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.