Hispidulin ameliorates androgenetic alopecia by inhibiting dermal papilla cell ferroptosis via TRPML1 channel activation.

Androgenetic alopecia (AGA), the most prevalent form of hair loss, is driven by progressive follicular miniaturization and dihydrotestosterone (DHT)-induced dysfunction of dermal papilla cells (DPCs). While oxidative stress is involved, the specific cell death modality and its upstream regulators remain poorly defined. Here, we demonstrate that ferroptosis-a regulated cell death process driven by iron-dependent lipid peroxidation-constitutes a key mechanism in DHT-induced DPC injury. Through structure-based molecular docking, we identified the natural flavonoid hispidulin as a novel agonist of the lysosomal cation channel TRPML1, a finding confirmed by cellular thermal shift assay (CETSA) and calcium imaging. In a DHT-induced mouse model of AGA, oral administration of hispidulin significantly promoted hair regeneration, restored anagen-phase follicular architecture, and upregulated crucial hair-growth factors (e.g., Ctnnb1, Vegf). Proteomic profiling and subsequent validation experiments revealed that hispidulin effectively suppressed ferroptosis in DPCs in vivo. Mechanistically, the therapeutic benefits of hispidulin, both in vivo and in vitro, were abolished by pharmacological inhibition (ML-SI3) or shRNA-mediated knockdown of TRPML1 (shTRPML1). Moreover, hispidulin-mediated restoration of DPC proliferative capacity and hair inductive function was completely reversed by the ferroptosis inducer Erastin. In summary, our work establishes TRPML1 as a crucial endogenous safeguard for DPC homeostasis, counteracting androgen-induced ferroptosis. Targeting the TRPML1-ferroptosis axis thus emerges as a promising therapeutic strategy for AGA, with hispidulin serving as a validated lead compound for this innovative approach.