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  2. VDAC1 Oligomerization-Mediated mtDNA Release under Sublethal Oxidative Stress: A Novel Inflammatory Mechanism in Vitiligo

VDAC1 Oligomerization-Mediated mtDNA Release under Sublethal Oxidative Stress: A Novel Inflammatory Mechanism in Vitiligo

  • Free Radic Biol Med. 2025 Sep 11:S0891-5849(25)00975-X. doi: 10.1016/j.freeradbiomed.2025.09.018.
Rongyin Gao 1 Duo Meng 2 Zhilin Zhao 2 Hui Xue 1 Nan Hu 1 Peiwen Jiang 2 Wenhao Yu 2 Wenhui Xu 2 Chuanwei Yin 2 Huansha Zhang 2 Jinpeng Lv 3
Affiliations

Affiliations

  • 1 Department of Pharmacy, The first people's Hospital of Changzhou, The third Affiliated Hospital of Soochow University, Changzhou 213000, China.
  • 2 Jiangsu Provincial Engineering Research Center for Drug Intelligent Manufacturing and Precision Delivery, School of Pharmacy, Changzhou University, Changzhou 213000, China.
  • 3 Jiangsu Provincial Engineering Research Center for Drug Intelligent Manufacturing and Precision Delivery, School of Pharmacy, Changzhou University, Changzhou 213000, China. Electronic address: lvjinpeng1988@cczu.edu.cn.
Abstract

Oxidative stress is a critical initiating factor in vitiligo, yet the early molecular events linking redox imbalance to melanocyte immune activation remain unclear. Here, we demonstrate that sub-lethal hydrogen peroxide (H2O2, 0.1 mM) exposure in human epidermal melanocytes induces a robust pro-inflammatory response independent of Apoptosis or Pyroptosis. This response is driven by the selective cytosolic release of mitochondrial DNA (mtDNA), which activates the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway. Mechanistically, voltage-dependent anion channel 1 (VDAC1) oligomerization cooperates with mitochondrial permeability transition pore (mPTP) opening to mediate mtDNA release. Both genetic VDAC1 knockdown and pharmacological inhibition blocked mtDNA leakage and downstream cytokine production. In H2O2-induced vitiligo mice, intradermal administration of the VDAC1 oligomerization inhibitor VBIT-4 restored melanin pigmentation, reduced CD8+ T cell infiltration, and alleviated cutaneous inflammation. These findings identify VDAC1-dependent mtDNA release as a key driver of innate immune activation in melanocytes and highlight VDAC1 as a potentially druggable therapeutic target for early intervention in vitiligo.

Keywords

VDAC1 oligomerization; cGAS-STING; melanocytes; mitochondrial DNA; sublethal oxidative stress; vitiligo.

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