3.1.2 Ferroptosis is involved in AS foam cell formation and death and promotes plaque formation
HIF-1α, an upregulated DEG between atherosclerosis and normal, co-regulates autophagy and ferroptosis. HIF-1α inhibitor PX-478 attenuates foam cell formation and lessens atherosclerosis by enhancing autophagy and depressing ferroptosis in macrophages64. Nuclear factor NF-E2-related factor (Nrf2) has been considered as a major regulator of antioxidant in previous studies, which can mediate the transcriptional regulation of multiple target genes and play a key role in regulating ferroptosis. It was found that by inducing a macrophage autophagy defect model, the Nrf2-mediated antioxidant defense was turned off, while the negative effects of Nrf2 manipulation were initiated, leading to iron deposition and lipid peroxidation, and finally ferroptosis of foam cells65. It has also been shown that a high level of uric acid-induced iron death in macrophages is involved in the formation of atherosclerotic plaques. More importantly, inhibition of ferroptosis by activation of Nrf2 may attenuate atherosclerosis induced by high levels of uric acid5. In conclusion, ferroptosis is not only involved in inducing the formation and death of foam cells in AS but also in promoting the formation of AS plaques. At the same time, the regulation of the Nrf2 pathway may be an important mechanism of ferroptosis resistance in AS.