In conclusion, we reported that Ash2l was a new regulator of endothelial injury and atherosclerosis, which was supported by two evidence chains: (1) Ash2l-PPARγ-SRs signaling axis drived oxidation lipid uptake by ECs; (2) CD36/TLR4-NF-κB signal axis activated ECs to produce a large number of inflammatory mediators, suggesting Ash2l might be an attractive therapeutic target for anti-atherosclerosis. This evidence concerns the gene TLR4 and atherosclerosis.