Natural phenylethanoid glycoside forsythoside A alleviates androgenetic alopecia by selectively inhibiting TRPV3 channels in mice.

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 Ca2+-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 IC50 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.