CYP2C18-EETs-mediated arachidonic acid metabolism results in ferroptosis in arsenic-induced hepatic insulin resistance

Arsenic is an environmental pollutant that threatens public health and is significantly correlated with the risk of developing type 2 diabetes (T2D). Sodium arsenate (NaAsO₂) exposure can cause lipid peroxidation, leading to hepatic insulin resistance (IR) and ferroptosis. However, the specific mechanism remains unclear. We performed an oxidative lipidomics analysis of liver tissue from rats with NaAsO₂-induced IR by mass spectrometry. Differential enrichment most often involved arachidonic acid (AA) metabolites. However, whether CYP450-epoxyeicosatrienoic acid (EET)-mediated AA metabolism influenced arsenic-induced ferroptosis and hepatic IR remains unknown. We found that NaAsO₂ inhibited CYP2C18-EET-mediated AA metabolism that led to an increase of reactive oxygen species (ROS) that promoted ferroptosis. In addition, CYP2C18 and EETs reversed NaAsO₂-impaired hepatic insulin sensitivity. In conclusion, NaAsO₂ suppressed CYP2C18-EETs mediated AA metabolism and induced ferroptosis in rats with hepatic IR. The study results increase our understanding of potential targets for the prevention and treatment of diabetes.