Single-Cell Profiling Reveals a Protective WNT5A-ATF3-FOSB Signaling Axis in Hair Follicle Stem Cells During Androgenetic Alopecia.

Androgenetic alopecia (AGA) is a common form of hair loss with limited treatment options, driven by poorly understood molecular mechanisms. Using single-cell RNA sequencing of human scalp follicles from balding and non-balding regions, we constructed a high-resolution molecular anatomy atlas of the hair follicle and its microenvironment. We identified significant silencing of Wingless-related integration site 5A (WNT5A) signaling, which was widely known as the trigger of non-canonical WNT signaling pathway, in hair follicle stem cells (HFSCs) from balding areas, leading to downregulation of the transcription factor ATF3 and its target FOSB. Therapeutically, functional validation showed that activating the WNT5A-ATF3-FOSB axis maintained HFSC competence in AGA murine models and significantly inhibited the progression of AGA. Our findings reveal a critical molecular axis in AGA pathogenesis, highlighting its potential as a therapeutic target for hair loss disorders.