Lee Ye-Jin, Hyun Chang-Gu
Jeju Inside Agency and Cosmetic Science Center, Department of Chemistry and Cosmetics, Jeju National University, Jeju 63243, Republic of Korea.
Int J Mol Sci. 2025 Aug 10;26(16):7721. doi: 10.3390/ijms26167721.
Melanin overproduction contributes to hyperpigmentation disorders such as melasma and solar lentigines, leading to increasing demand for safe and effective skin-lightening agents. D-cycloserine (DCS), a known antimicrobial agent, has not been previously evaluated for dermatological applications. This study aimed to explore the potential of DCS as a novel anti-melanogenic compound and to elucidate its underlying molecular mechanisms in melanogenesis inhibition. The cytotoxicity and anti-melanogenic effects of DCS were assessed in B16F10 melanoma cells stimulated with α-MSH. Cell viability was determined via MTT assays, while melanin content, tyrosinase activity, and the expression levels of MITF, TYR, TRP-1, TRP-2, and major signaling proteins (e.g., CREB, MAPKs, GSK-3β/β-catenin) were evaluated using colorimetric assays and Western blotting. A 3D human skin model was also used to confirm in vitro findings, and a primary skin irritation test was conducted to assess dermal safety. DCS significantly reduced α-MSH-induced melanin content and tyrosinase activity without cytotoxicity at concentrations ≤100 µM. It downregulated MITF and melanogenic enzyme expression and modulated signaling pathways by enhancing ERK activation while inhibiting CREB, JNK, and p38 phosphorylation. Additionally, DCS suppressed β-catenin stabilization via GSK-3β activation. These effects were confirmed in a 3D human skin model, and a clinical skin irritation study revealed no adverse reactions in human volunteers. DCS exerts its anti-melanogenic effect by targeting multiple pathways, including CREB/MITF, MAPK, and GSK-3β/β-catenin signaling. Its efficacy and safety profiles support its potential as a novel cosmeceutical agent for the treatment of hyperpigmentation. Further clinical studies are warranted to confirm its therapeutic utility in human skin pigmentation disorders.
黑色素过度生成会导致黄褐斑和日光性雀斑等色素沉着紊乱，这使得对安全有效的皮肤美白剂的需求不断增加。D-环丝氨酸（DCS）是一种已知的抗菌剂，此前尚未针对皮肤科应用进行评估。本研究旨在探索DCS作为一种新型抗黑色素生成化合物的潜力，并阐明其抑制黑色素生成的潜在分子机制。在α-MSH刺激的B16F10黑色素瘤细胞中评估了DCS的细胞毒性和抗黑色素生成作用。通过MTT法测定细胞活力，同时使用比色法和蛋白质印迹法评估黑色素含量、酪氨酸酶活性以及MITF、TYR、TRP-1、TRP-2和主要信号蛋白（如CREB、MAPKs、GSK-3β/β-连环蛋白）的表达水平。还使用3D人体皮肤模型来证实体外研究结果，并进行了原发性皮肤刺激试验以评估皮肤安全性。在浓度≤100 µM时，DCS显著降低了α-MSH诱导的黑色素含量和酪氨酸酶活性，且无细胞毒性。它下调了MITF和黑色素生成酶的表达，并通过增强ERK激活同时抑制CREB、JNK和p38磷酸化来调节信号通路。此外，DCS通过激活GSK-3β抑制β-连环蛋白的稳定性。这些作用在3D人体皮肤模型中得到证实，并且一项临床皮肤刺激研究显示人类志愿者没有不良反应。DCS通过靶向多种途径发挥其抗黑色素生成作用，包括CREB/MITF、MAPK和GSK-3β/β-连环蛋白信号通路。其功效和安全性概况支持其作为一种新型药妆剂用于治疗色素沉着的潜力。有必要进行进一步的临床研究以证实其在人类皮肤色素沉着紊乱中的治疗效用。
