OGT-mediated O-GlcNAcylation of MAGI1 exacerbates high glucose-triggered inflammation and dedifferentiation of vascular smooth muscle cells by activating the PI3K/AKT pathway.

BACKGROUND: Vasculopathy is a vital complication of diabetes mellitus (DM), and the dysfunction of vascular smooth muscle cells (VSMCs) is a central event in its pathogenesis. O-GlcNAc transferase (OGT), the enzyme catalyzing O-GlcNAcylation, is implicated in diabetic complications, yet its specific role in VSMC dysfunction remains poorly defined. This study aimed to elucidate the function of OGT and its downstream signaling in high glucose (HG)-induced VSMC injury. METHODS: A cellular model of DM was established by treating human VSMCs with HG. Expression analysis was performed by RT-qPCR and western blot, respectively. Cell viability, proliferation, and migration/invasion were assessed using CCK-8, EdU, and transwell assays. Inflammatory cytokine secretion was measured by ELISA. A diabetic mouse model was established by streptozotocin (STZ) to validate the in vivo relevance. RESULTS: Membrane-associated guanylate kinase with an inverted domain structure-1 (MAGI1) was up-regulated in DM patients and HG-induced VSMCs. Functionally, MAGI1 knockdown attenuated HG-induced VSMC dysfunction, suppressing proliferation, migration, invasion, inflammatory response, and dedifferentiation. Conversely, MAGI1 overexpression exacerbated these pathological phenotypes. Mechanistically, MAGI1 activated the PI3K/AKT signaling pathway in HG-induced VSMCs. Moreover, OGT mediated the O-GlcNAcylation and stability of MAGI1. Knockdown of OGT alleviated HG-induced VSMC dysfunction and inhibited the PI3K/AKT pathway by reducing MAGI1 expression. In vivo, OGT deficiency ameliorated kidney injury and systemic inflammation in STZ-induced diabetic mice. CONCLUSION: This study demonstrates that OGT promotes MAGI1 expression through O-GlcNAc modification to drive VSMC dysfunction. This study not only delineates a previously unrecognized mechanism but also identifies the OGT/MAGI1 axis as a potential therapeutic target for preventing vascular complications in diabetes. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s41065-026-00643-4.