RBM15 promotes hyperglycemia-induced retinal endothelial cell injury by regulating FOXO3 stability via m6A modification.

Diabetic retinopathy (DR), a common microvascular complication of diabetes mellitus, is a leading cause of vision loss among working-age adults. Although N6-methyladenosine (m6A), a prevalent post-transcriptional mRNA modification, is emerging as a key regulator in DR, the specific role of the m6A writer RBM15 in hyperglycemia-induced retinal endothelial cell injury remains poorly defined. Here, we found that RBM15 is upregulated in the retinas of diabetic mice as well as in endothelial cells (ECs) challenged with high glucose (HG). Knockdown of RBM15 significantly mitigated HG-induced apoptosis and rescued autophagy deficiency in retinal ECs. In vivo, downregulation of RBM15 effectively attenuated retinal thinning, acellular capillary formation, and vascular leakage in diabetic mice. Mechanistically, we demonstrated that RBM15 regulates HG-induced apoptosis and autophagy deficiency in ECs by modulating FOXO3 mRNA stability in an m6A-dependent manner. In conclusion, our findings identify the RBM15/m6A/FOXO3 signaling pathway as a critical regulator of HG-induced retinal microvascular dysfunction and highlight RBM15 as a potential therapeutic target for the treatment of DR.