METTL3/YTHDC1 mediates up-regulation of lncRNA OGRU in an m6A-dependent manner involving in oxidative stress and inflammation of HG-induced Müller cells

•Up-regulation of m6A and METTL3 levels in DR.•LncRNA OGRU was stabilized by METTL3-mediated m6A with assistance of YTHDC1.•si-METTL3 inhibited HG-induced oxidative injury and inflammation in Müller cells.•si-METTL3-mediated protective action was abolished by OGRU overexpression. Diabetic retinopathy (DR) is a common complication of diabetes, which may cause visual disturbance and even loss of sight. Oxidative stress and inflammation are two crucial pathological factors of DR; however, their specific regulatory mechanisms in DR remain obscure. DR models were established in streptozotocin-challenged rats and high glucose (HG)-stimulated Müller cells. Western blotting and RT-qPCR were performed to determine target molecule levels. ROS release was evaluated by DCFH-DA staining, and the levels of MDA, GSH, SOD, and CAT were detected using commercial kits. The levels of proinflammatory factors (TNF-α, IL-1β, IL-6, MCP-1, and CXCL-1) were analyzed by RT-qPCR and ELISA. The subcellular localization of OGRU was observed by FISH. Molecular interaction was evaluated by RIP. M6A level was assessed by MeRIP and colorimetric quantification kit. HG stimulation or diabetic stress resulted in an elevation in the overall m6A level, as well as expression level of methyltransferase-like 3 (METTL3) in the experimental models of DR. M6A writer METTL3 stabilized lncRNA OGRU via m6A modification. Functionally, METTL3 deficiency relieved HG-induced oxidative stress damage and inflammation in Müller cells. Rescue assays demonstrated that OGRU overexpression reversed METTL3 silencing-mediated protection against HG-stimulated Müller cells. Furthermore, YTH Domain-Containing Protein 1 (YTHDC1) coordinated with METTL3 to enhance OGRU stability in an m6A-dependent manner. METTL3-mediated m6A modification stabilized OGRU with assistance of YTHDC1, which led to oxidative stress and inflammation during DR progression. Targeting METTL3/YTHDC1/OGRU axis might be a potential therapeutic strategy for DR. [Display omitted]