<b>VDAC1 O-GlcNAcylation promotes mtDNA release and activates ZBP1-dependent neuroinflammation in diabetic retinopathy</b>

<jats:p>&lt;p dir="ltr"&gt;Diabetic retinopathy (DR) is a major cause of vision loss in working-age adults with diabetes. Increasing evidence implicates that neuroinflammation is a vital element in the disease process of DR, yet the molecular mechanisms by which neuroinflammation activation occurs have not been fully understood. This study shows that elevated glucose levels enhance O-GlcNAcylation of voltage-dependent anion channel 1 (VDAC1) at threonine 165 (T165). This modification promotes VDAC1 oligomerization, facilitating cytosolic translocation of mtDNA. The cytosolic mtDNA activates Z-DNA binding protein 1 (ZBP1), leading to its activation and subsequent inflammatory responses. Importantly, mtDNA levels in the vitreous fluid from DR patients were higher, and mtDNA levels were positively correlated with the retinal thickness and negatively correlated with visual acuity. Taken together, our findings reveal a hyperglycemia-driven signaling axis in Müller cells that couples metabolic dysregulation with neuroinflammation, offering mechanistic insights and therapeutic opportunities for DR.&lt;/p&gt;</jats:p>