Sesamin alleviates androgenetic alopecia by targeting the AR MAPK Wnt axis

Androgenetic alopecia (AGA) represents the most common form of hair loss, yet it lacks truly effective therapeutic options. Sesamum has been used for treating hair loss by ancient Chinese doctors. Nevertheless, the mechanism of sesamum is unclear. Sesamin is a key ingredient in sesamum, which shows multiple biological activities. We proposed that sesamin might improve influence molecular processes relevant to AGA by regulating the growth cycling of skin cells, and elucidated our proposal with in vitro researches. Network pharmacology was employed to predict sesamin-AGA targets and pathways. High-confidence targets were mapped into a protein-protein interaction network and functionally annotated by GO and KEGG enrichment. Molecular docking quantified binding affinities between sesamin and key proteins. Cytotoxicity was assessed by MTT in HaCaT keratinocytes. The regulatory capacity of sesamin was validated in DHT-stimulated HaCaT cells by Western blotting for AR, p38 MAPK, apoptosis (BAX/BCL2) and WNT10B signaling. Fifteen overlapping targets were identified, with AR, EGFR, ESR1 and CASP3 forming the core network. Enrichment analyses highlighted steroid hormone response, cell proliferation and MAPK/Wnt cascades. Docking showed high-affinity binding of sesamin to AR (- 9.1 kcal·mol⁻¹). Cell assays revealed that 10-80 µM sesamin reversed DHT-induced p38 phosphorylation, normalized AR expression, down-regulated pro-apoptotic BAX, restored anti-apoptotic BCL2, and elevated WNT10B. Our findings provided mechanistic evidences that sesamin modulates the AR-MAPK-Wnt signaling axis in DHT-challenged HaCaT cells, suggesting its potential multi-target activity against molecular events implicated in androgenetic alopecia.