MGAT5 regulates ferroptosis via the Nrf2/HO-1 signaling pathway in diabetic nephropathy

Diabetic nephropathy (DN) is a major complication of diabetes mellitus, and identifying effective therapeutic targets remains an urgent need. In this study, genes associated with DN were obtained from the gene expression omnibus (GEO) database, and Bioinformatics analysis revealed that mannosyl (alpha-1,6-)-glycoprotein beta-1,6-N-acetylglucosaminyltransferase (MGAT5) was downregulated in DN. Functional experiments demonstrated that MGAT5 overexpression activated the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway, enhanced DN-related cell viability, and reduced the levels of lactate dehydrogenase (LDH), cleaved caspase-3 (C-casp3), Bcl-2-associated X protein (Bax), interleukin-6 (IL-6), interleukin-1 beta (IL-1β), tumor necrosis factor-alpha (TNF-α), malondialdehyde (MDA), acyl-CoA synthetase long-chain family member 4 (ACSL4), prostaglandin-endoperoxide synthase 2/cyclooxygenase-2 (PTGS2/COX-2), Fe²⁺ content, ROS production, and apoptosis. Meanwhile, MGAT5 overexpression increased the levels of B-cell lymphoma 2 (Bcl-2), glutathione (GSH), and glutathione peroxidase 4 (GPX4). Conversely, MGAT5 knockdown partially reversed these protective effects. These findings suggest that MGAT5 may alleviate DN-associated cellular injury by activating the Nrf2/HO-1 pathway and regulating oxidative stress, inflammatory responses, ferroptosis, and apoptosis. MGAT5 may represent a potential therapeutic candidate for further investigation in diabetic nephropathy.