FGF21 inhibits atherosclerosis by reducing endothelial ferroptosis via activation of AMPK/Nrf2 signaling.

BACKGROUND: Atherosclerosis is a chronic vascular disease characterized by endothelial dysfunction and lipid accumulation. Ferroptosis, an iron-dependent form of regulated cell death characterized by excessive lipid peroxidation, plays a pivotal role in endothelial injury and the progression of atherosclerosis. Fibroblast growth factor 21 (FGF21) has been reported to protect against atherosclerosis; however, its role and underlying mechanisms in hypercholesterolemia-induced endothelial ferroptosis remain unclear. METHODS: FGF21 expression and ferroptosis were assessed in vascular endothelial cells from high-fat diet (HFD)-fed ApoE-/- mice and oxidized low-density lipoprotein (ox-LDL)-treated human umbilical vein endothelial cells (HUVECs). Endothelial dysfunction and ferroptosis were evaluated using western blotting, immunofluorescence staining, transmission electron microscopy, mitochondrial membrane potential analysis, and immunohistochemistry. RESULTS: FGF21 expression and ferroptosis were markedly increased in vascular endothelial cells from HFD-fed ApoE-/- mice and ox-LDL-treated HUVECs. Recombinant FGF21 significantly alleviated ox-LDL-induced endothelial dysfunction by inhibiting ferroptosis, with effects similar to those of the ferroptosis inhibitor ferrostatin-1. Mechanistically, FGF21 suppressed endothelial ferroptosis by activating the AMPK/Nrf2 signaling pathway. In vivo, FGF21 treatment markedly reduced atherosclerotic lesion formation and endothelial ferroptosis in HFD-fed ApoE-/-mice, accompanied by enhanced AMPK/Nrf2 signaling activity. CONCLUSION: FGF21 attenuates atherosclerotic progression, at least partially, by alleviating endothelial ferroptosis. AMPK/Nrf2 signaling pathway contributes to the protective effects of FGF21 against atherosclerosis.