Lentinan Attenuates Experimental Atherosclerosis by Regulating Macrophage HCK/GUSB Expression and Amino Acid Metabolic Remodeling.

Atherosclerosis (AS) is a chronic inflammatory vascular disease characterized by lipid accumulation, immune activation, and plaque formation. This study investigated the anti-atherosclerotic effects of Lentinan (LNT) and explored its potential macrophage-associated mechanisms. In high-fat diet-fed ApoE⁻/⁻ mice, LNT markedly attenuated aortic plaque formation, lipid deposition, serum pro-inflammatory cytokine levels, and dyslipidemia, indicating a protective effect against AS progression. Integrated target screening and transcriptomic analyses identified HCK and GUSB as key candidate targets associated with the response to LNT. Both genes were upregulated in atherosclerotic tissues and were further assessed in an independent human dataset. Experimental validation in ApoE⁻/⁻ mouse aortic tissues showed that LNT reduced HCK and GUSB expression, while single-cell transcriptomic analysis indicated that both genes were predominantly enriched in macrophage populations within atherosclerotic lesions. In ox-LDL-induced RAW264.7 foam cells, LNT decreased intracellular lipid accumulation and downregulated HCK and GUSB expression, further supporting a macrophage-related protective mechanism. In addition, targeted metabolomic analysis suggested that LNT reshaped amino acid metabolism, which may contribute to improvement of the inflammatory and immunometabolic microenvironment in AS. Molecular docking and molecular dynamics simulations further indicated potential interactions between LNT and HCK/GUSB. Overall, these findings suggest that LNT attenuates experimental atherosclerosis by regulating macrophage-associated HCK/GUSB expression, suppressing foam cell formation, and modulating amino acid metabolic remodeling.