What question did this study set out to answer?

This study aims to determine the protective role of IDH2 against ferroptosis in endothelial cells triggered by diabetes.

June 3, 2026

Protective Effect of Idh2 Against Diabetes-Induced Ferroptosis in Vascular Endothelial Cells

Key Points

This study aims to determine the protective role of IDH2 against ferroptosis in endothelial cells triggered by diabetes.
Human umbilical vein endothelial cells (HUVECs) were exposed to high glucose and high lipid (HGHL) conditions to induce ferroptosis.
IDH2 expression was modified using siRNA knockdown or plasmid overexpression to study its effects on cell viability and ROS levels.
Animal models of type 2 diabetes and IDH2 knockout mice were utilized to assess vascular injury and ferroptosis-related markers.
HGHL exposure significantly reduced cell viability (p<0.01), increased lipid ROS and malondialdehyde (MDA) levels, and decreased GPX4 protein expression.
IDH2 overexpression restored antioxidant balance and GPX4 expression, while knockdown led to a ferroptotic phenotype.
In diabetic mice, reduced endothelial IDH2 levels correlated with elevated aortic ferroptosis markers and worsened vascular injury.

Abstract

Objective: Endothelial cell injury plays a critical role in vascular complications of type 2 diabetes mellitus (T2DM). Recent evidence suggests that ferroptosis, an iron-dependent form of regulated cell death, contributes to endothelial dysfunction in diabetic conditions. This study aimed to investigate whether isocitrate dehydrogenase 2 (IDH2), a mitochondrial NADPH-producing enzyme, protects against diabetes-induced ferroptosis in endothelial cells and to elucidate the underlying mechanisms.Design and method: Human umbilical vein endothelial cells (HUVECs) were exposed to high glucose and high lipid (HGHL) conditions to induce ferroptosis. IDH2 expression was modulated using siRNA knockdown or plasmid-mediated overexpression. Cell viability, GSH/GSSG and NADP+/NADPH ratios, lipid reactive oxygen species (ROS), malondialdehyde (MDA), iron content, and GPX4 protein levels were evaluated. In vivo, type 2 diabetic mouse models and endothelial cell-specific IDH2 knockout (IDH2-EKO) mice were used to assess aortic ferroptosis markers and vascular injury. Results: HGHL exposure led to reduced cell viability, increased lipid ROS, MDA, and iron accumulation, and downregulation of GPX4 protein in HUVECs. IDH2 expression and enzymatic activity were significantly reduced under HGHL conditions, with concomitant disruption of redox homeostasis. IDH2 knockdown mimicked the ferroptotic phenotype, whereas IDH2 overexpression restored antioxidant balance and increased GPX4 expression. In diabetic mice, endothelial IDH2 expression was reduced, and aortic ferroptosis markers were elevated. Endothelial-specific deletion of IDH2 exacerbated vascular injury, increased medial thickness, and elevated pro-fibrotic and inflammatory markers. Conclusions: IDH2 protects endothelial cells from diabetes-induced ferroptosis by maintaining NADPH-dependent redox balance and supporting GPX4 expression. These findings highlight the therapeutic potential of targeting IDH2 to prevent or mitigate vascular complications in T2DM.

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