Targeting Endogenous Wnt Antagonists for Therapy Development in AGA: a Focus on DKKs and sFRPs

Androgenetic alopecia(AGA) is the most common form of hair loss worldwide. By middle age, approximately two-thirds of men and 40% of women are affected. The pathophysiology of AGA involves complex interactions among genetic predisposition, androgen sensitivity, and dysregulation of the hair follicles (HFs) cycle. Among the key regulatory pathways, the Wnt/β-catenin signaling pathway plays a central role in maintaining homeostasis of hair follicle stem cell (HFSCs) and dermal papilla cells (DPCs), as well as in promoting the transition to the anagen phase. Endogenous Wnt inhibitors, such as dickkopfs (DKKs) and secreted frizzled-related proteins (sFRPs), are upregulated under the influence of dihydrotestosterone and can modulate canonical Wnt signaling in DPCs and HFSCs via paracrine mechanisms, potentially contributing to the development of AGA. Targeted inhibition of these endogenous negative regulators may therefore represent a promising therapeutic strategy for AGA. This review summarizes current insights into the role of Wnt signaling in hair follicle biology, the characteristics and functions of DKKs and sFRPs in AGA, and their potential as therapeutic targets.