SGK1 contributes to endothelial cell ferroptosis in coronary heart disease through the NEDD4L/NF-κB pathway

The prevalence of coronary heart disease (CHD) has increased significantly with the aging population worldwide. It is unclear whether ferroptosis occurs during CHD. Hence, we aimed to investigate the potential mechanisms associated with ferroptosis in CHD. Bioinformatics was used to characterize differentially expressed genes (DEGs) in CHD-related datasets (GSE21610 and GSE66360), and enrichment analysis was performed via protein‒protein interaction (PPI) network analysis. Proteins that interact with SGK1 as predicted by the String database. Flow cytometry and western blot analysis revealed alterations in lipid peroxidation, Fe accumulation, and ferroptosis-related marker expression in MAECs following lentivirus-mediated modulation of SGK1 and NEDD4L expression. A total of 76 and 689 DEGs were involved in pathways associated with immune and inflammatory responses, respectively. DDX3Y, EIF1AY, KDM5D, RPS4Y1, SGK1, USP9Y, and NSG1 showed intersecting DEGs. The differences in the number of circulating endothelial cells (ECs) between healthy individuals and CHD patients are consistent with the results of bioinformatics analysis. SGK1 may interact with NEDD4L and promote NEDD4L and p-P65 expression in MAECs according to the String database. Additionally, SGK1 knockdown alleviated the Erastin-induced downregulation of SLC7A11, GPX4, GSH, and GSSG, as well as the upregulation of lipid peroxidation, Fe accumulation, p-P65 expression, and mitochondrial damage. NEDD4L and PMA (NF-κB pathway activator) were rescued with overexpression. SGK1 contributes to EC ferroptosis by regulating the NEDD4L-NF-κB pathway. SGK1 could be recognized as a therapeutic target related to ferroptosis in CHD.