Targeting VDAC1-dependent mtDNA release attenuates fibroblast innate immune activation and vitiligo pathogenesis.

Abstract

Vitiligo is a chronic depigmentary disorder initiated by oxidative stress, which activates inflammatory signaling and innate immunity, ultimately leading to melanocyte destruction. Although melanocyte defects have been widely studied, dermal fibroblasts-the predominant stromal regulators of cutaneous immunity-remain insufficiently characterized in vitiligo pathogenesis. Here, we demonstrate that subtoxic oxidative stress in normal human dermal fibroblasts (NHDFs) induces a VDAC1-dependent, non-apoptotic release of mitochondrial DNA (mtDNA), thereby linking redox imbalance to immune activation. Low-dose hydrogen peroxide preserved mitochondrial morphology while promoting VDAC1 oligomerization, forming pores that enabled selective mtDNA efflux from structurally intact mitochondria. The released mtDNA activated the cGAS-STING pathway and the NLRP3 inflammasome, driving the expression of IL-1β, IL-6, ICAM-1, and Occludin-a pattern consistent with a senescence-associated secretory phenotype. Pharmacological interventions using ethidium bromide, RU.521, VBIT-4, and exogenous mtDNA established mtDNA release as an upstream event in fibroblast innate immune activation. Notably, inhibiting VDAC1 oligomerization with VBIT-4 effectively prevented mtDNA leakage, attenuated fibroblast senescence and inflammatory signaling, and restored epidermal repigmentation in a vitiligo mouse model. These findings identify dermal fibroblasts as active sensors and amplifiers of oxidative stress via the VDAC1-mtDNA-cGAS-STING axis and highlight VDAC1 oligomerization as a promising therapeutic target.