Oxidative stress-induced release of mitochondrial DNA (mtDNA) promotes the progression of vitiligo by activating the cGAS-STING signaling pathway in monocytes.

Vitiligo, driven by cytotoxic CD8+ T cells destroying melanocytes, has recently been linked to mitochondrial DNA (mtDNA), a DAMP known to trigger innate immunity. However, the precise role of mtDNA in vitiligo pathogenesis remains poorly understood. In this study, we observed significantly elevated mtDNA levels in both the serum and depigmented lesions of vitiligo patients. Importantly, we found that oxidative stress induces mtDNA production in keratinocytes and vascular endothelial cells, providing a plausible source for its systemic and localized accumulation. Using the mouse odel, we demonstrated that exogenous mtDNA administration markedly accelerated progression of vitiligo, as evidenced by pronounced tail depigmentation. Mechanistically, mtDNA can activate the cGAS-STING-IFN-α/β pathway in monocytes, leading to an increased production of IFN-γ by CD8+ T cells while simultaneously reducing the frequency and functionality of regulatory CD4+ T cells (Tregs). Consistent with these findings, mtDNA treatment in vitiligo mice led to heightened infiltration of IFN-γ+ CD8+ T cells into affected tissues, accompanied by a significant decrease in Treg numbers and activity, thereby exacerbating the autoimmune response. Collectively, these findings underscore the pivotal role of mtDNA-STING signaling in vitiligo progression and highlight this pathway as a promising target for therapeutic intervention. Our findings suggest that mtDNA may serve as a crucial mediator in the pathogenesis of vitiligo and other autoimmune diseases, providing new insights into potential therapeutic targets.