Fut8 regulated Unc5b hyperfucosylation reduces macrophage emigration and accelerates atherosclerosis development via the ferroptosis pathway.

The accumulation of foam cells in the arterial walls is a defining characteristic of atherosclerosis. Enhancing their migration from plaques may represent a key strategy for slowing disease progression. Recent studies suggest that fucosyltransferase 8 (Fut8) impairs macrophage migration from the intima by modifying the Unc5b membrane receptor, thereby influencing the development of atherosclerosis. This study investigated the roles of Fut8 and Unc5b in foam cell migration using ApoE-/- mouse and foam cell models, employing techniques such as western blotting, mitochondrial function assays, wound healing experiments, and immunofluorescence staining. The findings indicate that Fut8 upregulation increases P53 expression and reduces SLC7A11 and GPX4 levels, leading to altered intracellular concentrations of GSH and Fe2+, impaired mitochondrial function, and reduced migration capacity, all of which promote atherosclerosis. These mechanisms are closely associated with ferroptosis. Intervention with N-acetylcysteine (NAC) and buthionine sulfoximine (BSO) demonstrated that NAC mitigates oxidative stress and migration inhibition, induced by oxidized low-density lipoprotein (ox-LDL). Additionally, inhibiting ferroptosis slowed the progression of atherosclerosis in ApoE-/- mice. Together, these results highlight that Fut8 exacerbates atherosclerosis through a P53/SLC7A11-mediated enhancement of ferroptosis in foam cells, offering a novel perspective on the pathophysiology of atherosclerosis.