Stress-immune-Repigmentation niche in vitiligo: Mechanistic integration and therapeutic implications

Vitiligo is an autoimmune depigmenting disorder characterized by selective melanocyte loss and a chronic relapsing course. Increasing evidence supports a network model in which immune activation, cellular stress responses, and microenvironmental imbalance converge to drive disease activity and repigmentation stability. Interferon-γ-driven JAK/STAT signaling induces chemokines such as CXCL10 and promotes CXCR3-dependent recruitment of cytotoxic T cells, reinforcing melanocyte-directed inflammation. In parallel, impaired Nrf2-mediated antioxidant defenses and enhanced lipid peroxidation lower melanocyte resilience and may predispose to ferroptosis, highlighting regulatory nodes including SLC3A2, SIRT7, and GPX4 as potential stress-adaptation regulators. Persistence and recurrence are increasingly linked to IL-15-supported tissue-resident memory T (TRM) cells and inflammatory microenvironments that can suppress hair follicle melanocyte stem cell function, thereby destabilizing repigmentation. Therapeutically, topical and systemic JAK inhibitors have demonstrated clinically meaningful repigmentation benefits, while emerging strategies targeting immune memory (e.g., IL-15/TRM pathways) and restoring the repigmentation niche-through Wnt/β-catenin, AhR-related pathways, and antioxidant/anti-ferroptosis programs-may improve durability and reduce relapse. Future progress will require biomarker-guided stratification and well-designed randomized trials to define temporal combination regimens that block dominant inflammatory hubs during active disease and reinforce melanocyte resilience during maintenance.