ACSS2 promotes macrophage senescence and atherosclerosis by upregulating histone H3 lysine 9 crotonylation

Atherosclerosis (AS) is an aging-related chronic inflammatory disease. Histone lysine crotonylation (Kcr) is a posttranslational modification, which is widespread as acetylation; however, its roles are largely unknown in senescent macrophage of atherosclerosis. In this study, we report that histone Kcr of macrophages is abnormally elevated in atherosclerosis. Here, we show that ACSS2 (acyl-CoA synthetase short chain family member 2) is identified to increase the histone 3 lysine 9 crotonylation (H3K9cr) level in macrophages. Mechanistically, under pathological stimuli, the elevated ACSS2 increases H3K9cr expression, which enriches at the promoter of senescence-associated secretory phenotype genes, driving senescence and atherosclerosis. Functional analysis demonstrates that ACSS2 knockdown inhibits atherosclerosis in male mice by decreasing H3K9cr expression. We also verify the ACSS2 specific inhibitor, VY-3-135, as a potentially promising therapeutic agent for alleviating atherosclerosis. Furthermore, increased ACSS2 and H3K9cr correlate with senescence in human atherosclerotic lesions. Collectively, our work lays foundation for understanding the macrophage senescence mediated by Kcr and provides a potential therapeutic target for AS.