S100 signaling in hair follicle biology: emerging mechanistic insights and therapeutic opportunities.

S100 proteins are a conserved family of calcium-binding proteins that regulate diverse cellular processes across multiple tissues, with particularly important roles in skin biology. In the hair follicle (HF), different S100 members are expressed in epithelial, mesenchymal, and immune compartments, where they have been linked to keratinocyte differentiation, hair cycle regulation, redox balance, and local immune control. This Review summarizes current evidence on the distribution and function of S100 proteins in HF biology and hair disease. We focus on how individual S100 isoforms contribute to intracellular calcium sensing, extracellular alarmin activity, epithelial-mesenchymal communication, and inflammatory signaling within the HF microenvironment. Studies in human skin, cultured HF-related cells, and animal models indicate that S100 proteins can influence pathways relevant to HF regeneration and pathology, including Wnt/β-catenin, NF-κB, MAPK, and oxidative stress-related signaling. However, the field remains fragmented, and many proposed functions are still inferred from expression patterns rather than direct biochemical or genetic evidence. Clarifying the cellular sources, downstream targets, and context-specific actions of S100 proteins will be essential for understanding their roles in HF physiology and disease.