IDH2 deficiency enhances ferroptosis-induced vascular inflammation and remodeling in diabetes

Endothelial dysfunction is a central feature of vascular complications in type 2 diabetes mellitus (T2DM). Given that ferroptosis contributes to endothelial injury in metabolic disorders, we investigated the role of isocitrate dehydrogenase 2 (IDH2) in regulating endothelial ferroptosis under diabetic conditions. In endothelial cells, combined high glucose and palmitate (HGHL) treatment induced ferroptosis by decreasing the protein expression of both the key antioxidant enzyme GPX4 and IDH2. Mechanistically, the HGHL- or IDH2 deficiency-induced reduction in GPX4 expression was found to be markedly restored by the presence of isopentenyl pyrophosphate (IPP), suggesting that downregulation of the mevalonate pathway is linked to impaired GPX4 translation. IDH2 overexpression mitigated HGHL-induced ferroptosis, restored GPX4 levels, and suppressed the expression of inflammatory/adhesion molecules and mitochondrial ROS. In vivo, T2DM mouse aortas showed increased ferroptosis markers and decreased endothelial GPX4/IDH2. Significantly, endothelial-specific deletion of IDH2 further exacerbated vascular injury, increasing ferroptosis markers, aortic wall thickness, and pro-fibrotic/inflammatory mediators. In conclusion, IDH2 modulates endothelial ferroptosis through redox regulation and GPX4 expression. IDH2 deficiency is a major contributor to diabetic vascular pathology. Therefore, targeting IDH2 presents a novel and promising therapeutic strategy for preventing diabetic vascular complications.