Abstract

Diabetic retinopathy (DR), a leading cause of blindness, is driven by pathological angiogenesis and vascular leakage, but the underlying epigenetic mechanisms remain poorly defined. Here, we identify the histone demethylase KDM6A as a critical epigenetic regulator promoting DR pathogenesis via Müller cells. KDM6A expression is significantly elevated in human DR retinas and diabetic mouse models. Intravitreal silencing of Kdm6a ameliorates retinal vascular dysfunction, reducing neovascularization, leakage, and acellular capillaries while restoring endothelial tight junctions. Single-cell RNA sequencing revealed that Kdm6a knockdown specifically suppresses VEGF signaling and attenuates ferroptosis. Müller cell-specific Kdm6a overexpression exacerbated DR vascular pathology, while in vitro co-cultures confirmed that KDM6A in Müller cells induces endothelial dysfunction. Mechanistically, KDM6A demethylates H3K27me3 at the promoters of pro-ferroptotic genes (e.g., Tfr1 , Cybb , Atg7 ), thereby promoting ferroptosis in Müller cells under high glucose conditions. Crucially, pharmacological or genetic inhibition of KDM6A mitigated high glucose-induced ferroptosis. Our findings establish KDM6A-mediated epigenetic control of Müller cell ferroptosis as a fundamental regulator of diabetic retinal vasculopathy and nominate KDM6A as a promising therapeutic target for DR. The alternative text for this image may have been generated using AI.