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.