Academic Journal
Hispidulin ameliorates androgenetic alopecia by inhibiting dermal papilla cell ferroptosis via TRPML1 channel activation.
| Τίτλος: | Hispidulin ameliorates androgenetic alopecia by inhibiting dermal papilla cell ferroptosis via TRPML1 channel activation. |
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| Συγγραφείς: | Jin X; Zhejiang University School of Medicine, Department of Dermatology, Hangzhou Third People's Hospital, Affiliated Hangzhou Dermatology Hospital, Hangzhou, China., Zhang H; Department of Dermatology, Hangzhou Third People's Hospital, Affiliated Hangzhou Dermatology Hospital, Hangzhou, China., Shi Y; Zhejiang Chinese Medical University, Department of Dermatology, Hangzhou Third People's Hospital, Hangzhou, Zhejiang Province, China., Wei D; Department of Dermatology, Beijing Friendship Hospital, Capital Medical University, Beijing, China., Xu W; Department of Dermatology, Hangzhou Third People's Hospital, Affiliated Hangzhou Dermatology Hospital, Hangzhou, China., Fu S; Zhejiang Chinese Medical University, Department of Dermatology, Hangzhou Third People's Hospital, Hangzhou, Zhejiang Province, China., Chen H; Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China; Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Hangzhou, China., Song X; Zhejiang University School of Medicine, Department of Dermatology, Hangzhou Third People's Hospital, Affiliated Hangzhou Dermatology Hospital, Hangzhou, China. Electronic address: songxiuzu@sina.com. |
| Πηγή: | Free radical biology & medicine [Free Radic Biol Med] 2026 Nov; Vol. 255, pp. 519-535. Date of Electronic Publication: 2026 Jul 27. |
| Τύπος έκδοσης: | Journal Article |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: Elsevier Science Country of Publication: United States NLM ID: 8709159 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1873-4596 (Electronic) Linking ISSN: 08915849 NLM ISO Abbreviation: Free Radic Biol Med Subsets: MEDLINE |
| Imprint Name(s): | Publication: Tarrytown, NY : Elsevier Science Original Publication: New York : Pergamon, c1987- |
| Ιατρικοί όροι (MeSH): | Alopecia*/drug therapy , Alopecia*/pathology , Alopecia*/metabolism , Alopecia*/chemically induced , Ferroptosis*/drug effects , Flavones*/pharmacology , Transient Receptor Potential Channels*/metabolism , Transient Receptor Potential Channels*/genetics , Dermis*/drug effects , Dermis*/metabolism , Dermis*/pathology, Hair Follicle/drug effects ; Hair Follicle/metabolism ; Hair Follicle/pathology ; Dihydrotestosterone/toxicity ; Oxidative Stress/drug effects ; Animals ; Mice ; Humans ; Male ; Molecular Docking Simulation ; Disease Models, Animal ; Mice, Inbred C57BL |
| Περίληψη: | 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. (Copyright © 2026 Elsevier Inc. All rights reserved.) |
| Competing Interests: | Declaration of interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. |
| Contributed Indexing: | Keywords: Androgenetic alopecia; Dermal papilla cells; Ferroptosis; Hispidulin; Molecular docking; TRPML1 |
| Substance Nomenclature: | N7F61604C2 (hispidulin) 0 (Flavones) 0 (Transient Receptor Potential Channels) 08J2K08A3Y (Dihydrotestosterone) |
| Entry Date(s): | Date Created: 20260727 Date Completed: 20260905 Latest Revision: 20260905 |
| Update Code: | 20260906 |
| DOI: | 10.1016/j.freeradbiomed.2026.07.040 |
| PMID: | 42508670 |
| Βάση Δεδομένων: | MEDLINE |
| ISSN: | 1873-4596 |
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| DOI: | 10.1016/j.freeradbiomed.2026.07.040 |