Inhibition of ferroptosis alleviates atherosclerosis and foam cell formation by regulating lipid metabolism via AMPK activation.

Atherosclerosis (AS) is a lipid disorder characterised by lipid accumulation in the aortic wall and foam cell formation. Recent studies have shown that excess iron accelerates AS progression and foam cell formation by inducing ferroptosis. GPx4, an anti-erroptotic protein, promotes SCARB1 expression, which inhibits macrophage foam cell formation by interacting with HDL. Thus, a complex association exists between ferroptosis and lipid metabolism. However, the underlying mechanisms remain unclear. AMPK signalling is a key regulator of metabolism and is involved in the regulation of ferroptosis. In this study, we used the ferroptosis inhibitor ferrostatin-1 (Fer-1) to assay the effect of ferroptosis inhibition on AS and foam cell formation and to investigate the underlying mechanism. Our results showed that Fer-1 alleviated AS lesions and foam cell formation both in vivo and in vitro. Additionally, Fer-1 reduced iron content and lipid accumulation in oxidized low-density lipoprotein (ox-LDL)-treated macrophages by upregulating the levels of FTH, GPx4, and SCARB1 via AMPK activation. The inhibition of AMPK reduces the effect of Fer-1 on iron and lipid accumulation in macrophages, which may contribute to a deeper understanding of the pathological process of AS and provide a therapeutic target for AS.