Abstract Body: Lipid peroxidation is an emerging driver of many vascular diseases, as evidenced by its role in promoting inflammation and impairing vascular integrity. However, the molecular mechanisms underlying pathogenesis are too complex to identify a clear intervention target. The recent discovery of ferroptosis highlights lipid peroxidation-promoted cell death and inflammation in metabolic diseases. The end products of ferroptosis, 4-hydroxynonenal (4-HNE), promote oxidative DNA damage. We developed an algorithm (FerroEnrich) to calculate the ferroptosis index and identify the predominant regulator of pathogenesis in various metabolic diseases. As a result, we identified the enriched ferroptosis pathway and NgBR as a predominant ferroptosis regulator in diabetic endothelial cells. We assessed the hypothesis that NgBR is essential for suppressing ferroptosis. As a cell surface protein, NgBR interacts with solute carrier family 7 member 11 (SLC7A11), a key regulator of ferroptosis, as shown by our proteomics studies. SLC7A11 (also commonly known as xCT) is a functional subunit of the cystine/glutamine antiporter (system Xc) that regulates ferroptosis. Previous studies suggested that SLC7A11, located at the plasma membrane, imports cysteine for glutathione (GSH) biosynthesis, a critical antioxidant that prevents lipid peroxidation and ferroptosis. Our preliminary data show that NgBR is required for proper localization of SLC7A11 at the plasma membrane; without NgBR, SLC7A11 is degraded in the cytoplasm, leading to impaired GSH biosynthesis and increased ferroptosis. Loss of NgBR expression in response to a hyperglycemia challenge is responsible for impaired vascular resilience in diabetic mouse models. We determined the impact of NgBR loss on vascular integrity and the pathogenesis of acute lung injury in diabetic mouse models. Interestingly, we also found that hyperglycemia-induced DNA methylation is responsible for NgBR loss and that a DNA methylation inhibitor or NgBR overexpression can mitigate vascular injury in diabetic mice. Furthermore, we developed epigenetic intervention strategies to restore NgBR and SLC7A11 expression and to suppress lipid peroxidation-promoted ferroptosis and vascular injury. In conclusion, our findings demonstrate that NgBR is a resilience factor that protects against lipid peroxidation-induced vascular injury by suppressing ferroptosis.