Lentinan-induced FUBP1 O-GlcNAcylation suppresses macrophage ferroptosis and atherosclerosis via the Tp53/SLC7A11 axis.

Abstract

Atherosclerosis remains a leading cause of cardiovascular mortality, driven by macrophage dysfunction and necrotic core expansion. Ferroptosis, an iron-dependent cell death, is a critical driver of plaque instability; however, pharmacological interventions targeting ferroptosis remain scarce. Lentinan (LNT), a bioactive β-(1,3)-glucan extracted from shiitake mushrooms, exhibits potent antioxidant properties but its potential role in the modulation of macrophage ferroptosis remains unexplored. We investigated the therapeutic potential and molecular mechanisms of action of LNT in atherosclerosis. LNT administration significantly attenuated atherosclerotic progression in mice. Specifically, LNT mitigated macrophage ferroptosis by enhancing glutathione homeostasis and reducing lipid peroxidation. Notably, these protective effects were significantly abrogated in mice deficient in solute carrier family 7 member 11 (SLC7A11), indicating that the effect of LNT is dependent on this molecule. We found that LNT directly binds to far upstream binding protein 1 (FUBP1) and that T559 is required for FUBP1 O-GlcNAcylation and subsequent nuclear translocation. In the nucleus, FUBP1 binds to tumor protein p53 (Tp53), thereby relieving the transcriptional repression of SLC7A11. The resulting activation of the SLC7A11 signaling axis not only inhibits ferroptosis but also promotes scavenger receptor B type 1 (SR-B1)-mediated cholesterol efflux. These findings highlight LNT as a novel modulator of the FUBP1/Tp53/SLC7A11 axis, offering a promising natural therapeutic strategy to stabilize atherosclerotic plaques.