Molecular Mechanisms of Programmed Cell Death in Androgenetic Alopecia

Androgenetic alopecia (AGA) is a common hair loss disease that is pathologically featured by progressive hair follicle miniaturization. Its molecular pathogenesis is closely linked to aberrant activation of androgen signaling and dysregulation of multiple programmed cell death (PCD) pathways. This review mainly summarizes the regulatory roles of several PCD modalities, including apoptosis, necroptosis, pyroptosis, ferroptosis and autophagy, in the development of AGA. During hair follicle regression, endogenous metabolic disturbances and extrinsic microenvironmental stimuli such as androgen abnormality, oxidative stress and inflammatory signals can aberrantly activate the above-mentioned cell death mechanisms, resulting in dysfunction of dermal papilla cells and disrupted homeostasis of hair follicle stem cells. These events perturb normal hair follicle cycling, ultimately shortening the anagen phase, accelerating catagen progression and prolonging the telogen phase, thereby aggravating hair shedding. Most current studies only address the role of a single PCD subtype in AGA, lacking systematic integration of these five PCD forms. Comprehensive reviews concerning their spatiotemporal distribution, pathway crosstalk and shared regulatory targets during hair follicle miniaturization are still insufficient, which also hinders the interpretation of broad multi-pathway effects observed for most candidate drugs. Herein, we systematically collate molecular evidence supporting the involvement of the five PCD forms in pathological injury of AGA, summarize the molecular characteristics and intervention strategies of each pathway, and dissect interaction patterns and common regulatory nodes across distinct PCD pathways. Meanwhile, we highlight limitations in this field, including insufficient validation of causal relationships, scarcity of pathological evidence from human tissues, shortage of time-series intervention experiments, and obstacles in clinical translation. This review aims to deepen the understanding of the degenerative injury mechanism of hair follicles in AGA and provide theoretical support for developing novel therapeutic strategies for AGA by targeting PCD.