone (1 mg/day per body weight) was administered via intraperitoneal injections, and dorsal hair removal was timed to align with the telogen phase. Each group received oral treatments for a period of 23 days. In this study, we assessed hair growth activity, examined histological changes, and performed immunoblot analysis. We noted improvements in hair length and thickness. Additionally, the protein expression of growth factors associated with hair growth, including vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), and insulin-like growth factor-1 (IGF-1), showed significant increases in the group treated with RWE. Additionally, treatment with RWE suppressed the protein expression of hair growth inhibitory factors, including dickkopf WNT signaling pathway inhibitor 1 (DKK1) and interleukin (IL)-6. Moreover, hair growth regulatory pathway related factors, including ERK, AKT, and GSK-3β, were activated. These findings indicate that RWE could serve as a promising natural therapy for preventing hair loss by enhancing the production of factors that promote hair growth while inhibiting those that suppress it.
29Minoxidil use in dermatology, side effects and recent patents.PubMed
Alfredo Rossi, Carmen Cantisani, Luca Melis, et al.
Recent Pat Inflamm Allergy Drug Discov. 2012 May;6(2):130-6. doi: 10.2174/187221312800166859.
Minoxidil, a vasodilator medication known for its ability to slow or stop hair loss and promote hair regrowth, was first introduced, exclusively as an oral drug, to treat high blood pressure. It was however discovered to have the important side-effect of increasing growth or darkening of fine body hairs; this led to the development of a topical formulation as a 2% concentration solution for the treatment of female androgenic alopecia or 5% for treating male androgenic alopecia. Measurable changes disappear within months after discontinuation of treatment. The mechanism by which it promotes hair growth is not fully understood. Minoxidil is a potassium channel opener, causing hyperpolarization of cell membranes and it is also a vasodilator, it is speculated that, by widening blood vessels and opening potassium channels, it allows more oxygen, blood and nutrients to the follicle. This can also cause follicles in the telogen phase to shed, usually soon to be replaced by new, thicker hairs in a new anagen phase. It needs to be applied regularly, once or twice daily, for hair gained to be maintained, and side effects are common. The most common adverse reactions of the topical formulation are limited to irritant and allergic contact dermatitis on the scalp. There have been cases of allergic reactions to the nonactive ingredient propylene glycol, which is found in some topical solution especially if they are galenic. Increased hair loss which can occur during Minoxidil use, is due to the synchronization of the hair cycle that the treatment induces. In this review, we described its mechanism of action, use in dermatology and some patents related to alternative treatment of allergic reactions due to its use.
30MinoxidilPubMed
Preeti Patel, Trevor A. Nessel, Dinesh Kumar D
Minoxidil, also known as 2,4-pyrimidinediamine, 6-(1-piperidinyl)-, 3-oxide, was initially developed in the 1970s as a potent peripheral vasodilator agent for the treatment of severe refractory hypertension. Minoxidil exerts its antihypertensive effect by opening adenosine triphosphate (ATP)-sensitive potassium channels, thereby reducing peripheral resistance and lowering blood pressure levels in patients. However, owing to the significant adverse effects of taking oral minoxidil, this drug is currently used only for patients with resistant hypertension who do not adequately respond to the maximum doses of 3 different classes of antihypertensive medications. In 1987, a topical formulation of minoxidil was developed to treat androgenic alopecia, initially targeting males and later expanding its use to include females. This activity comprehensively reviews the indications, contraindications, mechanism of action, pharmacokinetics, adverse effects, and other crucial aspects of topical and oral minoxidil therapy in a clinical setting. This activity aims to improve the collaboration and the competence of the interprofessional healthcare team members to provide quality care for patients experiencing hair loss and resistant hypertension.
31Minoxidil: mechanisms of action on hair growth.PubMed
A G Messenger, J Rundegren
Br J Dermatol. 2004 Feb;150(2):186-94. doi: 10.1111/j.1365-2133.2004.05785.x.
We have known for over 30 years that minoxidil stimulates hair growth, yet our understanding of its mechanism of action on the hair follicle is very limited. In animal studies, topical minoxidil shortens telogen, causing premature entry of resting hair follicles into anagen, and it probably has a similar action in humans. Minoxidil may also cause prolongation of anagen and increases hair follicle size. Orally administered minoxidil lowers blood pressure by relaxing vascular smooth muscle through the action of its sulphated metabolite, minoxidil sulphate, as an opener of sarcolemmal KATP channels. There is some evidence that the stimulatory effect of minoxidil on hair growth is also due to the opening of potassium channels by minoxidil sulphate, but this idea has been difficult to prove and to date there has been no clear demonstration that KATP channels are expressed in the hair follicle. A number of in vitro effects of minoxidil have been described in monocultures of various skin and hair follicle cell types including stimulation of cell proliferation, inhibition of collagen synthesis, and stimulation of vascular endothelial growth factor and prostaglandin synthesis. Some or all of these effects may be relevant to hair growth, but the application of results obtained in cell culture studies to the complex biology of the hair follicle is uncertain. In this article we review the current state of knowledge on the mode of action of minoxidil on hair growth and indicate lines of future research.
32Minoxidil: a comprehensive review.PubMed
A K Gupta, M Talukder, M Venkataraman, et al.
J Dermatolog Treat. 2022 Jun;33(4):1896-1906. doi: 10.1080/09546634.2021.1945527. Epub 2021 Jul 20.
Topical minoxidil (5% foam, 5% solution, and 2% solution) is FDA-approved for androgenetic alopecia (AGA) in men and women. Minoxidil acts through multiple pathways (vasodilator, anti-inflammatory agent, inducer of the Wnt/β-catenin signaling pathway, an antiandrogen), and may also affect the length of the anagen and telogen phases. Approximately 1.4% of topical minoxidil is absorbed through the skin. Minoxidil is a prodrug that is metabolized by follicular sulfotransferase to minoxidil sulfate (active form). Those with higher sulfotransferase activity may respond better than patients with lower sulfotransferase activity. In a five-year study, 2% minoxidil exhibited peak hair growth in males at year one with a decline in subsequent years. Topical minoxidil causes hair regrowth in both frontotemporal and vertex areas. The 5% solution and foam were not significantly different in efficacy from the 2% solution. After 6 months of administration, minoxidil 5 mg/day was significantly more effective than topical 5% and 2% in male AGA. Low-dose 0.5-5 mg/day may also be safe and effective for female pattern hair loss and chronic telogen effluvium. Sublingual minoxidil may be safe and effective in male and female pattern hair loss.
33Comparison of oral minoxidil, finasteride, and dutasteride for treating androgenetic alopecia.PubMed
Aditya K Gupta, Mesbah Talukder, Greg Williams
J Dermatolog Treat. 2022 Nov;33(7):2946-2962. doi: 10.1080/09546634.2022.2109567. Epub 2022 Aug 15.
BACKGROUND: Androgenetic alopecia (AGA) is the most common cause of hair loss, often challenging to treat. While oral finasteride (1 mg/d) is an FDA-approved treatment for male AGA, oral minoxidil and oral dutasteride are not approved yet. However, clinicians have been increasingly using these two drugs off-label for hair loss. Recently, Japan and South Korea have approved oral dutasteride (0.5 mg/d) for male AGA. EFFICACY AND SAFETY: A probable efficacy ranking, in decreasing order, is - dutasteride 0.5 mg/d, finasteride 5 mg/d, minoxidil 5 mg/d, finasteride 1 mg/d, followed by minoxidil 0.25 mg/d. Oral minoxidil predominantly causes hypertrichosis and cardiovascular system (CVS) symptoms/signs in a dose-dependent manner, whereas oral finasteride and dutasteride are associated with sexual dysfunction and neuropsychiatric side effects. PHARMACOKINETICS AND PHARMACODYNAMICS: The average plasma half-lives of minoxidil, finasteride, and dutasteride are ∼4 h, ∼4.5 h, and ∼5 weeks, respectively. Minoxidil acts through multiple pathways to promote hair growth. It has been shown as a vasodilator, an anti-inflammatory agent, a Wnt/β-catenin signaling inducer, and an antiandrogen. Finasteride inhibits 5α-reductase (5AR) type II isoenzyme, while dutasteride inhibits both type I and type II. Thus, dutasteride suppresses DHT levels more than finasteride in the serum and scalp.
34Potassium channels in health, disease & development of channel modulators.PubMed
Selvarajan Sandhiya, Steven Aibor Dkhar
Indian J Med Res. 2009 Mar;129(3):223-32.
Ion channels present in the plasma membrane and intracellular organelles of all cells, play an important role in maintaining cellular integrity, smooth muscle contraction, secretion of hormones and neurotransmitters. Among the ion channels, potassium channels (K(+)) are the most abundant having important role in cardiac repolarization, smooth muscle relaxation and insulin release. These are also involved in the regulation of physiological functions like gastrointestinal peristalsis. These channels are the most diverse of all ion channels and are coded by at least 75 genes. Moreover, these have different subunits which co-assemble to form diverse functional channels. Abnormalities in K(+) channels are associated with diseases like long QT syndrome, Anderson Tawil syndrome, epilepsy, type 2 diabetes mellitus, etc. A number of naturally occurring as well as synthetic compounds have been identified that modulate the opening and closure of K(ATP) Channels. Some of the currently available K(+) channel modulators like sulphonylureas, minoxidil, amiodarone, etc. lack tissue selectivity and have adverse effects. Hence, the success of K(ATP) channel modulators depend on their tissue selectivity. Molecular level studies are needed to understand the type of K(+) channels as this can lead to the development of newer drugs with tissue selectivity for various diseases.
36Effects of oral minoxidil on serum VEGF and hair regrowth in androgenetic alopecia.PubMed
Ahmed Abdulhussein Kawen
Acta Dermatovenerol Alp Pannonica Adriat. 2025 Mar;34(1):7-12.
INTRODUCTION: Androgenetic alopecia (AGA) is a common hair loss condition characterized by follicular miniaturization. Vascular endothelial growth factor (VEGF) plays a key role in promoting angiogenesis and supporting hair follicle growth. Oral minoxidil has been suggested to upregulate VEGF levels, enhancing hair regrowth. METHODS: This prospective study included 50 participants divided into two groups: oral minoxidil (1 mg/day; n = 25) and control (n = 25). Serum VEGF levels were measured at baseline and after 12 weeks of treatment. Hair growth parameters, including hair count, diameter, shedding, and pull test results, were assessed systematically. RESULTS: Baseline VEGF levels were similar between groups (p = 0.1873). Post-treatment, VEGF levels increased significantly in the minoxidil group (217.88 ± 22.65 pg/ml vs. 142.81 ± 23.14 pg/ml in the control, p < 0.0001). Hair count and diameter improved significantly (p < 0.0001 and p = 0.0040, respectively), with reductions in shedding and pull test results (p < 0.0001). Positive correlations were observed between VEGF and hair count (r = 0.9965), whereas shedding showed negative correlations (r = -0.5374). CONCLUSIONS: Oral minoxidil significantly enhances VEGF levels, promoting hair growth and reducing shedding. VEGF serves as a promising biomarker for assessing treatment effectiveness and understanding the angiogenic mechanisms involved in AGA.
37Hydrogel forming microneedles loaded with VEGF and Ritlecitinib/polyhydroxyalkanoates nanoparticles for mini-invasive androgenetic alopecia treatment.PubMed
Yan-Wen Ding, Yang Li, Zhi-Wei Zhang, et al.
Bioact Mater. 2024 Apr 23;38:95-108. doi: 10.1016/j.bioactmat.2024.04.020. eCollection 2024 Aug.
Androgenetic alopecia (AGA), the most prevalent clinical hair loss, lacks safe and effective treatments due to downregulated angiogenic genes and insufficient vascularization in the perifollicular microenvironment of the bald scalp in AGA patients. In this study, a hyaluronic acid (HA) based hydrogel-formed microneedle (MN) was designed, referred to as V-R-MNs, which was simultaneously loaded with vascular endothelial growth factor (VEGF) and the novel hair loss drug Ritlecitinib, the latter is encapsulated in slowly biodegradable polyhydroxyalkanoates (PHAs) nanoparticles (R-PHA NPs) for minimally invasive AGA treatment. The integration of HA based hydrogel alongside PHA nanoparticles significantly bolstered the mechanical characteristics of microneedles and enhanced skin penetration efficiency. Due to the biosafety, mechanical strength, and controlled degradation properties of HA hydrogel formed microneedles, V-R-MNs can effectively penetrate the skin's stratum corneum, facilitating the direct delivery of VEGF and Ritlecitinib in a minimally invasive, painless and long-term sustained release manner. V-R-MNs not only promoted angiogenesis and improve the immune microenvironment around the hair follicle to promote the proliferation and development of hair follicle cells, but also the application of MNs to the skin to produce certain mechanical stimulation could also promote angiogenesis. In comparison to the clinical drug minoxidil for AGA treatment, the hair regeneration effect of V-R-MN in AGA model mice is characterized by a rapid onset of the anagen phase, improved hair quality, and greater coverage. This introduces a new, clinically safer, and more efficient strategy for AGA treatment, and serving as a reference for the treatment of other related diseases.
38Management of androgenic alopecia: a systematic review of the literature.PubMed
Amanda Rosenthal, Geena Conde, Joseph F Greco, et al.
J Cosmet Laser Ther. 2024 Jan-Jun;26(1-4):1-16. doi: 10.1080/14764172.2024.2362126. Epub 2024 Jun 9.
We aimed to determine the efficacy of the various available oral, topical, and procedural treatment options for hair loss in individuals with androgenic alopecia. Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, a systematic review of the National Library of Medicine was performed. Overall, 141 unique studies met our inclusion criteria. We demonstrate that many over the counter (e.g. topical minoxidil, supplements, low-level light treatment), prescription (e.g. oral minoxidil, finasteride, dutasteride), and procedural (e.g. platelet-rich plasma, fractionated lasers, hair transplantation) treatments successfully promote hair growth, highlighting the superiority of a multifaceted and individualized approach to management.
39Finasteride for hair loss: a review.PubMed
A K Gupta, M Venkataraman, M Talukder, et al.
J Dermatolog Treat. 2022 Jun;33(4):1938-1946. doi: 10.1080/09546634.2021.1959506. Epub 2021 Aug 2.
BACKGROUND AND OBJECTIVES: Finasteride 1 mg/day is indicated for androgen-dependent conditions such as male androgenetic alopecia (AGA). METHODS: The literature is comprehensively summarized on the pharmacodynamics, pharmacokinetics, mechanism of action, and metabolism of finasteride. Pairwise and network meta-analyses were performed to assess the efficacy of finasteride reported in clinical trials. The adverse events profile is described along with the post-marketing reports. RESULTS AND CONCLUSION: Finasteride 1 mg/day significantly increased total hair count compared to placebo after 24 weeks (mean difference = 12.4 hairs/cm, < .05), and 48 weeks (mean difference = 16.4 hairs/cm, < .05). The efficacy of the two doses of finasteride (5 mg/day and 1 mg/day) and topical finasteride (1% solution) were not significantly different. The most commonly reported sexual events include erectile dysfunction and decreased libido. Increasing patient complaints and analysis of the FAERS database led to the inclusion of depression in the FDA label in 2011, as men were found to be at a risk of suicide due to the persistent sexual side effects, commonly termed as post-finasteride syndrome. Finasteride is shown to be reasonably tolerated in both men and women; however, patients need to be educated about the possible short- and long-term side-effects.
40A randomized, active- and placebo-controlled study of the efficacy and safety of different doses of dutasteride versus placebo and finasteride in the treatment of male subjects with androgenetic alopecia.PubMed
Walter Gubelin Harcha, Julia Barboza Martínez, Tsen-Fang Tsai, et al.
J Am Acad Dermatol. 2014 Mar;70(3):489-498.e3. doi: 10.1016/j.jaad.2013.10.049. Epub 2014 Jan 9.
BACKGROUND: Dihydrotestosterone is the main androgen causative of androgenetic alopecia, a psychologically and physically harmful condition warranting medical treatment. OBJECTIVE: We sought to compare the efficacy and safety of dutasteride (type 1 and 2 5-alpha reductase inhibitor) with finasteride (type 2 5-alpha reductase inhibitor) and placebo in men with androgenetic alopecia. METHODS: Men aged 20 to 50 years with androgenetic alopecia were randomized to receive dutasteride (0.02, 0.1, or 0.5 mg/d), finasteride (1 mg/d), or placebo for 24 weeks. The primary end point was hair count (2.54-cm diameter) at week 24. Other assessments included hair count (1.13-cm diameter) and width, photographic assessments (investigators and panel), change in stage, and health outcomes. RESULTS: In total, 917 men were randomized. Hair count and width increased dose dependently with dutasteride. Dutasteride 0.5 mg significantly increased hair count and width in a 2.54-cm diameter and improved hair growth (frontal view; panel photographic assessment) at week 24 compared with finasteride (P = .003, P = .004, and P = .002, respectively) and placebo (all P < .001). The number and severity of adverse events were similar among treatment groups. LIMITATIONS: The study was limited to 24 weeks. CONCLUSIONS: Dutasteride increased hair growth and restoration in men with androgenetic alopecia and was relatively well tolerated.
41Topical Finasteride: A Comprehensive Review of Androgenetic Alopecia Management for Men and Women.PubMed
Akshunna Keerti, Bhushan Madke, Akshaya Keerti, et al.
Cureus. 2023 Sep 9;15(9):e44949. doi: 10.7759/cureus.44949. eCollection 2023 Sep.
The most prevalent kind of alopecia, androgenetic alopecia, commonly known as male or female pattern hair loss, affects both men and women, with the frequency rising with advancing years. Even though practicing dermatologists and hair experts frequently encounter it, it might be one of the most challenging disorders to treat since choosing a course of action frequently requires a comprehensive analysis of several variables and moral judgment. Effectiveness, side effect profiles, practicability, promoting compliance, and treatment cost are the most important factors to take into account, especially given the chronic nature of androgenetic alopecia. A clinician's ability to select the optimum course of treatment for each patient may be constrained and clouded by their knowledge base, experience, and financial compensation. A search was done to find research on the effectiveness of topical finasteride therapy, including clinically pertinent case reports and papers. Only topical minoxidil and oral finasteride are now approved by the Food and Drug Administration and the European Medicines Agency for the treatment of androgenetic alopecia. Despite being effective for hair regeneration, systemic use of finasteride is accompanied by adverse effects that prevent long-term use. Investigating topical finasteride as another possible treatment plan may be fruitful. Early research on the use of topical finasteride is safe and encouraging, despite its limitations. More research on drug distribution, ideal topical strength and usage regularity, adverse effects, and application for other alopecias would aid in elucidating the range of topical finasteride use.
42Sexual side effects of 5-α-reductase inhibitors finasteride and dutasteride: A comprehensive review.PubMed
Raymond M Fertig, A Caresse Gamret, Evan Darwin, et al.
Dermatol Online J. 2017 Nov 11;23(11):13030/qt24k8q743.
The 5-α-reductase inhibitors finasteride and dutasteride are frequently used in the treatment of androgenetic alopecia and benign prostatichyperplasia. These drugs are effective at reducing levels of dihydrotestosterone, the primary androgen responsible for the pathogenesis of both these conditions. However, finasteride and dutasteride have also been shown to produce an increase in the incidence of sexual dysfunction, namely, impotence, decreased libido, and ejaculation disorder. The purpose of this study is to review the existing medical literature with regard to the sexual side effects of 5-α-reductase inhibitor therapy. This review is an extensive look at the sexual effects of 5-α-reductase inhibitors and compares outcomes for finasteride versus dutasteride in addition to comparing sexualside effects for each of the different dosages prescribed of finasteride and dutasteride.
43Adverse Sexual Effects of Treatment with Finasteride or Dutasteride for Male Androgenetic Alopecia: A Systematic Review and Meta-analysis.PubMed
Solam Lee, Young Bin Lee, Sung Jay Choe, et al.
Acta Derm Venereol. 2019 Jan 1;99(1):12-17. doi: 10.2340/00015555-3035.
Treatment of male androgenetic alopecia with 5α-reductase inhibitors is efficacious. However, the risk of adverse sexual effects remains controversial. This systematic review and meta-analysis investigated the risk of adverse sexual effects due to treatment of androgenetic alopecia in male patients with finasteride, 1 mg/day, or dutasteride, 0.5 mg/day. Fifteen randomized double-blinded placebo-controlled trials (4,495 subjects) were meta-analysed. Use of 5α-reductase inhibitors carried a 1.57-fold risk of sexual dysfunction (95% confidence interval (95% CI) 1.19-2.08). The relative risk was 1.66 (95% CI 1.20-2.30) for finasteride and 1.37 (95% CI 0.81-2.32) for dutasteride. Both drugs were associated with an increased risk, although the increase was not statistically significant for dutasteride. As studies into dutasteride were limited, further trials are required. It is important that physicians are aware of, and assess, the possibility of sexual dysfunction in patients treated with 5α-reductase inhibitors.
44Post-finasteride syndrome: a surmountable challenge for clinicians.PubMed
Abdulmaged M Traish
Fertil Steril. 2020 Jan;113(1):21-50. doi: 10.1016/j.fertnstert.2019.11.030.
Post-finasteride syndrome (PFS) is a constellation of serious adverse side effects manifested in clinical symptoms that develop and persist in patients during and/or after discontinuing finasteride treatment in men with pattern hair loss (androgenetic alopecia) or benign prostatic hyperplasia. These serious adverse side effects include persistent or irreversible sexual, neurological, physical and mental side effects. To date, there are no evidence-based effective treatments for PFS. Although increasing number of men report persistent side effects, the medical community has yet to recognize this syndrome nor are there any specific measures to address this serious and debilitating symptoms. Here we evaluate the scientific and clinical evidence in the contemporary medical literature to address the very fundamental question: Is PFS a real clinical condition caused by finasteride use or are the reported symptoms only incidentally associated with but not caused by finasteride use? One key indisputable clinical evidence noted in all reported studies with finasteride and dutasteride was that use of these drugs is associated with development of sexual dysfunction, which may persist in a subset of men, irrespective of age, drug dose or duration of study. Also, increased depression, anxiety and suicidal ideation in a subset of men treated with these drugs were commonly reported in a number of studies. It is important to note that many clinical studies suffer from incomplete or inadequate assessment of adverse events and often limited or inaccurate data reporting regarding harm. Based on the existing body of evidence in the contemporary clinical literature, the author believes that finasteride and dutasteride induce a constellation of persistent sexual, neurological and physical adverse side effects, in a subset of men. These constellations of symptoms constitute the basis for PFS in individuals predisposed to epigenetic susceptibility. Indeed, delineating the pathophysiological mechanisms underlying PFS will be of paramount importance to the understanding of this syndrome and to development of potential novel therapeutic modalities.
45Disposition and pharmacokinetics of [14C]finasteride after oral administration in humans.PubMed
J R Carlin, P Höglund, L O Eriksson, et al.
Drug Metab Dispos. 1992 Mar-Apr;20(2):148-55.
The disposition of [14C]finasteride, a competitive inhibitor of steroid 5 alpha-reductase, was investigated after oral administration of 38.1 mg (18.4 microCi) of drug in six healthy volunteers. Plasma, urine, and feces were collected for 7 days and assayed for total radioactivity. Concentrations of finasteride and its neutral metabolite, omega-hydroxyfinasteride (monohydroxylated on the t-butyl side chain), in plasma and urine were determined by HPLC assay. Mean excretion of radioactivity equivalents in urine and feces equaled 39.1 +/- 4.7% and 56.8 +/- 5.0% of the dose, respectively. The mean peak plasma concentrations reached for total radioactivity (ng equivalents), finasteride, and omega-hydroxyfinasteride were 596.5 +/- 88.3, 313.8 +/- 99.4, and 73.7 +/- 11.8 ng/ml, respectively, at approximately 2 hr; the mean terminal half-life for drug and metabolite was 5.9 +/- 1.3 and 8.4 +/- 1.7 hr, respectively. Of the 24-hr plasma radioactivity, 40.9% was finasteride, 11.8% was the neutral metabolite, and 26.7% was characterized as an acidic fraction of radioactivity. Binding of [14C]finasteride to plasma protein was extensive (91.3 to 89.8%), with a trend suggesting concentration dependency (range 0.02 to 2 micrograms/ml). Little of the dose was excreted in urine as parent (0.04%) or omega-hydroxyfinasteride (0.4%). Urinary excretion of radioactivity was largely in the form of acidic metabolite(s)--18.4 +/- 1.7% of the dose was eliminated as the omega-monocarboxylic acid metabolite. Finasteride was scarcely excreted unchanged in feces. In humans, finasteride is extensively metabolized through oxidative pathways.(ABSTRACT TRUNCATED AT 250 WORDS)
46A novel finasteride 0.25% topical solution for androgenetic alopecia: pharmacokinetics and effects on plasma androgen levels in healthy male volunteers.PubMed
Maurizio Caserini, Milko Radicioni, Chiara Leuratti, et al.
Int J Clin Pharmacol Ther. 2014 Oct;52(10):842-9. doi: 10.5414/CP202119.
OBJECTIVE: Finasteride, a selective inhibitor of type 2 5-α reductase isoenzyme, inhibits the conversion of testosterone to dihydrotestosterone (DHT) and is indicated in the treatment of male androgenetic alopecia. The study objective was to evaluate a newly developed finasteride 0.25% topical solution in comparison to the marketed finasteride 1 mg tablet, with respect to finasteride pharmacokinetics and suppressive effects on plasma DHT. METHODS: 24 healthy men with androgenetic alopecia were randomized in a single center, open-label, parallel-group, exploratory study, and received either multiple scalp applications of the topical solution b.i.d. or oral doses of the reference tablet o.d. for 7 days. Plasma finasteride, testosterone and DHT concentrations were determined. RESULTS: After multiple doses, mean (± SD) finasteride C(max) and AUC(0-t) corresponded to 0.46 ± 0.28 ng/mL and 6.64 ± 7.50 ng/mL x h for the topical solution and to 6.86 ± 1.78 ng/mL and 57.93 ± 29.38 ng/mL x h for the tablet. Plasma DHT was reduced by ~ 68 - 75% with the topical solution and by ~ 62 - 72% with the tablet. No relevant changes occurred for plasma testosterone with either treatment. No clinically significant adverse events occurred. CONCLUSIONS: A strong and similar inhibition of plasma DHT was found after 1 week of treatment with the topical and tablet finasteride ormulations, albeit finasteride plasma exposure was significantly lower with the topical than with the oral product (p < 0.0001).
47The Pharmacokinetics of Topical Finasteride 0.25% Spray in Chinese Adult Male Volunteers with Androgenic Alopecia: A Phase I Study.PubMed
Zongguang Tai, Zhen Cui, Xinwei Shi, et al.
Adv Ther. 2025 Mar;42(3):1494-1505. doi: 10.1007/s12325-025-03106-w. Epub 2025 Feb 5.
INTRODUCTION: This study aimed to evaluate the pharmacokinetics (PK), safety, and local tolerability of local finasteride spray (0.25% solution in HPCH, once daily, volume 200 μL) after single and multiple doses in Chinese male volunteers with androgenetic alopecia. METHODS: Twelve male patients with androgenetic alopecia received once-daily scalp application of the solution for 7 days. Blood samples were collected at specified time points (on day 1, days 3-6, and day 7 of the trial) and plasma finasteride concentrations were determined by HPLC-MS. RESULTS: After single-dose administration, the C of finasteride was 15.2 ± 5.54 pg/mL, T was 11.00 (3.00, 20.00) h, AUC was 263 ± 76.6 h·pg/mL, t was 35.3 ± 47.7 h, and CL/F was 974 ± 518 L/h. After 7 days of multiple doses, C was 29.7 ± 12.9 pg/mL, T was 8.00 (3.00, 12.00) h, AUC was 530 ± 251 h·pg/mL, AUC was 790 ± 464 h·pg/mL, t was 22.6 ± 10.7 h, and CL/T was 1080 ± 658 L/h. No clinically significant adverse events occurred during the study. CONCLUSION: Compared to single-dose administration, multiple-dose administration of finasteride resulted in a stable half-life, minimal changes in clearance rate, and approximately twofold accumulation in exposure over 7 days. Multiple-dose administration of finasteride spray was well tolerated in Chinese male volunteers with androgenetic alopecia.
48Efficacy and safety of topical finasteride spray solution for male androgenetic alopecia: a phase III, randomized, controlled clinical trial.PubMed
B M Piraccini, U Blume-Peytavi, F Scarci, et al.
J Eur Acad Dermatol Venereol. 2022 Feb;36(2):286-294. doi: 10.1111/jdv.17738. Epub 2021 Oct 25.
BACKGROUND: Oral finasteride is a well-established treatment for men with androgenetic alopecia (AGA), but long-term therapy is not always acceptable to patients. A topical finasteride formulation has been developed to minimize systemic exposure by acting specifically on hair follicles. OBJECTIVES: To evaluate the efficacy and safety of topical finasteride compared with placebo, and to analyse systemic exposure and overall benefit compared with oral finasteride. METHODS: This randomized, double-blind, double dummy, parallel-group, 24-week study was conducted in adult male outpatients with AGA at 45 sites in Europe. Efficacy and safety were evaluated. Finasteride, testosterone and dihydrotestosterone (DHT) concentrations were measured. RESULTS: Of 458 randomized patients, 323 completed the study and 446 were evaluated for safety. Change from baseline in target area hair count (TAHC) at week 24 (primary efficacy endpoint) was significantly greater with topical finasteride than placebo (adjusted mean change 20.2 vs. 6.7 hairs; P < 0.001), and numerically similar between topical and oral finasteride. Statistically significant differences favouring topical finasteride over placebo were observed for change from baseline in TAHC at week 12 and investigator-assessed change from baseline in patient hair growth/loss at week 24. Incidence and type of adverse events, and cause of discontinuation, did not differ meaningfully between topical finasteride and placebo. No serious adverse events were treatment related. As maximum plasma finasteride concentrations were >100 times lower, and reduction from baseline in mean serum DHT concentration was lower (34.5 vs. 55.6%), with topical vs. oral finasteride, there is less likelihood of systemic adverse reactions of a sexual nature related to a decrease in DHT with topical finasteride. CONCLUSION: Topical finasteride significantly improves hair count compared to placebo and is well tolerated. Its effect is similar to that of oral finasteride, but with markedly lower systemic exposure and less impact on serum DHT concentrations.
49Plant Nanovesicles Integrate Bioactivity and Transdermal Finasteride Delivery for Androgenetic Alopecia.PubMed
Fan Qi, Huijun Xie, Xun Guo, et al.
ACS Appl Mater Interfaces. 2025 Dec 10;17(49):66313-66329. doi: 10.1021/acsami.5c15594. Epub 2025 Nov 25.
Androgenetic alopecia (AGA) is a progressive hair loss disorder with limited effective therapeutic options. Although finasteride (FIN) remains a first-line treatment, its oral administration is frequently associated with systemic side effects. To overcome this limitation, we developed biomimetic -derived nanovesicles (PcNs)─a traditional medicinal herb known for its hair-growth-promoting properties─as multifunctional carriers for transdermal FIN delivery. PcNs significantly enhanced skin permeation and local drug retention, promoting drug accumulation within the epidermal and dermal layers, while concurrently reducing oxidative stress. In a testosterone-induced AGA mouse model, topical application of FIN-loaded PcNs (FIN-PcNs) effectively reversed hair follicle miniaturization and robustly stimulated hair regeneration. Compared to minoxidil, FIN-PcNs exhibited superior therapeutic efficacy in promoting hair regrowth. Mechanistically, PcNs alleviated hair loss by scavenging reactive oxygen species, modulating inflammatory signaling pathways, and upregulating key genes associated with hair follicle regeneration. Collectively, this study presents a plant-derived nanovesicle-based transdermal platform that integrates intrinsic bioactivity with local drug delivery, offering a safe and effective strategy for AGA treatment and underscoring the broader potential of plant-derived nanocarriers in precision dermatology.
50Effect of finasteride particle size reduction on its pharmacokinetic, tissue distribution and cellular permeation.PubMed
Tarek A Ahmed, Ahmed M Al-Abd
Drug Deliv. 2018 Nov;25(1):555-563. doi: 10.1080/10717544.2018.1440446.
Finasteride (FSD), a specific competitive inhibitor of the steroid type-II 5α-reductase enzyme, is used in treatment of benign prostate hyperplasia (BPH) and male pattern baldness. The drug is of limited solubility that affect its dissolution and bioavailability. The aim was to study the effect of FSD particle size reduction on the pharmacokinetic, tissue distribution and cellular permeation. An optimized drug micro- and nano-particles were developed, characterized, administered to group of rats, and systemic pharmacokinetic and tissue distribution within target and not-target organs were determined using near-infrared (NIR) spectroscopy technique. Moreover, the cellular permeation of the prepared formulations through normal prostate epithelial cells was assessed and compared to pure FSD. The developed micro- and nano-particles were of 930 and 645 nm, respectively. Plasma maximum drug levels (C) and overall exposure (AUC) of both formulations were not significantly higher than unformulated drug. However, micronized FSD achieved significant higher concentration within the target tissue (prostate) within the current study compared to pure drug and nano-sized formulation as well. Yet, this is explained by the higher sequestration ability of spleen tissue to the nano-sized formula compared to micro-sized FSD. At the cellular level, permeation of nano-sized FSD through prostate epithelial cells was superior to the unformulated FSD as well as the micro-sized drug formulation. FSD particle size reduction significantly influences its cellular permeation and to a lesser extend affect its systemic pharmacokinetics and tissue distribution after oral administration.
51What's New in Therapy for Male Androgenetic Alopecia?PubMed
David Saceda-Corralo, Miguel Domínguez-Santas, Sergio Vañó-Galván, et al.
Am J Clin Dermatol. 2023 Jan;24(1):15-24. doi: 10.1007/s40257-022-00730-y. Epub 2022 Sep 28.
Male androgenetic alopecia is a common condition and represents a major concern for patients who experience this condition. While there are different treatments to stop hair loss and improve hair density, the 5-alpha reductase inhibitors have demonstrated to be effective in improving androgenetic alopecia in men and can maintain a positive response for many years. Oral finasteride 1 mg is a US FDA-approved option, but dutasteride 0.5 mg has been proven to induce better responses, especially in the frontal area. Both have been shown to be safe in clinical trials but there is widespread concern about sexual adverse effects among patients. The use of topical finasteride has increased during the last few years as a useful option to avoid systemic therapy. The efficacy of topical finasteride 0.25% daily has been demonstrated in clinical trials, with a less marked decrease in serum dihydrotestosterone levels than with oral intake. Mesotherapy with dutasteride has also become more widespread recently, although evidence of its effectiveness is limited to retrospective studies in real clinical practice. The use of oral minoxidil in androgenetic alopecia has not been approved by the FDA, however several clinical studies have shown that it is an effective treatment option. The initial dose recommended to treat male hair loss is 2.5 mg daily, although the dose is frequently increased to 5 mg daily. The main adverse effect of oral minoxidil is hypertrichosis, followed by dizziness or lower limb edema, which are much less common. Platelet-rich plasma is a non-pharmacological option to treat male androgenetic alopecia, with some clinical trials demonstrating an improvement in hair count after several months. Among the published studies, the main limitation to compare its efficacy is the heterogeneity of the procedure. The most frequent regimens propose treatment every 4 weeks for 3 months initially to assess the individual response. Another treatment alternative is the use of light devices with wavelengths of between 630 and 660 nm, known as low-level laser therapy. These devices can be used at home every day for 15-30 min. Their efficacy has been shown in a limited number of clinical trials; however, there is a lack of evidence about the efficacy of these devices compared with other medical options or as a complementary therapy in hair loss. The pipeline of potential new treatments for male androgenetic alopecia is strong. Pyrilutamide and GT20029 are being studied as topical antagonists of the androgen receptor, while cetirizine is another topical option with some initial promising results. Furthermore, according to isolated studies with heterogeneous treatment schemes, the use of botulinum toxin in the scalp might improve androgenetic alopecia, and lastly, scalp threading might increase the total hair count as growth factors are released during implantation.
52Curcumin-zinc framework encapsulated microneedle patch for promoting hair growth.PubMed
Yating Yang, Pei Wang, Yan Gong, et al.
Theranostics. 2023 Jun 26;13(11):3675-3688. doi: 10.7150/thno.84118. eCollection 2023.
Hair loss is a growing esthetic condition driven by complex mechanisms that has numerous psycho-social implications. Conventional drug applications usually focus on a single treatment target, and the penetration depth restricts the post-delivery effect. We fabricated a curcumin-zinc framework (ZnMOF) encapsulated gamma-polyglutamic acid (γ-PGA) microneedle patch (ZnMOF-MN) as a multifunctional biosafe transdermal drug delivery system. ZnMOF was characterized with the field emission scanning electron microscope (FE-SEM), dynamic light scattering (DLS), elemental mapping, and X-ray diffraction (XRD). The topographical and hygroscopic features of ZnMOF-MN were characterized with SEM. The ZnMOF release profile and the penetration of ZnMOF-MN were also evaluated. The anti-oxidant, anti-apoptosis, and antiandrogen effects of ZnMOF solution and ZnMOF-MN extract were studied on mouse dermal papilla cells (DPCs). Two animal models (in C57BL/6 mice), including androgenic alopecia (AGA) model and wound healing model, were used to identify the therapeutic effect of ZnMOF-MN on hair regrowth and wound healing . Hair follicles, surrounding vessels (CD31+), and proliferating cells (Ki67+) were evaluated by histological staining. ZnMOF crystals were cone-shaped nanoparticles with a size distribution of 424.9 ± 59.01 nm. ZnMOF-MN patch can create temporary holes in the skin to directly and evenly deliver bioactive ZnMOF particles to the targeted depth and achieve a steady and sustained release of Zn and curcumin. , ZnMOF significantly improved the viability of DPCs against the excess reactive oxygen species (ROS) and inhibited the apoptosis induced by zinc deficiency. In addition, it also reversed the inhibitory effects of dihydrotestosterone (DHT) infiltration. Moreover, the ZnMOF-MN treatment has been proved to accelerate wound healing and increase hair follicles in wound healing models, and improved the hair regrowth in AGA animal models. Enhanced capillary density and cell proliferation observed in the CD31+ and Ki67+ staining of ZnMOF-MN group in both animal models also suggested that ZnMOF can facilitate angiogenesis and promote cell proliferation in the skin, respectively. The ZnMOF-MN treatment is a comprehensive solution with excellent therapeutic efficacy and patient-friendly features for promoting hair growth under various clinical conditions.
53Curcumin-primed milk-derived extracellular vesicles remodel hair follicle microenvironment for the treatment of androgenetic alopecia.PubMed
Chongchao Hou, Sihua Wang, Zihang Li, et al.
Regen Biomater. 2025 May 30;12:rbaf051. doi: 10.1093/rb/rbaf051. eCollection 2025.
Androgenetic alopecia (AGA) is a globally prevalent condition, with limited treatment options and significant adverse effects associated with existing therapies. The primary pathogenic mechanisms of AGA involve androgen-mediated regulatory pathways, molecular alterations affecting hair regeneration, and inflammation in the perifollicular microenvironment. In this study, we first investigated the topical application of testosterone with varied doses for AGA mouse model induction, in which the High-dose group exhibited the most robust model development and provided a more comprehensive set of criteria for successful AGA model establishment. Then, curcumin-primed milk-derived extracellular vesicles (Cur-mEVs) were fabricated for the therapy of AGA with the in-house developed mouse model described above. It was demonstrated that Cur-mEVs remodeled the hair follicle microenvironment, evidenced by the activation of the Wnt/β-catenin signaling pathway, downregulation of transforming growth factor beta 1 expression and alleviation of perifollicular inflammation. These effects collectively regulated the hair follicle cycle and promoted hair regeneration. Overall, our results highlighted a promising therapeutic approach for AGA with potential translational possibilities.
54Promotion of hair growth by ginseng radix on cultured mouse vibrissal hair follicles.PubMed
Hideaki Matsuda, Miho Yamazaki, Yusuke Asanuma, et al.
Phytother Res. 2003 Aug;17(7):797-800. doi: 10.1002/ptr.1241.
A 70% methanol extract from red ginseng (steamed and dried roots of Panax ginseng C. A. Meyer, a kind of Ginseng Radix) had superior activity to that of white ginseng (peeled and dried root of P. ginseng, another kind of Ginseng Radix) in a hair growth promoting assay using mouse vibrissal follicles in organ culture. Of the major constituents of P. ginseng, ginsenoside-Rb(1) (G-Rb(1)) exhibited activity, but ginsenoside-Rg(1) (G-Rg(1)) and -Ro (G-Ro) were ineffective. Additionally, 20(S)-ginsenoside-Rg(3) (20(S)-G-Rg(3)) formed by the processing of red ginseng from the crude root of P. ginseng also showed hair growth promoting activity. These results indicate that Ginseng Radix possesses hair growth promoting activity, and its bioactive components are partially attributable to the ginseng saponin components mentioned above.
56Topical Alternatives for Hair Loss: Beyond the Conventional.PubMed
Chingshubam Bikash
Int J Trichology. 2025 Jan-Feb;17(1):13-19. doi: 10.4103/ijt.ijt_8_23. Epub 2025 Jun 23.
Topical hair growth supplements in the form of hair growth serums, oils, and shampoos have flooded the cosmeceutical market. The gullible masses are targeted with sponsored marketing gimmicks through social media platforms. This review article brings to light the most hyped active ingredients or peptides in these products along with their clinical evidence available in the literature. The topical actives include Redensyl, Procapil, Capixyl, Baicapil, AnaGain, onion juice, coffee extract, saw palmetto extract, pumpkin seed oil (PSO), and rosemary oil. PubMed, Google Scholar, and Google databases were searched with the keywords: topical, hair growth, hair loss, and the respective active agents. Twenty-four relevant articles and technical files were extracted and reviewed. They have been studied mostly as combined formulations with other agents in randomized controlled trials or prospective cohort studies and have shown promising results. However, most of the studies have limited sample size, lack of comparison with standard therapies, nonuniformity between study groups, nondisclosure of the type of alopecia treated, and conflicts of interest. These topicals with their less significant side effect profile may find their use as an add-on therapy or as an alternative in patients not tolerating standard therapies. In this fast-growing commercialized world, it is imperative that we remain vigilant and understand the pros and cons of these products and ultimately guide our patients to the right track.
57Hyaluronic Acid Microneedles Loaded with Chinese Herbal Extracts as an Intradermal Delivery System for Hair Regeneration.PubMed
Jiaquan Hong, Bocheng Xu, Xiaole Hu, et al.
Biomacromolecules. 2025 May 12;26(5):2945-2959. doi: 10.1021/acs.biomac.5c00018. Epub 2025 Apr 12.
Androgenic alopecia is one of the most common chronic problems for dermatologists worldwide. Some Chinese herbal extracts have been shown to promote hair growth, but the active ingredients are difficult to enter the dermis. Therefore, delivering the active ingredients into the dermis becomes a key factor. Herein, leaf extract (PO-ex) was obtained using ethanol as a solvent, and then hyaluronic acid methacrylate/hyaluronic acid (HAMA/HA) hydrogel was loaded with PO-ex to prepare hyaluronic acid microneedles (PO-ex MN). The double cross-linked HAMA/HA provides sufficient mechanical strength to pierce the stratum corneum and deliver PO-ex into the dermis; PO-ex can effectively improve the environment for hair follicle cell proliferation by removing reactive oxygen free radicals; in addition, the self-repair reaction caused by microneedle mechanical stimulation activates the Wnt/β-catenin pathway associated with trauma repair and promotes hair follicle growth. PO-ex MN is a potential therapeutic strategy for the treatment of androgenic alopecia.
58New Plant Extracts Exert Complementary Anti-Hair Loss Properties in Human In Vitro and Ex Vivo Models.PubMed
Daniel Bacqueville, Marguerite Lévêque, Camille Mas, et al.
J Cosmet Dermatol. 2024 Dec;23 Suppl 5(Suppl 5):1-11. doi: 10.1111/jocd.16616.
BACKGROUND: Hair loss is linked to dysfunction of the growth (anagen), regression (catagen) and rest (telogen) phases of the hair follicle (HF) cycle. AIMS: To evaluate the effects of a Silybum marianum extract (SME), manganese PCA (MnPCA), and a Lespedeza capitata extract (LCE) on markers of hair growth and anchorage in human follicle dermal papilla cells (HFDPCs), and to investigate the ability of a topical serum containing these active ingredients to improve HF growth in an ex vivo human scalp skin model. METHODS: In HFDPCs, we assessed receptor tyrosine kinase phosphorylation and Wnt/β-catenin pathway activation; quantified versican, vascular endothelial growth factor (VEGF) and Dickkopf-1 (DDK1) secretion; and evaluated 5α-reductase (5αR) activity. Using scalp skin biopsies from two female donors, we measured hair shaft elongation, analyzed hair matrix keratinocyte proliferation and apoptosis, and determined HF cycle stage and score. RESULTS: Compared to untreated HFDPCs, SME upregulated phosphorylation of growth factor receptors (EGFR:1.9 × and PDGFR: 2.8 ×) and their downstream effectors (ERK, GSK3, Akt, and STAT: 1.2-2.0 ×); MnPCA enhanced versican (33.0 ×) and VEGF (3.3 ×) secretion, and stimulated the Wnt/β-catenin pathway (+80%); and LCE reduced DKK1 secretion (-72%) and 5αR activity (dihydrotestosterone/testosterone ratio: -60%). Compared to untreated scalp skin biopsies, the serum enhanced hair shaft elongation (+102%), and significantly prolonged the anagen phase by improving hair cycle scores and stimulating hair matrix keratinocyte proliferation (+58%). CONCLUSIONS: SME, MnPCA, and LCE displayed complementary anti-hair loss properties. The serum combining these active ingredients may be useful in hair loss treatment.
59Hair growth potential of extract and its associated mechanisms.PubMed
Guang-Ri Jin, Yi-Lin Zhang, Jonathan Yap, et al.
Pharm Biol. 2020 Dec;58(1):400-409. doi: 10.1080/13880209.2020.1759654.
Although (SP) R. Brown (Labiatae) is known to possess various biological activities, the effects of SP on hair growth have not been elucidated. To investigate the hair growth potential of SP extract by using human dermal papilla cells (hDPCs) and C57BL/6 mice. The entire SP plant sample was ground into powder and extracted with 99.9% methyl alcohol. Various concentrations of SP extract were added to hDPCs to evaluate the proliferation, migration, and factors related to hair growth and cycling. Effect of topical SP administration on hair regrowth was tested in male C57BL/6 mice for 21 days. SP extract significantly increased the proliferation of cultured hDPCs at doses of 15.6 and 31.3 μg/mL compared to control group by 123% and 132%, respectively. Expression of hepatocyte growth factor increased while the level of TGF-β1 and SMAD2/3 decreased when treated with SP extract. At the molecular level, the extract activated Wnt/β-catenin signalling by raising β-catenin and phospho-GSK3β expression. SP extract also exerted anti-apoptotic and proliferative effects in hDPCs by increasing the Bcl-2/Bax ratio and activating cell proliferation-related proteins, ERK and Akt. Finally, the extract caused an induction of the anagen phase leading to significantly enhanced hair growth in treated male mice. Our results indicate that SP extract has the capacity to activate hDPCs into a proliferative state to promote hair growth. Further research is necessary to determine the bioactive components and their mechanisms of action responsible for SP-related hair growth effect.
60bark extract rich in flavonoids promotes hair growth in dorsal skin by regulating inflammatory cytokines and increasing growth factors in mice.PubMed
Young Her, Tae-Kyeong Lee, Hyejin Sim, et al.
Mol Med Rep. 2022 Mar;25(3). doi: 10.3892/mmr.2022.12616. Epub 2022 Jan 28.
Korean maritime pine bark () has been used as an alternative medicine due to its beneficial properties, including anti‑inflammatory effects. To date, the anti‑inflammatory and hair growth‑promoting effects of bark extract have remained elusive. Therefore, in the present study, bark was extracted with pure water (100˚C) and the extract was examined to determine its polyphenol and flavonoid content. C57BL/6 mice were used to assess the effects of the extract to promote hair growth. The extract (1, 2 and 4%) was topically applied onto shaved dorsal skin and hair growth was observed for 17 days. A significant increase in hair growth was observed with 2 and 4% extract. Based on this finding, the optimal dose of the extract for effective hair growth promotion was determined to be 2%. The mechanisms of hair growth promotion were investigated via immunohistochemical analysis of changes in inflammatory cytokines and growth factors in the hair follicles following treatment with 2% extract. The treatment reduced the levels of TNF‑α and IL‑1β, which are pro‑inflammatory cytokines, while it enhanced the levels of IL‑4 and IL‑13, which are anti‑inflammatory cytokines, in the hair follicles. In addition, elevated insulin‑like growth factor I and vascular epidermal growth factor were detected in hair follicles following treatment. Based on these findings, it was suggested that the extract of bark may be utilized for hair loss prevention and/or hair growth promotion.
61Identifying the active components and mechanisms of Persicae Semen in treating androgenetic alopecia: Insights from network pharmacology and experimental evaluations.PubMed
Xiaojuan Li, Xiaoli Liu, Bin Li, et al.
J Ethnopharmacol. 2025 May 12;347:119755. doi: 10.1016/j.jep.2025.119755. Epub 2025 Apr 11.
ETHNOPHARMACOLOGICAL RELEVANCE: Androgenic alopecia (AGA) is the most prevalent form of hair loss, which affects self-perception and life satisfaction. Current treatments for AGA are limited. In Traditional Chinese Medicine, Persicae Semen (Taoren, TR) is used in formula to mitigate alopecia. However, the principal active constituents and their mechanisms of action in anti-alopecia effects remain fully undefined. AIM OF THE STUDY: This study aimed to elucidate the active constituents and multifaceted mechanisms of TR in AGA treatment through network pharmacology analysis, molecular docking, and experimental validation. MATERIALS AND METHODS: The chemical constituents of TR were systematically characterized using ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS). In addition, a comprehensive compound-disease-target interaction network was constructed to elucidate the molecular mechanism underlying its therapeutic effects on AGA. Molecular docking was performed to validate the interactions between the key bioactive components and core targets. Furthermore, a multi-level pharmacological investigation comprising in vitro cellular assays, ex vivo organ studies, and in vivo animal experiments was conducted to preliminarily explore the therapeutic mechanisms by which high-content active compound treated AGA. RESULTS: UPLC-Q-TOF-MS analysis identified 32 chemical constituents in TR. Through integrated network pharmacology analysis, six bioactive components and 10 core targets were systematically screened for molecular docking, which revealed therapeutic pathways primarily involved in anti-inflammatory responses, angiogenesis, and hair follicle microenvironment modulation. Given its high abundance and superior bioactivity, amygdalin (Am) was selected as the primary research focus. Combined with the pathological mechanism of the disease, which was confirmed through in vitro and in vivo experiments, Am promoted hair regeneration by regulating genes, proteins and inflammatory factors related to the androgen, Wnt/β-catenin, and vascular endothelial growth factor pathways. CONCLUSIONS: In this study the multi-component, multi-target, and multi-pathway mechanisms underlying the therapeutic effects of TR on AGA as well as the molecular mechanism by which Am treats AGA was elucidated. These findings provide substantial theoretical foundations and experimental evidence for the development of novel AGA therapeutics based on TR and its active constituents.
62Enhancing hair growth through phytochemicals: mechanisms, supporting evidence, and future directions.PubMed
Rasaq Onikola, Aminat Mohammed, Ridwan Shittu, et al.
J Pharm Pharmacol. 2025 Jul 1;77(7):897-910. doi: 10.1093/jpp/rgaf023.
AIMS: To explore the mechanisms, formulations, delivery strategies, and therapeutic potential of phytochemicals in promoting hair growth, emphasizing their effects on hair follicle physiology and growth cycles. METHODS: Databases including PubMed, Springer, Wiley Online Library, Web of Science, CBM, CNKI, Elsevier, Google Scholar, and other databases were searched using key terms such as "phytochemicals," "hair growth," "hair follicles," "growth factors," and "natural treatments" were used to identify experimental and clinical studies on phytochemicals affecting hair growth. KEY FINDINGS: Key phytochemicals stimulate hair follicles and promote keratinocyte proliferation. Malva verticillata influences the (Wingless/Integrated and β-catenin) Wnt/β-catenin pathway and AKT (protein kinase B) signaling. Elephantopus scaber L. extracts elevate insulin-like growth factor 1 (IGF-1) and vascular endothelial growth factor (VEGF), while Sophora flavescens boosts IGF-1 and keratinocyte growth factor (KGF) by increasing mRNA levels. Similarly, Epigallocatechin-3-gallate activates AKT signaling, caffeine reduces transforming growth factor-β2 (TGF-β2) and raises IGF-1, and Carthamus tinctorius enhances VEGF and KGF while suppressing TGF-β1. Although evidence highlights their potential, challenges remain in improving bioavailability and standardizing formulations. CONCLUSIONS: Phytochemicals offer natural, safer alternatives for promoting hair growth with fewer side effects than conventional drugs. Further research is needed to optimize formulations and improve bioavailability.
63Hair growth-promoting effects of Camellia seed cake extract in human dermal papilla cells and C57BL/6 mice.PubMed
Jing Wang, Huchi Shen, Timson Chen, et al.
J Cosmet Dermatol. 2022 Oct;21(10):5018-5025. doi: 10.1111/jocd.14955. Epub 2022 Apr 12.
OBJECTIVES: Camellia seed cake is a by-product of Camellia oleifera Abel seed after oil extraction. Washing hair with Camellia seed cake extract is a traditional Chinese custom that has lasted for over one thousand years. However, the hair growth-promoting effects of Camellia seed cake extract were not investigated so far. This work examined the effects of de-saponinated Camellia seed cake extracts (DS-CSE) on hair growth, using in vitro and in vivo models. METHODS: The studies on cell proliferation, cell cycle regulation, and K channels activation effects of DS-CSE were performed on human dermal papilla cells (DPCs). Relative expression of insulin-like growth factor-1 (IGF-1), vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), and transforming growth factor-β (TGF-β1) in DPCs was determined by RT-PCR. Relative expression of ERK and AKT was determined by Western blot analysis. Hair growth-promoting effects were also measured in C57BL/6J mice model. RESULTS: DS-CSE treatment significantly proliferated DPCs, relating to the increased proportion of DPCs in S and G /M phases, the activation of potassium channels and the promoted phosphorylation of ERK and AKT in DPCs. DS-CSE treatment also significantly upregulated the mRNA levels of HGF, VEGF and IGF-1, and downregulated the mRNA level of TGF-β1. Topical application of DS-CSE promoted hair growth on shaven back mice and also upregulated the expression of VEGF in mice. CONCLUSION: Our results demonstrated that DS-CSE exerts a hair growth-promoting effect in vitro and in vivo by proliferating DPCs through the ERK and AKT signaling pathways and regulating the expression of growth factors.
64Pea Sprout Extract Promotes Hair Follicle Regeneration via Anagen Phase Prolongation and Dual Modulation of Oxidative and Inflammatory Signaling.PubMed
Yujin Kim, So Hyeon You, Daewon Yoon, et al.
J Microbiol Biotechnol. 2025 Nov 26;35:e2508011. doi: 10.4014/jmb.2508.08011.
Hair loss is a prevalent condition that affects individuals across all ages and genders. Its causes are multifactorial, involving genetic predisposition, hormonal imbalances, aging, stress and air pollution factors. A previous randomized clinical trial, reveals that daily administration of 100mg of pea sprout extract (PSE) for 8 weeks significantly increased hair density in patients, however, the underlying mechanisms remained unclear. Therefore, this study aims to investigate the efficacy and underlying mechanisms of PSE in promoting hair growth. experiments were conducted using human dermal papilla cells (hDPCs) and RAW 264.7 macrophage cells alongside an study in a C57BL/6 mouse model. Our study demonstrates that PSE promotes hair growth by activating the Wnt/β-catenin signaling pathway, upregulating hair growth-promoting factors, including IGF-1 and FGF7, while downregulating growth inhibitory factors, including IL-1β and BMP4. This indicates that PSE effectively modulates the balance of growth factors by enhancing dermal papilla-associated signaling, thereby harmonizing the hair growth cycle. Furthermore, our results reveal that PSE exhibits anti-oxidant and anti-inflammatory properties, which may help protect hair follicles from oxidative stress and inflammatory damage, processes that can be influenced by environmental pollutants. Inflammation relief involves the use of anti-inflammatory agents to suppress pro inflammatory cytokines, thereby improving the microenvironment surrounding hair follicles and supporting hair growth. PSE is a promising natural ingredient, offering potential benefits in combating hair loss and promoting healthier hair growth by modulating key signaling pathways and providing protective effects. Its potential as a potential natural alopecia treatment warrants more research.
65Oxyresveratrol enhances hair regeneration in human dermal papilla cell and androgenetic alopecia mouse model.PubMed
Hung Gia Tran, Aussavashai Shuayprom, Alisa Ruchusatsawat, et al.
Sci Rep. 2025 May 20;15(1):17551. doi: 10.1038/s41598-025-02581-z.
Alopecia, or hair loss, is a common dermatological condition caused by multiple factors. Oxyresveratrol (ORV), a compound derived from the heartwood of Artocarpus lakoocha, is recognized for its potent antioxidant properties, with recent studies highlighting its anti-inflammatory effect across various cell types. This study aims to explore the therapeutic potential of ORV in treating alopecia. We evaluated the effects of ORV on Human Follicle Dermal Papilla Cells (HFDPCs) and an androgenetic alopecia (AGA) mouse model. Oxidative stress in HFDPCs was induced using hydrogen peroxide (HO), and dihydrotestosterone (DHT) was used to simulate AGA in both HFDPCs and C57BL/6NJcl mice. Our finding demonstrated that ORV significantly enhanced HFDPCs proliferation. In HO-induced oxidative stress conditions, pretreatment with ORV decreased reactive oxygen species (ROS) levels and reduced the production of pro-inflammatory cytokine. In the AGA model, ORV inhibited β-Catenin phosphorylation in HFDPCs, thereby promoting hair growth and maintaining skin thickness, hair bulb size, and count in mice. Overall, ORV demonstrated anti-inflammatory and hair-regenerative effects in both in vitro and in vivo models of alopecia. These findings suggest that ORV is a promising candidate for the treatment of hair loss.
66Argan (Argania Spinosa) press cake extract enhances cell proliferation and prevents oxidative stress and inflammation of human dermal papilla cells.PubMed
Meriem Bejaoui, Noamane Taarji, Masako Saito, et al.
J Dermatol Sci. 2021 Jul;103(1):33-40. doi: 10.1016/j.jdermsci.2021.06.003. Epub 2021 Jun 8.
BACKGROUND: Hair follicle undergoes a growth cycle under the regulation of dermal papilla cells. Due to their enormous roles, these fibroblast cells have been used in various in vitro studies as a screening model to evaluate the effect of hair growth regulating agents. OBJECTIVE: In the current study, we aim to check the hair growth potential effect of Argan press cake (APC) extracted using 50 or 80 % aqueous ethanol on human hair follicle dermal papilla cells (HFDPCs) and to determine the molecular mechanism. METHODS: APC were applied to HFDPCs, then cell proliferation assays, mitochondrial biogenesis assay, and oxidative stress assay were assessed. DNA microarray was performed from the cells treated with our samples and minoxidil. Validation of the results was done using Quantitative Real-Time PCR with primers for hair-growth related genes. GC/MS analysis was used to determine the compounds contained in APC 50 and 80 %. RESULTS: APC enhanced cell proliferation along with the stimulation of the ATP content. Additionally, APC had an anti-oxidant activity against HO mediated oxidative stress preventing dermal papilla cell senescence. Consistent with this, global gene profiling analysis showed an activation of hair growth-related pathway, and a downregulation of inflammation- and oxidative stress-related genes by APC extracts. GC/MS analysis revealed that these extracts contained pure fatty acids, derived sugar chains, and pure compounds including tocopherols, squalene, and spinasterol. CONCLUSION: Taken together, here we showed that APC extracts had an effect on stimulating hair growth while inhibiting the inflammation and the oxidative stress of HFDPCs and thus can potentially contribute to an anti-hair loss drug development.
67Shen-Ying-Yang-Zhen formula promotes angiogenesis around hair follicles, alleviates oxidative stress, and inhibits hair follicle apoptosis through the VEGF/Akt/Caspase-9 signaling axis.PubMed
Huixing Zhang, Lin Su, Yan Qiang, et al.
Phytomedicine. 2025 Sep;145:156963. doi: 10.1016/j.phymed.2025.156963. Epub 2025 Jun 15.
BACKGROUND: Androgenic alopecia (AGA) represents the most predominant form of hair loss in clinical practice, yet currently approved pharmacological options (e.g., finasteride and minoxidil) face limitations in safety and long-term efficacy. Shen-Ying-Yang-Zhen formula (SYF) is a classical prescription in traditional Chinese medicine to AGA; nevertheless, its specific mechanisms of action in addressing AGA remain to be further explored and elucidated. In our study, we for the first time propose that SYF uniquely reshapes the perifollicular microenvironment through dual regulation of oxidative stress and angiogenesis, thus providing a potential medication for AGA. METHODS: In this study, the chemical constituents of SYF were identified using UPLC-MS. An AGA mouse model was established by induction with testosterone propionate (TP), and a human dermal papilla cell (HDPC) model was induced by dihydrotestosterone (DHT). The mechanism underlying SYF treatment for AGA was examined by merging network pharmacology with RNA sequencing, and the findings were corroborated through flow cytometry, multiple immunofluorescences, Western blotting, RT-qPCR, and ELISA techniques. RESULTS: In the AGA mouse model, histological analysis revealed that oral administration of SYF significantly increased skin thickness and hair follicle density (2.8-fold vs. TP group, p < 0.001). Immunofluorescence staining further confirmed that SYF treatment promoted a 2.9-fold increase in p-S6-positive hair follicles-indicative of anagen-phase induction (p < 0.001). Network pharmacology and RNA-seq analyses showed that SYF treatment was associated with cellular oxidative stress and the angiogenic microenvironment around AGA hair follicles, which may be related to targets such as VEGF and Akt Additionally, expression of Ki67, SRY-box transcription factor 9, phospho-S6 ribosomal protein (p-S6), and Nrf2 was enhanced in the skin of the SYF-treated mice, whereas reactive oxygen species expression was decreased. RT-qPCR analysis revealed downregulation of follicle degradation-related factors DKK1, IL-6, and TGFβ1, along with decreased Caspase-9 expression and upregulated key targets VEGF and Akt in the VEGF/Akt/Caspase-9 signaling axis. In the DHT-HDPC model, SYF promoted the proliferation of HDPCs and elevated the Bcl-2/Bax ratio, which in turn suppressed apoptosis of HDPCs in vitro. CONCLUSION: SYF shows promise as a therapeutic agent for prevention of hair loss by improving oxidative stress and angiogenesis in the area surrounding hair follicles in AGA. It reduces apoptosis in DHT-treated HDPCs by regulating the VEGF/Akt/Caspase-9 signaling axis. This multi-target, systems-level approach highlights SYF's potential as a novel therapeutic agent for AGA.
68Hair Growth Promoting Effect of Hottuynia cordata Extract in Cultured Human Hair Follicle Dermal Papilla Cells.PubMed
Jaeyoon Kim, Jae Young Shin, Yun-Ho Choi, et al.
Biol Pharm Bull. 2019;42(10):1665-1673. doi: 10.1248/bpb.b19-00254.
Houttuynia cordata (HC) is a traditional oriental herbal medicinal plant widely used as a component of complex prescriptions in Asia for alopecia treatment. The effect of HC on hair growth and its underlying mechanism, however, have not been demonstrated or clarified. In this study, we investigated the hair growth promoting effect of HC in cultured human dermal papilla cells (hDPCs). HC extract was found to stimulate the proliferation of hDPCs and this stimulation might be in part a consequence of activated cellular energy metabolism, because treatment of HC extract increased the generation of nicotinamide adenine dinucleotide (NADH) and ATP through increasing the mitochondrial membrane potential (ΔΨ). In the context of cell cycle, HC extract increased the expression of CDK4 and decreased the expression of CCNA2 and CCNB1, implying that HC extract might induce G1 phase progression of DPCs which resulted in enhanced proliferation. HC extract increased the expression of Bcl2 essential for maintaining hair follicle anagen stage and cell survival. On the contrary, the expression of p16 and p21 was down-regulated by HC extract. In addition, HC extract enhanced the secretion of platelet-derived growth factor (PDGF)-aa and vascular endothelial growth factor (VEGF) and induced phosphorylation of extracellular signal-regulated kinase (ERK) and AKT. Furthermore, HC extract prolonged anagen stage in organ cultured human hair follicles. Our data strongly suggest that HC extract could support hair growth by stimulating proliferation of DPCs and elongating anagen stage, resulted from enhanced cellular energy metabolism and modulation of gene expression related to cell cycle, apoptosis, and growth factors.
69The effects of centipedegrass extract on hair growth via promotion of anagen inductive activity.PubMed
Fatuma Jumapili Ramadhani, Dong-Ho Bak, Seong Hee Kang, et al.
PLoS One. 2022 Mar 23;17(3):e0265532. doi: 10.1371/journal.pone.0265532. eCollection 2022.
To investigate the CGE on hair growth and to explore the mechanism that is involved in the acceleration of anagen induction, we investigated the effects of CGE studied on cell proliferation and molecular mechanism in human hair dermal papilla cells (hDPCs) and keratinocytes (HaCaT cells). Additionally, hair growth evaluation was carried out following topical treatment of the dorsal skin of telogen C57BL/6 mice with CGE for 14 days. As result, CGE increased cell viability and ALP activity in hDPCs. Moreover, CGE increased the expression of catenin beta 1 (CTNNB1), ALP, sex-determining region Y-box 2 (SOX2), insulin-like growth factor 1 (IGF1), and vascular endothelial growth factor A (VEGFA) genes in hDPCs. CGE increased the expression of proteins such as ALP, β-catenin, and phosphorylation of glycogen synthase kinase 3β (pGSK3β), and protein kinase B (pAKT) in hDPCs. Furthermore, CGE induced the proliferation of HaCaT cells and up-regulated AKT-ERK-GSKβ-β-catenin signaling in HaCaT cells. Additionally, the anagen induction effects of CGE were confirmed on the telogen-anagen transition mice model. these findings demonstrated that CGE promoted the entering the growth phase of hair follicle via activation of β-catenin signaling pathways in vivo. Thus, this study suggests that CGE might be a potential therapeutic reagent for hair growth.
70Emerging and traditional 5-α reductase inhibitors and androgen receptor antagonists for male androgenetic alopecia.PubMed
Aditya K Gupta, Mesbah Talukder, Greg Williams
Expert Opin Emerg Drugs. 2024 Sep;29(3):251-261. doi: 10.1080/14728214.2024.2346590. Epub 2024 Apr 26.
INTRODUCTION: Androgenetic alopecia (AGA) is the most prevalent cause of male hair loss, often requiring medical and/or surgical intervention. The US FDA has approved topical minoxidil and oral finasteride for male AGA treatment. However, some AGA patients fail to respond satisfactorily to these FDA-approved treatments and/or may experience side effects, based on their individual profiles. To mitigate the shortcomings of these treatments, researchers are now exploring alternative treatments such as newer 5-α reductase inhibitors (5-ARIs) and androgen receptor antagonists (ARAs). AREAS COVERED: This article reviews the safety and effectiveness of well-known 5-α reductase inhibitors (5-ARIs) like finasteride and dutasteride, as well as the newer 5-ARIs, emerging androgen receptor antagonists (ARAs), and natural products such as saw palmetto and pumpkin seed oil in the treatment of male AGA. EXPERT OPINION: Although several newer 5-ARIs, ARAs, and natural products have exhibited promise in clinical trials, additional research is essential to confirm their safety and efficacy in treating male AGA. Until additional evidence is available for these agents, the preferred treatment choices for male AGA are the FDA-approved treatments, topical minoxidil, and oral finasteride.
71A Comprehensive Review of Natural Alternatives for Treatment of Alopecia with an Overview of Market Products.PubMed
Alaa Youssef, Dalia A Al-Mahdy, Rabab H Sayed, et al.
J Med Food. 2022 Sep;25(9):869-881. doi: 10.1089/jmf.2021.0156. Epub 2022 Jul 7.
Alopecia or hair loss is a widespread issue that has significant effects on personal well-being for both genders nationally and internationally. In addition, alopecia causes extreme emotional stress and negatively impacts the psychological health and self-esteem of cancer patients suffering from chemotherapy-induced alopecia. Unfortunately, available synthetic medications are costly, invasive, or have extreme adverse effects. On the contrary, natural and herbal hair loss products are widely available in the local and international markets in variable pharmaceutical forms with different mechanisms of action, namely, androgen antagonists, nutritional supplements, vasodilators, and 5-reductase inhibitors or dihydrotestosterone blockers. Thus, it is of great importance to encourage researchers to investigate these natural alternatives that can act as potent therapeutic agents having diverse mechanisms of action as well as limited side effects. Currently, natural remedies are considered a fast-rising pharmaceutical segment with demand from a wide range of consumers. In this study, we present a review of reported herbal remedies and herb combinations recommended for hair loss and their mode of action, along with an overview of available market products and formulations, their composition, and declared effects. In addition, a general outline of the different forms of alopecia, its causes, and recommended treatments are mentioned as well. This was all done with the aim of assisting further studies with developing standardized natural formulations for alopecia as many were found to lack standardization of their bioactive ingredients and efficiency confirmation.
72Wnt/β-catenin signaling activator restores hair regeneration suppressed by diabetes mellitus.PubMed
Yeong Chan Ryu, You-Rin Kim, Jiyeon Park, et al.
BMB Rep. 2022 Nov;55(11):559-564. doi: 10.5483/BMBRep.2022.55.11.081.
Diabetes mellitus is one of the most prevalent diseases in modern society. Many complicationssuch as hepatic cirrhosis, neuropathy, cardiac infarction, and so on are associated with diabetes. Although a relationship between diabetes and hair loss has been recently reported, the treatment of diabetic hair loss by Wnt/β-catenin activators has not been achieved yet. In this study, we found that the depilation-induced anagen phase was delayed in both db/db mice and high-fat diet (HFD) and streptozotocin (STZ)-induced diabetic mice. In diabetic mice, both hair regrowth and wound-induced hair follicle neogenesis (WIHN) were reduced because of suppression of Wnt/β-catenin signaling and decreased proliferation of hair follicle cells. We identified that KY19382, a small molecule that activates Wnt/β-catenin signaling, restored the capabilities of regrowth and WIHN in diabetic mice. The Wnt/β-catenin signaling activator also increased the length of the human hair follicle which was decreased under high glucose culture conditions. Overall, the diabetic condition reduced both hair regrowth and regeneration with suppression of the Wnt/β-catenin signaling pathway. Consequently, the usage of Wnt/β-catenin signaling activators could be a potential strategy to treat diabetes-induced alopecia patients. [BMB Reports 2022; 55(11): 559-564].
73Small molecule agents against alopecia: Potential targets and related pathways.PubMed
Xinyu Luo, Xinhua Ni, Jia Zhi, et al.
Eur J Med Chem. 2024 Oct 5;276:116666. doi: 10.1016/j.ejmech.2024.116666. Epub 2024 Jul 10.
Alopecia has emerged as a global concern, extending beyond the middle-aged and elderly population and increasingly affecting younger individuals. Despite its growing prevalence, the treatment options and effective drugs for alopecia remain limited due to the incomplete understanding of its underlying mechanisms. Therefore, it is urgent to explore the pathogenesis of alopecia and discover novel and safer therapeutic agents. This review provided an overview of the prevailing clinical disorders of alopecia, and the key pathways and targets involved in hair growth process. Additionally, it discusses FDA-approved drugs and clinical candidates for the treatment of alopecia, and explores small molecule compounds with anti-alopecia potential in the drug discovery phase. These endeavors are expected to provide researchers with valuable scientific insights and practical information for anti-alopecia drug discovery.
74Deoxyshikonin from Arnebiae Radix promotes hair growth by targeting the Wnt/β-catenin signaling pathway.PubMed
Yingna Li, Yanhong Mu, Xinyue Chen, et al.
Phytomedicine. 2025 May;140:156590. doi: 10.1016/j.phymed.2025.156590. Epub 2025 Mar 5.
BACKGROUND: Alopecia is a common skin condition with limited effective treatments. Arnebiae Radix (AR) is a traditional Asian herb used for various skin disorders. However, its specific components and the mechanisms underlying its hair growth-promoting effects remain elusive. Therefore, this study aimed to investigate the primary active components in AR that are responsible for hair growth as well as determine the molecular mechanisms responsible for treating alopecia. METHODS: Alopecia areata mice were employed to assess the influence of AR extracts on hair growth. The active AR components were identified via High-Performance Liquid Chromatography (HPLC). Furthermore, network pharmacology and molecular docking were carried out to predict the key targets of the main active AR compound, which were validated by Surface Plasma Resonance (SPR) analysis. Moreover, the mechanism of action of the identified active AR compound on human dermal papilla cells (HDPCs) and alopecia areata mice was investigated to determine its effects on relevant signaling pathways. RESULTS: It was found that Deoxyshikonin (Ds) was the active component in AR with hair growth-promoting potential. Furthermore, it was predicted that Ds targeted 112 alopecia-related targets, including biological processes (such as positive modulation of cell migration and protein phosphorylation) and pathways (including cell cycle- and Wnt signaling pathway-related genes pathways). Network analysis revealed that CCND1 and GSK3β were the hub targets of Ds when treating alopecia. Molecular docking showed a strong binding affinity between Ds and GSK3β, which was validated by SPR results. Moreover, Ds improved HDPC's proliferation ability and promoted hair regeneration in alopecia mice. Similarly, Ds increased VEGF and IGF-1, reduced TGF-β1 content and GSK3β expression, and enhanced the p-GSK3β and β-catenin expression in the Wnt/β-catenin pathway. CONCLUSION: This study showed that Ds was the main active AR component with promising potential as a hair growth stimulant. Mechanistically, Ds primarily targets GSK3β to promote the Wnt/β-catenin signaling pathway. This suggests that Ds could be an innovative therapeutic candidate for promoting hair regeneration.
75HaCaT‑conditioned medium supplemented with the small molecule inhibitors SB431542 and CHIR99021 and the growth factor PDGF‑AA prevents the dedifferentiation of dermal papilla cells .PubMed
Dongjie Sun, Zhehao Huang, Jinying Xu, et al.
Mol Med Rep. 2021 May;23(5). doi: 10.3892/mmr.2021.11965. Epub 2021 Mar 24.
Hair loss, including alopecia, is a common and distressing problem for men and women, and as a result, there is considerable interest in developing treatments that can prevent or reverse hair loss. Dermal papillae closely interact with epidermal cells and play a key role during hair follicle induction and hair morphogenesis. As dermal papilla cells (DPCs) lose their hair‑inducing ability in monolayer cultures , it is difficult to obtain hair follicle structures following DPC transplantation . The present study aimed to explore culture conditions to maintain DPC characteristics using conditioned media (CM) from the supernatant of cultured HaCaT keratinocyte cells supplemented with other components. Initially, it was observed that during passaging of monolayer DPC cultures, the Wnt/β‑catenin pathway was repressed, while the TGF‑β/Smad pathway was activated, and that HaCaT cells cultivated in 1% fetal bovine serum had higher levels of expression of Wnt3a and Wnt10b compared with normal keratinocytes. Culturing of high‑passage (P7) DPCs in CM from HaCaT cells (HaCaT‑CM) actively stimulated cell proliferation and maintained Sox2 and Versican expression levels. Supplementation of HaCaT‑CM with SB431542 (SB, a TGF‑β receptor inhibitor), CHIR99021, (CHIR, a GSK3α/β inhibitor and activator of Wnt signaling) and platelet‑derived growth factor (PDGF)‑AA further increased the expression levels of Sox2, Versican and alkaline phosphatase (ALP) in P7 DPCs. Three‑dimensional culture of P7 DPCs using hanging drop cultures in HaCaT‑CM supplemented with SB, CHIR and PDGF‑AA resulted in larger cell aggregates and a further significant upregulation of Sox2, ALP and Versican expression levels. Taken together, these findings demonstrated that HaCaT‑CM supplemented with SB, CHIR and PDGF‑AA may preserve the hair‑inducing ability of high‑passage DPCs and may therefore be useful in reconstructing new hair follicles .
76Macrophage-Derived Extracellular Vesicle Promotes Hair Growth.PubMed
Ramya Lakshmi Rajendran, Prakash Gangadaran, Chang Hoon Seo, et al.
Cells. 2020 Apr 1;9(4):856. doi: 10.3390/cells9040856.
Hair loss is a common medical problem affecting both males and females. Dermal papilla (DP) cells are the ultimate reservoir of cells with the potential of hair regeneration in hair loss patients. Here, we analyzed the role of macrophage-derived Wnts (3a and 7b) and macrophage extracellular vesicles (MAC-EVs) in promoting hair growth. We studied the proliferation, migration, and expression of growth factors of human-DP cells in the presence or absence of MAC-EVs. Additionally, we tested the effect of MAC-EV treatment on hair growth in a mouse model and human hair follicles. Data from western blot and flow cytometry showed that MAC-EVs were enriched with Wnt3a and Wnt7b, and more than 95% were associated with their membrane. The results suggest that Wnt proteins in MAC-EVs activate the Wnt/β-catenin signaling pathways, which leads to activation of transcription factors (). The MAC-EVs significantly enhanced the proliferation, migration, and levels of hair-inductive markers of DP cells. Additionally, MAC-EVs phosphorylated AKT and increased the levels of the survival protein Bcl-2. The DP cells treated with MAC-EVs showed increased expression of vascular endothelial growth factor (VEGF) and keratinocyte growth factor (KGF). Treatment of Balb/c mice with MAC-EVs promoted hair follicle (HF) growth in vivo and also increased hair shaft size in a short period in human HFs. Our findings suggest that MAC-EV treatment could be clinically used as a promising novel anagen inducer in the treatment of hair loss.
77JAK-STAT pathway inhibitors in dermatology.PubMed
Hélio Amante Miot, Paulo Ricardo Criado, Caio César Silva de Castro, et al.
An Bras Dermatol. 2023 Sep-Oct;98(5):656-677. doi: 10.1016/j.abd.2023.03.001. Epub 2023 May 23.
The JAK-STAT signaling pathway mediates important cellular processes such as immune response, carcinogenesis, cell differentiation, division and death. Therefore, drugs that interfere with different JAK-STAT signaling patterns have potential indications for various medical conditions. The main dermatological targets of JAK-STAT pathway inhibitors are inflammatory or autoimmune diseases such as psoriasis, vitiligo, atopic dermatitis and alopecia areata; however, several dermatoses are under investigation to expand this list of indications. As JAK-STAT pathway inhibitors should gradually occupy a relevant space in dermatological prescriptions, this review presents the main available drugs, their immunological effects, and their pharmacological characteristics, related to clinical efficacy and safety, aiming to validate the best dermatological practice.
78Two Phase 3 Trials of Baricitinib for Alopecia Areata.PubMed
Brett King, Manabu Ohyama, Ohsang Kwon, et al.
N Engl J Med. 2022 May 5;386(18):1687-1699. doi: 10.1056/NEJMoa2110343. Epub 2022 Mar 26.
BACKGROUND: Alopecia areata is an autoimmune condition characterized by rapid hair loss in the scalp, eyebrows, and eyelashes, for which treatments are limited. Baricitinib, an oral, selective, reversible inhibitor of Janus kinases 1 and 2, may interrupt cytokine signaling implicated in the pathogenesis of alopecia areata. METHODS: We conducted two randomized, placebo-controlled, phase 3 trials (BRAVE-AA1 and BRAVE-AA2) involving adults with severe alopecia areata with a Severity of Alopecia Tool (SALT) score of 50 or higher (range, 0 [no scalp hair loss] to 100 [complete scalp hair loss]). Patients were randomly assigned in a 3:2:2 ratio to receive once-daily baricitinib at a dose of 4 mg, baricitinib at a dose of 2 mg, or placebo. The primary outcome was a SALT score of 20 or less at week 36. RESULTS: We enrolled 654 patients in the BRAVE-AA1 trial and 546 in the BRAVE-AA2 trial. The estimated percentage of patients with a SALT score of 20 or less at week 36 was 38.8% with 4-mg baricitinib, 22.8% with 2-mg baricitinib, and 6.2% with placebo in BRAVE-AA1 and 35.9%, 19.4%, and 3.3%, respectively, in BRAVE-AA2. In BRAVE-AA1, the difference between 4-mg baricitinib and placebo was 32.6 percentage points (95% confidence interval [CI], 25.6 to 39.5), and the difference between 2-mg baricitinib and placebo was 16.6 percentage points (95% CI, 9.5 to 23.8) (P<0.001 for each dose vs. placebo). In BRAVE-AA2, the corresponding values were 32.6 percentage points (95% CI, 25.6 to 39.6) and 16.1 percentage points (95% CI, 9.1 to 23.2) (P<0.001 for each dose vs. placebo). Secondary outcomes for baricitinib at a dose of 4 mg but not at a dose of 2 mg generally favored baricitinib over placebo. Acne, elevated levels of creatine kinase, and increased levels of low- and high-density lipoprotein cholesterol were more common with baricitinib than with placebo. CONCLUSIONS: In two phase 3 trials involving patients with severe alopecia areata, oral baricitinib was superior to placebo with respect to hair regrowth at 36 weeks. Longer trials are required to assess the efficacy and safety of baricitinib for alopecia areata. (Funded by Eli Lilly under license from Incyte; BRAVE-AA1 and BRAVE-AA2 ClinicalTrials.gov numbers, NCT03570749 and NCT03899259.).
79Long-term efficacy and safety of baricitinib in patients with severe alopecia areata: 104-week results from BRAVE-AA1 and BRAVE-AA2.PubMed
M Senna, A Mostaghimi, M Ohyama, et al.
J Eur Acad Dermatol Venereol. 2024 Mar;38(3):583-593. doi: 10.1111/jdv.19665.
BACKGROUND: Efficacy of the Janus kinase (JAK) inhibitor baricitinib for severe alopecia areata (AA) continuously increased over 52 weeks in two Phase 3 trials. There are limited long-term data on JAK inhibitors in AA. OBJECTIVES: To evaluate efficacy and safety of baricitinib for severe AA through 104 weeks of continuous therapy. METHODS: Integrated data from the BRAVE-AA1 and BRAVE-AA2 Phase 3 trials included adults with Severity of Alopecia Tool (SALT) scores ≥50 (≥50% scalp hair loss) randomized to and continuously treated with 2-mg or 4-mg baricitinib through Week 104. Patients who qualified to remain on continuous treatment included subjects who achieved SALT score ≤20 at Week 52 (Week-52 responders; 2-mg: N = 65; 4-mg: N = 129) and baricitinib 4-mg-treated patients who had SALT score >20 at Week 52 but achieved SALT score ≤20 at prior visit(s) and/or had significant improvement in eyebrow or eyelash hair growth relative to baseline by Week 52 (Week-52 mixed responders; N = 110). Week-104 outcomes included the proportion of patients achieving SALT score ≤20 (≤20% scalp hair loss). Data were censored after treatment discontinuation. RESULTS: Among baricitinib 4-mg-treated and baricitinib 2-mg-treated Week-52 responders, 90.7% and 89.2%, respectively, maintained SALT score ≤20 at Week 104. Among Week-52 mixed responders, 39.1% reached SALT score ≤20 by Week 104. Continued improvement in eyebrow and eyelash regrowth was observed across groups. The most frequent treatment-emergent adverse events were COVID-19, upper respiratory tract infection, headache, nasopharyngitis, acne, urinary tract infection and creatine phosphokinase increase. CONCLUSIONS: Baricitinib demonstrated a high level of maintenance of efficacy over 104 weeks in patients with severe AA. Efficacy increased in Week-52 mixed responders, illustrating that long-term treatment is necessary to observe maximum benefit in some patients. No new safety signals were observed.
80Efficacy and safety of different JAK inhibitors in the treatment of alopecia areata: a network meta-analysis.PubMed
Dongfan Wei, Yi Chen, Yuqing Shen, et al.
Front Immunol. 2023 Apr 17;14:1152513. doi: 10.3389/fimmu.2023.1152513. eCollection 2023.
BACKGROUND: Alopecia areata (AA) is an immune disease characterized by non-scarring hair loss. With the widespread application of JAK inhibitors in immune-related diseases, attention is being given to their role in the treatment of AA. However, it is unclear which JAK inhibitors have a satisfactory or positive effect on AA. This network meta-analysis aimed to compare the efficacy and safety of different JAK inhibitors in the treatment of AA. METHODS: The network meta-analysis was performed according to the PRISMA guidelines. We included randomized controlled trials as well as a small number of cohort studies. The differences in efficacy and safety between the treatment and control groups were compared. RESULTS: Five randomized controlled trials, two retrospective studies, and two prospective studies involving 1689 patients were included in this network meta-analysis. In terms of efficacy, oral baricitinib and ruxolitinib significantly improved the response rate of patients compared to placebo [MD = 8.44, 95% CI (3.63, 19.63)] and [MD = 6.94, 95% CI, (1.72, 28.05)],respectively. Oral baricitinib treatment significantly improved the response rate compared to non-oral JAK inhibitor treatment [MD=7.56, 95% CI (1.32,43.36)]. Oral baricitinib, tofacitinib, and ruxolitinib treatments significantly improved the complete response rate compared to placebo [MD = 12.21, 95% CI (3.41, 43.79)], [MD = 10.16, 95% CI (1.02, 101.54)], and [MD = 9.79, 95% CI, (1.29, 74.27)], respectively. In terms of safety, oral baricitinib, tofacitinib, and ruxolitinib treatments significantly reduced treatment-emergent adverse event rates compared with conventional steroid treatment [MD = 0.08, 95% CI (0.02, 0.42)], [MD = 0.14, 95% CI (0.04, 0.55)], and [MD = 0.35, 95% CI, (0.14, 0.88)], respectively. CONCLUSION: Oral baricitinib and ruxolitinib are excellent options for the treatment of AA owing to their good efficacy and safety profiles. In contrast, non-oral JAK inhibitors do not appear to have satisfactory efficacy in treating AA. However, further studies are required to verify the optimal dose of JAK inhibitors for AA therapy.
81Comparative efficacy of oral Janus kinase inhibitors and biologics in adult alopecia areata: A systematic review and Bayesian network meta-analysis.PubMed
Husein Husein-ElAhmed, Sara Husein-ElAhmed
J Eur Acad Dermatol Venereol. 2024 May;38(5):835-843. doi: 10.1111/jdv.19797. Epub 2024 Jan 26.
Alopecia areata (AA) is an autoimmune disorder that affects the hair follicles, resulting in patchy recurrent hair loss. A large body of evidence has demonstrated the favourable clinical response of the Janus kinase (JAK) inhibitors and biologics, but a lack of comprehensive comparison among these therapies exists in the current literature. This study aimed to compare their efficacy. A systematic review and meta-analysis were performed including randomized trials that report the outcomes of the Severity of Alopecia Tool (SALT) and/or the mean change in SALT. These articles were pooled and a network meta-analysis (NAM) was conducted. Based on the surface under the cumulative ranking curve estimates obtained for the mean change in SALT score, baricitinib_4 mg (0.7949656) had the best probability of being the most effective therapy, followed by ritlecitinib_200_50 mg (0.7391906) and ivarmacitinib_4 mg (0.7292594). In contrast, dupilumab, secukinumab, tralokinumab and apremilast were less likely to be effective. Targeting the JAK signalling pathway holds great potential for restoring hair regrowth, albeit the contribution of JAK1, JAK2, JAK3 and TYK2 inhibition to the therapeutic effect on AA is apparently different. Baricitinib_4 mg and ritlecitinib 200_50 mg demonstrated notable efficacy, and both molecules displayed a dose-dependent effect, which is not observed with ivarmacitinib. Further investigations into the specific mechanisms of action of these JAK inhibitors are warranted to elucidate the reasons behind these differences.
82Hair Growth Promoting Effects of 15-Hydroxyprostaglandin Dehydrogenase Inhibitor in Human Follicle Dermal Papilla Cells.PubMed
Hye Won Lim, Hak Joong Kim, Chae Young Jeon, et al.
Int J Mol Sci. 2024 Jul 8;25(13):7485. doi: 10.3390/ijms25137485.
Prostaglandin E (PGE) is known to be effective in regenerating tissues, and bimatoprost, an analog of PGF, has been approved by the FDA as an eyelash growth promoter and has been proven effective in human hair follicles. Thus, to enhance PGE levels while improving hair loss, we found dihydroisoquinolinone piperidinylcarboxy pyrazolopyridine (DPP), an inhibitor of 15-hydroxyprostaglandin dehydrogenase (15-PGDH), using DeepZema, an AI-based drug development program. Here, we investigated whether DPP improved hair loss in human follicle dermal papilla cells (HFDPCs) damaged by dihydrotestosterone (DHT), which causes hair loss. We found that DPP enhanced wound healing and the expression level of alkaline phosphatase in DHT-damaged HFDPCs. We observed that DPP significantly down-regulated the generation of reactive oxygen species caused by DHT. DPP recovered the mitochondrial membrane potential in DHT-damaged HFDPCs. We demonstrated that DPP significantly increased the phosphorylation levels of the AKT/ERK and activated Wnt signaling pathways in DHT-damaged HFDPCs. We also revealed that DPP significantly enhanced the size of the three-dimensional spheroid in DHT-damaged HFDPCs and increased hair growth in ex vivo human hair follicle organ culture. These data suggest that DPP exhibits beneficial effects on DHT-damaged HFDPCs and can be utilized as a promising agent for improving hair loss.
83Necrosulfonamide promotes hair growth and ameliorates DHT-induced hair growth inhibition.PubMed
Yuanhong Liu, Shengbo Yang, Lina Tan, et al.
J Dermatol Sci. 2024 Aug;115(2):64-74. doi: 10.1016/j.jdermsci.2024.04.004. Epub 2024 Apr 26.
BACKGROUND: Alopecia affects patients' appearance and psychology. Mixed-lineage kinase domain-like pseudokinase (MLKL)-mediated necroptosis plays a role in various skin diseases, but its effect on hair growth is unclear. OBJECTIVE: To investigate the effects of MLKL on hair growth and its regulatory mechanisms and to determine the potential clinical value of Necrosulfonamide (NSA, a MLKL-targeting inhibitor) in promoting hair growth and counteracting dihydrotestosterone (DHT) inhibition of hair growth. METHODS: The expression level of MLKL was detected in the scalp of androgenetic alopecia (AGA) patients and the skin tissues of mice. Knock down MLKL expression or use NSA to observe hair growth in vivo and in vitro. RESULTS: In AGA patients, MLKL expression is elevated in the alopecia areas. In mice, MLKL is significantly expressed in the outer root sheath (ORS) cells of hair follicles, peaking during the catagen phase. Knockdown expression of MLKL in mice skin promoted hair growth. NSA enhanced hair growth and prevented hair follicle regression via the Wnt signaling. Reduced MLKL boosts ORS cell proliferation without directly impacting DPCs' growth. Interestingly, NSA boosts DPCs' proliferation and induction when co-cultured with ORS cells. Besides, NSA alleviated the inhibition of DHT on hair growth in vivo and vitro. CONCLUSION: NSA inhibited the activation of MLKL in ORS cells, promoted the activation of Wnt signal in DPC cells, and improved the inhibition of hair growth by DHT, illuminating a new alopecia mechanism and aiding anti-alopecia drug development.
84Aging of hair follicle stem cells and their niches.PubMed
Hansaem Jang, Yemin Jo, Jung Hyun Lee, et al.
BMB Rep. 2023 Jan;56(1):2-9. doi: 10.5483/BMBRep.2022-0183.
Hair follicles in the skin undergo cyclic rounds of regeneration, degeneration, and rest throughout life. Stem cells residing in hair follicles play a pivotal role in maintaining tissue homeostasis and hair growth cycles. Research on hair follicle aging and age-related hair loss has demonstrated that a decline in hair follicle stem cell (HFSC) activity with aging can decrease the regeneration capacity of hair follicles. This review summarizes our understanding of how age-associated HFSC intrinsic and extrinsic mechanisms can induce HFSC aging and hair loss. In addition, we discuss approaches developed to attenuate ageassociated changes in HFSCs and their niches, thereby promoting hair regrowth. [BMB Reports 2023; 56(1): 2-9].
85Escape of hair follicle stem cells causes stem cell exhaustion during aging.PubMed
Chi Zhang, Dongmei Wang, Jingjing Wang, et al.
Nat Aging. 2021 Oct;1(10):889-903. doi: 10.1038/s43587-021-00103-w. Epub 2021 Oct 4.
Stem cell (SC) exhaustion is a hallmark of aging. However, the process of SC depletion during aging has not been observed in live animals, and the underlying mechanism contributing to tissue deterioration remains obscure. We find that, in aged mice, epithelial cells escape from the hair follicle (HF) SC compartment to the dermis, contributing to HF miniaturization. Single-cell RNA-seq and assay for transposase-accessible chromatin using sequencing (ATAC-seq) reveal reduced expression of cell adhesion and extracellular matrix genes in aged HF-SCs, many of which are regulated by Foxc1 and Nfatc1. Deletion of Foxc1 and Nfatc1 recapitulates HF miniaturization and causes hair loss. Live imaging captures individual epithelial cells migrating away from the SC compartment and HF disintegration. This study illuminates a hitherto unknown activity of epithelial cells escaping from their niche as a mechanism underlying SC reduction and tissue degeneration. Identification of homeless epithelial cells in aged tissues provides a new perspective for understanding aging-associated diseases.
86MCL‑1 safeguards activated hair follicle stem cells to enable adult hair regeneration.PubMed
Hui San Chin, Jinming Cheng, Shih Han Hsu, et al.
Nat Commun. 2025 Mar 22;16(1):2829. doi: 10.1038/s41467-025-58150-5.
Hair follicles cycle through expansion, regression and quiescence. To investigate the role of MCL‑1, a BCL‑2 family protein with anti‑apoptotic and apoptosis‑unrelated functions, we delete Mcl‑1 within the skin epithelium using constitutive and inducible systems. Constitutive Mcl‑1 deletion does not impair hair follicle organogenesis but leads to gradual hair loss and elimination of hair follicle stem cells. Acute Mcl‑1 deletion rapidly depletes activated hair follicle stem cells and completely blocks depilation‑induced hair regeneration in adult mice, while quiescent hair follicle stem cells remain unaffected. Single‑cell RNA‑seq profiling reveals the engagement of P53 and DNA mismatch repair signaling in hair follicle stem cells upon depilation‑induced activation. Trp53 deletion rescues hair regeneration defects caused by acute Mcl‑1 deletion, highlighting a critical interplay between P53 and MCL‑1 in balancing proliferation and death. The ERBB pathway plays a central role in sustaining the survival of adult activated hair follicle stem cells by promoting MCL‑1 protein expression. Remarkably, the loss of a single Bak allele, a pro‑apoptotic Bcl‑2 effector gene, rescues Mcl‑1 deletion‑induced defects in both hair follicles and mammary glands. These findings demonstrate the pivotal role of MCL‑1 in inhibiting proliferation stress‑induced apoptosis when quiescent stem cells activate to fuel tissue regeneration.
87Hair shaft miniaturization causes stem cell depletion through mechanosensory signals mediated by a Piezo1-calcium-TNF-α axis.PubMed
Yuhua Xie, Daoming Chen, Kaiju Jiang, et al.
Cell Stem Cell. 2022 Jan 6;29(1):70-85.e6. doi: 10.1016/j.stem.2021.09.009. Epub 2021 Oct 7.
In aging, androgenic alopecia, and genetic hypotrichosis disorders, hair shaft miniaturization is often associated with hair follicle stem cell (HFSC) loss. However, the mechanism causing this stem cell depletion in vivo remains elusive. Here we show that hair shaft loss or a reduction in diameter shrinks the physical niche size, which results in mechanical compression of HFSCs and their apoptotic loss. Mechanistically, cell compression activates the mechanosensitive channel Piezo1, which triggers calcium influx. This confers tumor necrosis factor alpha (TNF-α) sensitivity in a hair-cycle-dependent manner in otherwise resistant HFSCs and induces ectopic apoptosis. Persistent hair shaft miniaturization during aging and genetic hypotrichosis disorders causes long-term HFSC loss by inducing continuous ectopic apoptosis through Piezo1. Our results identify an unconventional role of the inert hair shaft structure as a functional niche component governing HFSC survival and reveal a mechanosensory axis that regulates physical-niche-atrophy-induced stem cell depletion in vivo.
88Proliferative defects in dyskeratosis congenita skin keratinocytes are corrected by expression of the telomerase reverse transcriptase, TERT, or by activation of endogenous telomerase through expression of papillomavirus E6/E7 or the telomerase RNA component, TERC.PubMed
Francoise A Gourronc, mckaylee M Robertson, Annie K Herrig, et al.
Exp Dermatol. 2010 Mar;19(3):279-88. doi: 10.1111/j.1600-0625.2009.00916.x. Epub 2009 Jun 23.
Dyskeratosis congenita (DC) is characterized by the triad of reticulate skin pigmentation, nail dystrophy and leukoplakia. Epidermal atrophy, hair growth defects, bone marrow failure and increased risk of cancer are also common in DC patients. DC is caused by mutations in genes encoding for telomerase complex factors. Although there is an association of epidermal abnormalities with DC, epidermal cells from DC donors have not been previously characterized. We have isolated skin keratinocytes from affected members of a family with an autosomal dominant form of DC that is caused by a mutation in the RNA component of telomerase, TERC. Here, we demonstrate that, similar to DC fibroblasts from these donors, DC keratinocytes have short telomeres and a short lifespan. DC keratinocytes also exhibited impaired colony forming efficiency (CFE) and migration capacity. Exogenous expression of the reverse transcriptase (RT) component of telomerase, TERT, activated telomerase levels to half that of TERT expressing normal cells and maintained telomeres at a short length with concomitant extension of lifespan. Unlike fibroblasts, transduction of human papillomavirus type 16 E6/E7 genes into DC keratinocytes activated telomerase to half that of E6/E7 expressing normal cells, and robust proliferation was observed. While expression of TERC has no measurable effect on telomerase in fibroblasts, expression of TERC in keratinocytes upregulated telomerase activity and, rarely, allowed rescue of proliferative defects. Our results point to important differences between DC fibroblasts and keratinocytes and show, for the first time, that expression of TERC can increase the lifespan of primary human epithelial cells.
89The role of telomerase in hair growth and relevant disorders: A review.PubMed
Chaofan Wang, Lingbo Bi, Yimei Du, et al.
J Cosmet Dermatol. 2023 Nov;22(11):2925-2929. doi: 10.1111/jocd.15992. Epub 2023 Sep 4.
BACKGROUND: Hair diseases may present with hair loss, hirsutism, hair melanin abnormalities and other manifestations. Hair follicles are known as mini-organs that undergo periodic remodeling, and their constant regeneration in vivo reflects interesting anti-aging functions. Telomerase prevents cellular senescence by maintaining telomere length, but its excessive proliferation in cancer cells may also induce cancer. However, the effects of telomerase in hair growth have rarely been reported. METHODS: In this study, we reviewed the role of telomerase in hair growth and the effects of hair disorders through literature search and analysis. RESULTS: There is growing evidence that telomerase plays an important role in maintaining hair follicle function and proliferation. Changes in telomerase levels in hair follicles have also been found in a variety of hair disorders. CONCLUSION: Telomerase plays a positive role in hair growth and is expected to become a new target for the treatment of alopecia or other hair diseases in the future.
90Evidence for UV-associated activation of telomerase in human skin.PubMed
M Ueda, A Ouhtit, T Bito, et al.
Cancer Res. 1997 Feb 1;57(3):370-4.
Telomerase activation plays a crucial role in the immortalization of human cells and carcinogenesis; however, the temporal and pathophysiological aspects of the activation in vivo are poorly understood. We found telomerase activity not only in malignant tumors (91%) but also in most benign (60%) and premalignant (89%) skin tumors. This suggests the involvement of telomerase activation in a crucial biological step of human skin carcinogenesis. Because UV light is a major factor in skin carcinogenesis, we further examined telomerase activity in normal skin samples and in normal skin samples adjacent to benign, premalignant, and malignant skin lesions. Data for chronically sun-exposed body sites were compared with those for covered sites. Among normal skin samples, 39% (26 of 67) had telomerase activity, and this activity was unrelated to neighboring lesions but strongly associated with the level of sun exposure. Fifty-four % (21 of 39) of normal skin samples from chronically sun-exposed sites were telomerase-positive, compared with only 12% (3 of 26) of samples from covered sites. When we examined telomerase activity and CC to TT mutations at codons 247/8 of the p53 gene (which are considered to be UV specific) in the same normal skin samples, only 43% (7 of 16) of telomerase-positive normal skin samples at sun-exposed sites contained the p53 mutations, whereas all (7 of 7) of the samples with UV-specific p53 mutations showed telomerase activity (P = 0.019). These data suggest that telomerase activation is involved at an early stage of human skin carcinogenesis and that activation may precede the acquisition of UV-associated p53 mutations in the skin. Telomerase activity was also found in plucked hair follicles and enzymatically separated epidermis, which may be associated with the presence of stem cells in the skin.
91Autophagy induces hair follicle stem cell activation and hair follicle regeneration by regulating glycolysis.PubMed
Pingping Sun, Zhan Wang, Sixiao Li, et al.
Cell Biosci. 2024 Jan 5;14(1):6. doi: 10.1186/s13578-023-01177-2.
BACKGROUND: Hair follicle stem cells (HFSCs) typically remain quiescent and are activated only during the transition from telogen to anagen to ensure that the hair follicle enters a new cycle. The metabolic behavior of stem cells in tissues is regulated by macroautophagy/autophagy, and changes in HFSC metabolism directly affect their activation and maintenance. However, the role of autophagy in the regulation of HFSC metabolism and function remains unclear. METHODS: Back skin samples were obtained from mice at different hair follicle cycle stages, and immunofluorescence staining was used to monitor autophagy in HFSCs. Mouse and human hair follicles were treated with rapamycin (Rapa, an autophagy activator) or 3-methyladenine (3-MA, an autophagy inhibitor). The effects of autophagy on the hair follicle cycle and HFSC were investigated by imaging, cell proliferation staining, and HFSC-specific marker staining. The influence and mechanism of autophagy on HFSC metabolism were explored using RNA sequencing, real-time polymerase chain reaction, immunohistochemical staining, and detection of lactate and glucose concentrations. Finally, the influence of autophagy-induced glycolysis on HFSC and the hair follicle cycle was verified by stem cell characteristics and in vivo functional experiments. RESULTS: Autophagy in HFSC was highest during the transition from telogen to anagen. Inhibiting autophagy with 3-MA led to early entry into catagen and prolonged telogen, whereas Rapa promoted autophagy and hair growth. Autophagy activated HFSC by increasing the expression and activity of HFSC lactate dehydrogenase (Ldha), thereby transforming HFSC metabolism into glycolysis. Inhibition of Ldha expression counteracted the effects of autophagy. CONCLUSIONS: Autophagy activated HFSC by promoting the transition from HFSC metabolism to glycolysis, ultimately initiating the hair follicle cycle and promoting hair growth.
92Isoquercitrin promotes hair growth through induction of autophagy and angiogenesis by targeting AMPK and IGF-1R.PubMed
Majid Manzoor, Danni Chen, Jiahui Lin, et al.
Phytomedicine. 2025 Jan;136:156289. doi: 10.1016/j.phymed.2024.156289. Epub 2024 Nov 26.
BACKGROUND: Hair follicles play a crucial role in hair growth, wound healing, thermoregulation, and sebum production. Hair loss affects millions of people worldwide, yet therapeutic options for managing hair loss and pattern baldness are limited. Isoquercitrin (IQ), a natural small molecule from drinkable Chinese tea, is famous for anti-aging properties. PURPOSE: This study aimed to explore the potential of IQ in treating and preventing hair loss, along with its underlying mechanisms. METHODS: The adult male and female, as well as middle-aged female sprague dawley (SD) rats were used to conduct hair growth experiments in vivo. Signaling pathways and target protein identification were analyzed through western blotting, drug affinity responsive target stability (DARTS), cellular thermal shift assay (CETSA) and surface plasmon resonance (SPR) analyses. Further, the targets were confirmed through in vivo inhibition experiments. RESULTS: IQ is reported here to stimulate anagen phase initiation and hair regrowth by directly interacting with adenosine 5'-monophosphate-activated protein kinase (AMPK) and insulin-like growth factor 1 receptor (IGF-1R). This process involves the AMPK/mammalian target of rapamycin (mTOR)/ unc-51-like autophagy-activating kinase 1 (ULK1) signalling pathway to trigger autophagy and the IGF-1R/phosphatidylinositol 3-kinase (PI3 K)/protein Kinase B (AKT), vascular endothelial growth factor (VEGF)/ vascular endothelial growth factor receptor (VEGFR)/ angiotensin (ANG) pathways to promote angiogenesis in female rats. Furthermore, the hair regrowth efficacy of IQ in adult male rats and middle-aged female rats was verified and shown. Similarly, our findings indicate that IQ promotes hair regrowth in middle-aged rats through autophagy and angiogenesis, akin to its effects in adult rats. CONCLUSION: AMPK and IGF-1R proteins are identified as the target proteins of IQ and the AMPK/mTOR/ULK1, IGF-1R/PI3K/AKT and VEGF/VEGFR/ANG signalling pathways take important roles in hair growth effect of IQ. Thus, these signaling pathways are crucial for developing future treatments and clinical strategies for hair regeneration.
93Exploring vitamin D signalling within skin cancer.PubMed
Neda Vishlaghi, Thomas S Lisse
Clin Endocrinol (Oxf). 2020 Apr;92(4):273-281. doi: 10.1111/cen.14150. Epub 2020 Jan 16.
Sunlight exposure of the skin is associated with both risks and benefits. On one hand, sunlight ultraviolet (UV) radiation can cause skin cancer through signature DNA mutations. On the other hand, it can be absorbed in the skin by 7-dehydrocholesterol to instigate endogenous synthesis of vitamin D to regulate anticancer effects. Thus, protecting one's skin from sunlight to avoid skin cancer may lead to impaired vitamin D levels arguing for sensible sun exposure practices. To limit cancer, vitamin D metabolites can promote uncharacterized and diverse sets of events such as repair responses to DNA damage, apoptosis of malignant cells, and suppression of immune surveillance, proliferation and angiogenesis. Recent findings also suggest that part of the anticancer effects of vitamin D within squamous cell carcinoma-a type of skin cancer most directly linked to sun exposure-involves the DDIT4-mTOR catabolic signalling pathway to enhance cell autophagy. As mTOR activity and cellular metabolism are modulated as part of the DNA damage response, insights into the means by which mTOR can be controlled by vitamin D to suppress cancer is of molecular and clinical importance. Overall, the research so far suggests that presence of vitamin D through sunlight exposure and supplementation are beneficial for human health in the face of cancer.
94Efficacy of an agonist of α-MSH, the palmitoyl tetrapeptide-20, in hair pigmentation.PubMed
S Almeida Scalvino, A Chapelle, N Hajem, et al.
Int J Cosmet Sci. 2018 Oct;40(5):516-524. doi: 10.1111/ics.12494. Epub 2018 Oct 8.
OBJECTIVE: Hair greying (i.e., canities) is a component of chronological ageing and occurs regardless of gender or ethnicity. Canities is directly linked to the loss of melanin and increase in oxidative stress in the hair follicle and shaft. To promote hair pigmentation and reduce the hair greying process, an agonist of α-melanocyte-stimulating hormone (α-MSH), a biomimetic peptide (palmitoyl tetrapeptide-20; PTP20) was developed. The aim of this study was to describe the effects of the designed peptide on hair greying. METHODS: Effect of the PTP20 on the enzymatic activity of catalase and the production of H O by Human Follicle Dermal Papilla Cells (HFDPC) was evaluated. Influence of PTP20 on the expression of melanocortin receptor-1 (MC1-R) and the production of melanin were investigated. Enzymatic activity of sirtuin 1 (SIRT1) after treatment with PTP20 was also determined. Ex vivo studies using human micro-dissected hairs allowed to visualize the effect of PTP20 on the expression in hair follicle of catalase, TRP-1, TRP-2, Melan-A, ASIP, and MC1-R. These investigations were completed by a clinical study on 15 human male volunteers suffering from premature canities. RESULTS: The in vitro and ex vivo studies revealed the capacity of the examined PTP20 peptide to enhance the expression of catalase and to decrease (30%) the intracellular level of H O . Moreover, PTP20 was shown to activate in vitro and ex vivo the melanogenesis process. In fact, an increase in the production of melanin was shown to be correlated with elevated expression of MC1-R, TRP-1, and Melan-A, and with the reduction in ASIP expression. A modulation on TRP-2 was also observed. The pivotal role of MC1-R was confirmed on protein expression analysed on volunteer's plucked hairs after 3 months of the daily application of lotion containing 10 ppm of PTP20 peptide. CONCLUSION: The current findings demonstrate the ability of the biomimetic PTP20 peptide to preserve the function of follicular melanocytes. The present results suggest potential cosmetic application of this newly designed agonist of α-MSH to promote hair pigmentation and thus, reduce the hair greying process.
95Rejuvenating senescent hair follicles: a novel conjugated linoleic acid based nanovesicle approach to treat androgenic alopecia.PubMed
Yating Dong, Yingying Sun, Aojie Li, et al.
J Nanobiotechnology. 2025 Nov 26;23(1):754. doi: 10.1186/s12951-025-03865-2.
Existing therapies for androgenetic alopecia (AGA) fall short of expectations due to the complex pathogenesis, deficient drug enrichment, and obvious adverse effects. Although elevated dihydrotestosterone (DHT) is responsible for the miniaturization of hair follicles (HFs), cell aging has been found to be closely associated with AGA, however not received sufficient attention before. In this study, we first explored the deleterious effects of DHT on HFs, then identified the anti-aging potential of conjugated linoleic acid (CLA) from several polyunsaturated fatty acids. We then developed CLA-loaded nanovesicles (Arg-CLAVs) capable of counteracting DHT-induced HF aging. Arg-CLAVs rejuvenated DHT-induced senescent cells by alleviating oxidative stress, reducing the production of senescence-associated secretory phenotype, and modulating the MAPK-ERK signaling pathway. Moreover, Arg-CLAVs enhanced the HF niche by facilitating angiogenesis, preserving local oxidative homeostasis, and promoting the proliferation and migration of dermal papilla cells. Given its unique properties of nanocarriers, Arg-CLAVs exhibited better skin retention and HF targeting ability compared to the normal tincture. Subsequently, minoxidil (MNX) was loaded into the nanovesicle (MNX@Arg-CLAVs) and evaluated for its hair growth-promoting efficacy in vivo. Our results demonstrated that, in both male and female AGA mice, MNX@Arg-CLAVs with reduced MNX dosage and lower organic solvent contents, exhibited stronger effects on hair regeneration promotion and anti-aging in HFs, while inducing less formulation-associated skin irritation than commercial topical MNX tincture. In sum, this study developed a novel nanoplatform with HF anti-aging activity for AGA that enables synergistic effects with existing drugs.
96Topical Application of Bio-Pulsed Avian MSC-Derived Extracellular Vesicles Enhances Hair Regrowth and Skin Rejuvenation: Evidence from Clinical Evaluation and miRNA Profiling.PubMed
Ju-Sheng Shieh, Yu-Tang Chin, Tsu-Te Yeh, et al.
Curr Issues Mol Biol. 2025 Jul 11;47(7):539. doi: 10.3390/cimb47070539.
Small extracellular vesicles (sEVs) derived from mesenchymal stem cells have emerged as promising therapeutic agents in regenerative dermatology. This study evaluated the safety and efficacy of Bio-Pulsed avian mesenchymal stem cell-derived sEVs (AMSC-sEVs), topically applied for hair follicle stimulation and skin rejuvenation. Two prospective, single-arm clinical trials were conducted: one involving 30 participants using a hair ampoule over 60 days, and the other involving 30 participants applying a facial essence for 28 days. Objective measurements demonstrated significant improvements in the anagen/telogen hair ratio, reduced shedding, increased collagen density, and reduced wrinkle depth and pigmentation. Small RNA sequencing and qPCR profiling confirmed that Bio-Pulsed AMSC-sEVs were enriched with regenerative microRNAs, such as miR-21-5p and miR-199a-5p, associated with anti-inflammatory and anti-aging effects. No adverse events were reported. These findings suggest that Bio-Pulsed AMSC-sEVs may offer a safe, non-invasive, and cell-free approach to enhance skin and hair regeneration in human subjects.