SREBP‐1‐mediated lipogenesis confers resistance to ferroptosis and improves endothelial injury

Abstract Atherosclerosis refers to a disease characterized by the formation of lipid plaque deposits within arterial walls, leading to reduced blood flow or blockage of blood outflow. The process of endothelial injury induced by oxidized low‐density lipoprotein (ox‐LDL) is considered the initial stage of atherosclerosis. Ferroptosis is a form of iron‐dependent, non‐apoptotic cell death, and current research suggests its association with coronary artery disease (CAD). In this study, we observed a correlation between reduced expression of SREBP‐1 and the occurrence of stable CAD. Additionally, during the process of endothelial injury induced by ox‐LDL, we also noted decreased expression of the SREBP‐1/SCD1/FADS2 and involvement in the ferroptosis process. Mechanistically, ox‐LDL induced endothelial injury by inhibiting the lipid biosynthesis process mediated by the SREBP‐1/SCD1/FADS2, thereby inducing lipid peroxidation and ferroptosis. On the contrary, overexpression of SREBP‐1 or supplementation with monounsaturated fatty acids counteracted iron accumulation, mitochondrial damage, and lipid peroxidation‐induced ferroptosis, thereby improving endothelial injury. Our study indicated that the decreased expression of peripheral blood SREBP‐1 mRNA is an independent risk factor for stable CAD. Furthermore, in endothelial cells, the lipid biosynthesis process mediated by SREBP‐1 could ameliorate endothelial injury by resisting ferroptosis. The study has been registered with the Chinese Clinical Trial Registry, which serves as a primary registry in the World Health Organization International Clinical Trials Registry Platform (ChiCTR2300074315, August 3rd, 2023).