Sinapic acid and glabridin synergistically mitigate androgenetic alopecia by modulating ferroptosis through stabilization of β-catenin against ubiquitin-dependent degradation.

Androgenetic alopecia (AGA), commonly known as male pattern hair loss, with limited effective treatments. Sinapic acid (S) and glabridin (G) are two ingredients in Zhimo herbal extract (ZMHE), identified with UPLC-Q/TOF-MS. We comparatively investigated the effects and mechanisms of S and G, individually and synergistically (S&G), on dihydrotestosterone (DHT)-induced AGA model mice and in dermal papilla cells (DPCs). In our work, S&G showed superior effect on DHT induced oxidative stress in DPCs and on hair growth in AGA mice, compared to application of these two compounds individually. Additionally, S&G significantly reversed the DHT induced abnormal high level of ferrous ions and 4-HNE, overexpressed ACSL4 and FTH1, and morphological variation of mitochondria in mice and in DPCs, as well as lipid peroxidation in DPCs assays. These results suggested that S&G has beneficial effect on DHT induced ferroptosis. To uncover the mechanism, we found that S&G could significantly improve the content of β-Catenin in DHT treated DPCs by inhibiting the phosphorylation induced ubiquitin-dependent degradation. The result of molecular docking and cellular thermal shift assay tests indicated that S&G enhanced the stability of β-Catenin by binding at Ser191 and Glu163/Gln165/Thr201. And the translocated β-Catenin/Tcf-4 triggered expression of GPX4 in DHT treated DPCs and murine skins, which ameliorated the DHT induced peroxidation and reversed the harmful effect of DHT on hair growth. This study suggested that S&G could be applied for AGA treatment, which could attenuate DHT induced ferroptosis by improving the ubiquitin-dependent degradation of β-Catenin.