Neddylation-Mediated hnRNPA2B1 Degradation Aggravates Retinal Endothelial Cell Dysfunction in Diabetic Retinopathy by Regulating miR-93-5p/VEGFA

Purpose: Retinal endothelial cells (RECs) are key targets of diabetes-induced microvascular complications. HnRNPA2B1 suppresses pathological neovascularization in diabetic retinopathy (DR). Although hnRNPA2B1 suppresses pathological neovascularization, its role in hyperglycemia-induced REC dysfunction remains unclear. Methods: Primary mouse retinal vascular endothelial cells (mRVECs) under high-glucose (HG) conditions and streptozotocin-induced diabetic mice were analyzed using quantitative real-time PCR (qRT-PCR), Western blotting, RNA immunoprecipitation, immunofluorescence staining, and functional assays (wound healing, Transwell invasion, and tube formation). Co-immunoprecipitation and pharmacological inhibitors were used to validate protein interactions and degradation pathways. Retinal morphology and vascular integrity were assessed using hematoxylin-eosin staining, optical coherence tomography angiography, Evans blue leakage, and trypsin digestion. Results: HG-induced neddylation mediated hnRNPA2B1 degradation, exacerbating REC dysfunction. Mechanistically, hnRNPA2B1 facilitated miR-93-5p maturation by recruiting DGCR8 within the microprocessor complex, thereby suppressing VEGFA expression via direct targeting of its 3'-untranslated regions. Intravitreal delivery of AAV2-hnRNPA2B1 or miR-93-5p into diabetic mice partially restored retinal hnRNPA2B1/miR-93-5p levels, reduced VEGFA overexpression, and improved retinal histological markers of microvascular damage. Conclusions: HG-induced effects associated with neddylation pathways lead to hnRNPA2B1 degradation, exacerbating REC dysfunction. HnRNPA2B1, as an RNA binding protein, facilitated miR-93-5p maturation by recruiting DGCR8 within the microprocessor complex. Targeting either hnRNPA2B1 or miR-93-5p may represent a potential therapeutic strategy for preserving retinal vascular homeostasis in diabetes pending functional validation.