Targeting non-genomic androgen receptor signaling in androgenetic alopecia: from membrane receptors to hair follicle pathology

Androgenetic alopecia (AGA) is a common, progressive form of hair loss with a strong genetic basis, and the androgen receptor (AR) acts as its principal androgen-specific effector. In addition to the classical genomic action of nuclear AR, androgens exert rapid non-genomic effects. These are initiated within seconds to minutes at the plasma membrane by the membrane-associated androgen receptor (mAR), including the structurally distinct ZIP9, GPRC6A, OXER1, and TRPM8, as well as by palmitoylated classical AR and AR splice variants. Downstream signaling mobilizes intracellular calcium (Ca 2+ ) and activates the Ras-Raf-MEK-ERK and PI3K-Akt-mTOR kinase cascades and NADPH oxidase-dependent reactive oxygen species, which together regulate hair follicle growth cycling, differentiation, senescence, and apoptosis. Local androgen metabolism further shapes these responses: 5α-reductase generates the more potent dihydrotestosterone (DHT), whereas aldo-keto reductase family 1 member C (AKR1C) enzymes inactivate DHT, and individual mAR subtypes differ in ligand preference. Crucially, most mechanistic evidence comes from non-hair-follicle systems, and direct relevance to human AGA must be established in follicle-specific models. Moreover, these pathways are not uniformly pathogenic; they also support physiological and pro-regenerative functions, and their net effect depends on cell type, signal intensity and duration, androgen concentration, and hair-cycle stage. We therefore propose dual targeting of genomic and non-genomic AR signaling, for example, combining low-dose finasteride with selective mAR or pathway modulators, as a rational strategy for AGA. This review integrates the mechanistic and translational evidence and outlines a prioritized research roadmap.