Pathogenic Mechanisms and Mechanism-Directed Therapies for Androgenetic Alopecia: Current Understanding and Future Directions

Abstract

Androgenetic alopecia (AGA) affects about half of men and many women worldwide, yet current treatments often fall short. This review summarizes key pathogenic mechanisms of AGA, centering on three interconnected processes: the dihydrotestosterone–prostaglandin D2 (DHT–PGD2) loop, oxidative stress and inflammation, and lipid metabolism dysregulation. These factors converge to suppress Wnt/β-catenin signaling, the core pathway for hair growth. DHT and PGD2 reinforce each other to drive follicular miniaturization via CXXC5 and GSK-3β activation. Oxidative stress and chronic inflammation—exacerbated by scalp microbiome imbalance, notably excess Cutibacterium acnes and Malassezia—further damage the follicular environment. Suppressed PPARγ signaling disrupts adipocyte-follicle crosstalk, reducing growth factor support. These insights reveal emerging therapeutic targets, including DP2 antagonists, CXXC5/GSK-3β inhibitors, antioxidants, microbiome modulators, and PPARγ agonists. By integrating molecular, microbial, and metabolic perspectives, this review outlines a framework for multitarget strategies to address the limitations of existing AGA treatments.