Wang Liqin, Mo Shilun, Zhang Guoji, Yue Xinying, Qu Yaxuan, Sun Xiaoying, Wang Kewei
Department of Natural Medicinal Chemistry and Pharmacognosy, School of Pharmacy, Qingdao Medical College of Qingdao University, Qingdao, China.
Department of Pharmacology, School of Pharmacy, Qingdao Medical College of Qingdao University, Qingdao, China.
Eur J Pharmacol. 2025 Mar 5;990:177264. doi: 10.1016/j.ejphar.2025.177264. Epub 2025 Jan 11.
Dihydrotestosterone (DHT), an androgen derivate, is known to be a key factor involved in androgenetic alopecia. DHT suppresses the growth of outer root sheath cells and induces apoptosis of hair keratinocytes, thereby causing hair follicle miniaturization and hair regrowth inhibition. Forsythoside A, a natural substance derived from Forsythia suspensa, has been shown to reduce DHT-induced apoptosis in human hair cells and suppress hair regrowth inhibition induced by DHT in mice. However, the molecular mechanism underlying the action of forsythoside A remains unclear. Here, we report that the alleviation of androgenetic alopecia by natural phenylethanoid glycoside forsythiaside A involves the selective inhibition of warmth-sensitive Ca-permeable transient receptor potential vanilloid-3 (TRPV3) channels. TRPV3 mRNA and protein expressions are upregulated in the skin of a mouse model of androgenetic alopecia induced by DHT. Ablation of the Trpv3 gene or subcutaneous injection of forsythoside A alleviates DHT-induced hair regrowth inhibition. In whole-cell patch clamp recordings, forsythoside A selectively inhibits macroscopic TRPV3 currents in a concentration-dependent manner with an IC value of 40.1 ± 4.8 μM. At the single-channel level, forsythoside A also reduces the channel open probability and open frequency without significantly altering the channel unitary conductance. Molecular docking combined with site-directed mutagenesis reveals two residues T636 and T665 critical for forsythoside A-mediated inhibition of TRPV3. Taken together, our findings demonstrate that TRPV3 inhibition is an important a mechanism by which natural forsythoside A ameliorates DHT-induced hair regrowth. Topical TRPV3 inhibitors may hold promise as a new therapeutic approach for treating androgenetic alopecia.
二氢睾酮（DHT）是一种雄激素衍生物，已知是雄激素性脱发的关键因素。DHT抑制外根鞘细胞的生长并诱导毛发角质形成细胞凋亡，从而导致毛囊小型化和毛发再生抑制。连翘酯苷A是一种从连翘中提取的天然物质，已被证明可减少DHT诱导的人毛发细胞凋亡，并抑制DHT诱导的小鼠毛发再生抑制。然而，连翘酯苷A作用的分子机制仍不清楚。在这里，我们报告天然苯乙醇苷连翘酯苷A对雄激素性脱发的缓解作用涉及对温度敏感的钙通透性瞬时受体电位香草酸亚型3（TRPV3）通道的选择性抑制。在由DHT诱导的雄激素性脱发小鼠模型的皮肤中，TRPV3 mRNA和蛋白表达上调。敲除Trpv3基因或皮下注射连翘酯苷A可缓解DHT诱导的毛发再生抑制。在全细胞膜片钳记录中，连翘酯苷A以浓度依赖性方式选择性抑制宏观TRPV3电流，IC值为40.1±4.8μM。在单通道水平上，连翘酯苷A还降低了通道开放概率和开放频率，而不会显著改变通道单位电导。分子对接结合定点诱变揭示了两个对连翘酯苷A介导的TRPV3抑制至关重要的残基T636和T665。综上所述，我们的研究结果表明，TRPV3抑制是天然连翘酯苷A改善DHT诱导的毛发再生的重要机制。局部TRPV3抑制剂有望成为治疗雄激素性脱发的新治疗方法。
