An N-glycosidic polysaccharide–peptide complex CMPS-80 was obtained from the fruiting body of C. militaris. Of importance, CMPS-80 significantly ameliorated formation of atherosclerotic lesions and plasma lipid profiles in apolipoprotein E-deficient mice. Integrated informatics analysis suggested that CMPS-80 can modulate multiple lncRNA–microRNA–mRNA axes. CMPS-80 has a potential application for prevention of hyperlipidemia and atherosclerosis.