Secreted Frizzled-Related Protein 2 (SFRP2) Induces Follistatin-Like 1 (FSTL1) to Regulate Dihydrotestosterone...

Androgenetic alopecia (AGA) is the most common form of non-scarring hair loss, driven by genetic factors and increased sensitivity of scalp hair follicles to dihydrotestosterone (DHT), which causes progressive miniaturization of dermal papilla cells and shortens the hair growth phase. The precise molecular pathogenesis of AGA remains incompletely understood. The study aimed to elucidate the regulatory mechanism between secreted frizzled-related protein 2 (SFRP2) and follistatin-like 1 (FSTL1), explore their impact on DHT-induced mitochondrial dysfunction and senescence in dermal papilla cells (DPCs), elucidate the effect of the SFRP2-FSTL1 axis on oxidative stress-related DPCs changes, and identify new therapeutic targets for AGA treatment. In the study, SFRP2 was highly expressed in the DPCs of AGA patients. Knocking down SFRP2 improved hair regeneration and follicle morphology within AGA model mice, promoting proliferation, migration, and invasion of DPCs in vitro. SFRP2 knockdown also alleviated inflammation, senescence, mitochondrial dysfunction, and oxidative stress. SFRP2 was found to bind to FSTL1, thereby promoting FSTL1 protein stability. Knocking down FSTL1 counteracted the negative effects of SFRP2 overexpression in vitro. In conclusion, SFRP2 emerges as a critical regulator in AGA by promoting stability and activity of FSTL1, establishing a novel SFRP2-FSTL1 axis that exacerbates DHT-driven pathogenic changes in DPCs. These findings identify SFRP2 and FSTL1 as key mediators of androgen-induced cellular dysfunction and suggest that disrupting this axis could offer a promising therapeutic strategy for slowing or reversing the progression of AGA.