Acetyl-CoA Short-Chain Synthetase-2 Regulates Myocardial Ischemia/Reperfusion Injury by Targeting Histone Acetylation.

Myocardial infarction (MI) remains a leading cause of mortality, and although reperfusion therapy is essential for myocardial salvage, it often results in ischemia-reperfusion (I/R) injury, which contributes substantially to cardiomyocyte necrosis. Although the mechanisms of cardiomyocyte necrosis remain unclear, we identified ACSS2 as a key regulator in myocardial I/R injury. ACSS2 was upregulated under oxidative stress and I/R conditions. Its knockdown reduced necrosis, while overexpression aggravated it. Mechanistically, nuclear translocation of ACSS2 enhanced H3K9 acetylation and activated necrosis-related genes. In vivo, ACSS2 silencing alleviated myocardial injury and improved cardiac function. These findings reveal that ACSS2 promotes necrosis via nuclear acetyl-CoA production and epigenetic regulation, offering a potential therapeutic target for I/R injury.