Ellagic acid alleviates the progression of atherosclerosis in rats by inhibiting oxidative damage in endothelial cells

The objective of this research was to examine the protective effects of ellagic acid (EA) against diabetes-induced atherosclerosis in rats and oxidative damage in vascular endothelial cells. In Type 2 diabetic rats induced by high-fat diet and streptozotocin (STZ), a four-week EA treatment noticeably reduced serum lipid deposition, improved oxidative stress indicators, alleviated aortic endothelial atherosclerosis, and restored the diversity and the composition of the gut microbiota. Correlation analysis demonstrated significant associations among oxidative damage markers and gut microbiota influenced by EA. RNA sequencing in EA-treated human umbilical vein endothelial cells (HUVECs) and network pharmacology identified NAD( P )H dehydrogenase quinone 1 (NQO1), heme oxygenase-1 (HO-1 ) , and superoxide dismutase-2 (SOD2) as potential key antioxidant genes. Furthermore, experiments in a high-glucose or hydrogen peroxide (H 2 O 2 )-induced oxidative damage model in HUVECs confirmed that EA significantly enhanced cellular vitality, reduced cellular oxidative damage, and upregulated NQO1, HO-1, and SOD2 expression at both gene and protein levels. In summary, these findings demonstrate that EA mitigates diabetic atherosclerosis by enhancing endothelial antioxidant capacity and modulating gut microbiota. • Ellagic acid (EA) alleviates diabetes-induced atherosclerosis and oxidative stress in rats. • EA improves lipid deposition, aortic endothelial lesions, and modulates gut microbiota composition. • NQO1, HO-1, and SOD2 were identified as key targets of EA via antioxidative mechanisms. • EA enhances viability and reduces oxidative damage in oxidative damage HUVECs.