Here, we found that treatment of apolipoprotein A (ApoE) knockout (ApoE−/−) mice with HSYA markedly ameliorated atherosclerosis evidenced by decreased levels of lipids, sphingosine‐1‐phosphate (S1P), inflammatory factors, oxidative stress, vascular endothelial permeability, and endothelial damage. Here, APOE is linked to atherosclerosis.