Hair follicle signalling networks: From molecular crosstalk to precision regenerative strategies

Hair follicles (HFs) are dynamic mini-organs that undergo cyclical phases of growth, regression, and rest, regulated by interconnected signalling pathways including Wnt/β-catenin, Hedgehog (HH), TGF-β/BMP, Notch, PI3K/AKT, androgen receptor (AR), and prostaglandin signalling. Although these pathways are often studied individually, increasing evidence indicates that their reciprocal interactions coordinate HF stem cell activation, lineage specification, dermal papilla (DP) function, and hair-cycle progression. Disruption of this signalling network can impair follicular homeostasis and contribute to hair-loss disorders. This review examines HF regeneration from a network perspective, with androgenetic alopecia (AGA) as the principal disease context and selected evidence from alopecia areata (AA) and other hair-loss disorders where mechanistically or therapeutically relevant, emphasizing how signalling crosstalk shapes follicular responses and therapeutic outcomes. We first summarize the biological functions of major signalling pathways and then their interactions across epithelial, mesenchymal, and niche compartments. We further evaluate pharmacological, cell-based, extracellular vesicle, antibody-based, and physical therapeutic strategies to modulate these signalling networks. On this basis, we propose a network-oriented framework in which effective hair regeneration depends not only on maximizing activation or inhibition of individual pathways, but on restoring signalling balance through context-dependent, cell-specific, and spatiotemporally controlled interventions. This framework provides a basis for developing rational combination and precision regenerative strategies for hair-loss disorders.