6-Gingerol Inhibits Ferroptosis in Endothelial Cells in Atherosclerosis by Activating the NRF2/HO-1 Pathway.

Targeting endothelial cell ferroptosis is a potential approach for the treatment of atherosclerosis (AS). 6-Gingerol (6-Gin) is an active substance in ginger that is beneficial for improving AS. We conducted this study to explore whether 6-Gin mediated AS progression by regulating ferroptosis of endothelial cells. ApoE-/- mice were fed a high-fat diet to establish AS mouse model. Additionally, oxidized low-density lipoprotein (ox-LDL) was used to treat human umbilical vein endothelial cells (HUVECs) to generate injured cell model. Ferroptosis was evaluated by propidium iodide staining assay, western blot, and detecting iron, glutathione, malonaldehyde, and reactive oxygen species levels. The results showed that ox-LDL inhibited the proliferation and induced inflammation and ferroptosis of HUVECs, which was reversed by 6-Gin treatment. Moreover, 6-Gin upregulated HO-1 and NQO1 levels and promoted nuclear translocation of NRF2 in ox-LDL-treated HUVECs. ATRA, an NRF2 inhibitor, abrogated the promotion of proliferation and the inhibition of inflammation and ferroptosis induced by 6-Gin. Additionally, 6-Gin alleviated AS and suppressed ferroptosis in vivo. In conclusion, 6-Gin inhibited endothelial cell ferroptosis by inactivating the NRF2/HO-1 pathway, thereby improving abnormal lipid metabolism in AS mice. These findings suggest that 6-Gin may be a novel therapeutic drug for AS.