Ferroptosis in Vitiligo and Melanoma: Opposing Susceptibilities, Shared Mechanisms, and Therapeutic Targets.

Vitiligo is a common acquired depigmentation disorder affecting approximately 0.5-2% of the global population, characterized by the selective destruction of melanocytes leading to white patches on the skin. The pathogenesis of vitiligo involves complex interactions between genetic susceptibility, autoimmune responses, oxidative stress, and melanocyte dysfunction. Recent studies have demonstrated that ferroptosis, a novel iron-dependent form of programmed cell death, may play a critical role in melanocyte loss in vitiligo. Ferroptosis is characterized by iron accumulation, lipid peroxidation, glutathione (GSH) depletion, and decreased glutathione peroxidase 4 (GPX4) activity. This form of cell death differs fundamentally from apoptosis, necrosis, and autophagy in its morphological, biochemical, and genetic characteristics. Understanding the role of ferroptosis in vitiligo pathogenesis opens new avenues for therapeutic intervention and may explain why melanocytes in vitiligo patients are particularly vulnerable to oxidative damage. Multiple experimental and clinical studies have now confirmed the upregulation of ferroptosis biomarkers including transferrin receptor 1 (TFR1), malondialdehyde (MDA), and 4-hydroxynonenal (4-HNE) in vitiligo lesions, alongside downregulation of GPX4 and the cystine/glutamate antiporter System Xc-. Emerging evidence further implicates epigenetic regulators such as SIRT7 and RNA-binding proteins such as SLC3A2 in modulating melanocyte ferroptosis susceptibility. This comprehensive review systematically summarizes current knowledge on ferroptosis mechanisms in vitiligo, including the System Xc-/GPX4 axis, iron metabolism dysregulation, lipid peroxidation pathways, and their interactions with autoimmune responses. We also explore emerging therapeutic strategies targeting ferroptosis-related pathways, including iron chelation, GPX4 enhancement, lipid peroxidation inhibitors, NRF2 activators, and natural compounds such as baicalein. By integrating basic research findings with clinical observations, this review provides novel insights into vitiligo pathogenesis and establishes a theoretical foundation for developing innovative treatment strategies based on ferroptosis regulation. Crucially, by contrasting the ferroptosis-hypersensitive profile of vitiligo melanocytes with the ferroptosis-resistant molecular landscape of melanoma cells, this review proposes a novel framework for melanocyte-lineage-selective ferroptosis modulation as a therapeutic strategy.