Protein O-GlcNAcylation coupled to Hippo signaling drives vascular dysfunction in diabetic retinopathy [9A]

Metabolic disorder is emerging as a crucial contributor to the pathogenesis of diabetic vascular complications including diabetic retinopathy (DR), the leading cause of blindness in the working-age population. Yet, the underlying molecular mechanisms of how the disturbed metabolic homeostasis contribute to vascular dysfunction in DR remain elusive. O-GlcNAcylation modification act as a nutrient sensor particularly sensitive to ambient glucose. Here, we observed pronounced O-GlcNAc elevation in retina endothelial cells (ECs) of DR patients and mouse models. Endothelial-specific depletion or pharmacological inhibition of O-GlcNAc transferase efficiently mitigated vascular dysfunctions. Mechanistically, we found that YAP/TAZ, key effectors of the Hippo pathway, are O-GlcNAcylated in DR. We identified Thr383 as an O-GlcNAc site on YAP, which inhibits its phosphorylation at Ser397, leading to its stabilization and activation. Consequently, highly activated YAP/TAZ, promotes vascular dysfunction by inducing a pro-angiogenic and glucose metabolic transcriptional program. These findings emphasize the critical role of O-GlcNAc-Hippo axis in DR pathogenesis and suggest its unique potential as a therapeutic target.