VDAC1 O-GlcNAcylation Promotes mtDNA Release and Activates ZBP1-Dependent Neuroinflammation in Diabetic Retinopathy.

Tan, Xin; Guan, Lipeng; Li, Wen; Zhang, Meng-Yuan; Zhu, Lingpeng; Yao, Yong; Wei, Ting-Ting · Diabetes · 2026

basic_science · Level V

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Abstract

The limited efficacy of anti-VEGF therapy in diabetic retinopathy (DR) highlights the importance of nonvascular mechanisms in disease progression. Hyperglycemia is a key driver of neuroinflammation in DR. Hyperglycemia results in VDAC1 O-GlcNAcylation in Müller glia, leading to mtDNA release and ZBP1 activation, thereby linking metabolic stress to neuroinflammation in DR. Targeting VDAC1-mediated mtDNA release or using vitreous mtDNA as a biomarker may enable earlier diagnosis and novel therapeutic strategies for DR.