Disulfidptosis in vitiligo: A narrative review on a novel paradigm of melanocyte destruction linking cystine metabolism, cytoskeletal collapse, and autoimmunity

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Vitiligo is a chronic autoimmune skin disorder that causes the melanocytes in the epidermis to disappear, creating sharply demarcated white patches. Current models agree on three drivers: intrinsic vulnerability of melanocytes, chronic oxidative stress, and cytotoxic CD8+ T cells. The exact biochemical pathway that results in the death of individual melanocytes has not been completely defined. Apoptosis, autophagy, and more recently ferroptosis have all been implicated, but none neatly explain the pre‑apoptotic detachment, cytoskeletal disarray, and redox collapse that characterize the stressed melanocyte. Disulfidptosis, a form of regulated cell death first described in 2023, provides a mechanism whose biochemical prerequisites overlap substantially with documented features of vitiligo melanocytes, and whose engagement of the actin cytoskeleton offers a cell-autonomous explanation for the pre-apoptotic detachment phenotype. Activation occurs when cells with high SLC7A11 activity become depleted of NADPH. Under these conditions cystine is taken into the cell but cannot be reduced . This causes the accumulation of intracellular disulfides, cross-linking of actin cytoskeletal proteins and disruption of the filamentous actin network . The cell dies in hours. SLC7A11 expression in melanocytes for cystine-dependent melanogenesis under chronic oxidative stress, glutathione and NADPH deficiencies in vitiligo. They also show actin-dependent detachment (melanocytorrhagy) early in disease, prior to any overt apoptotic features. This narrative review outlines the molecular logic of disulfidptosis, discusses the biochemical and immunologic milieu of vitiligo, and offers a unifying framework for how disulfidptosis participates in melanocyte destruction. We further discuss potential intersections of disulfidptosis with the interferon gamma and CXCR3 axis and current therapies, map current evidence of disulfidptosis in autoimmune diseases, and describe testable predictions to move this hypothesis from the conceptual to the experimental. We position the proposed framework as hypothesis-generating: it requires direct experimental validation in vitiligo melanocytes, and we outline a concrete roadmap for such validation