Abstract

Background Diabetic retinopathy (DR), a leading blinding microvascular complication of type 2 diabetes mellitus (T2DM), is projected to affect 161 million people globally by 2045. Methods This study enrolled 261 participants (127 T2DM controls and 134 T2DM with DR). Serum miR-501-5p levels were analyzed by qRT-PCR. Human Retinal Microvascular Endothelial Cells (HRMECs) under high-glucose conditions were transfected to modulate miR-501-5p expression or overexpress NR2F2 . The miR-501-5p– NR2F2 interaction was verified by dual-luciferase assay. Cell proliferation, VEGF, ROS, and endoplasmic reticulum stress markers (GRP78, CHOP) were assessed. Results miR-501-5p was identified as an independent protective factor for DR, showing significant downregulation in T2DM patients and high diagnostic accuracy (AUC = 0.907). In high-glucose conditions, miR-501-5p overexpression reduced VEGF, ROS, and ER stress markers and improved cell proliferation. NR2F2 was confirmed as a direct target of miR-501-5p, and its overexpression reversed the protective effects of miR-501-5p. Conclusion These findings suggest that miR-501-5p is strongly associated with DR and may serve as a potential biomarker and protective agent, possibly through targeting NR2F2 to ameliorate high glucose-induced retinal microvascular damage.