Chen Xinhui, Xu Qingling, Ding Wei, Wang Yu, Wang Puhan, Zhao Chunyige, Ao Xiang, Wang Jianxun
School of Basic Medicine, Qingdao University, Qingdao, China.
The Affiliated Hospital of Qingdao University, Qingdao Medical College, Qingdao University, Qingdao, China.
J Cardiovasc Transl Res. 2025 Jul 1. doi: 10.1007/s12265-025-10657-4.
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.
心肌梗死（MI）仍然是主要的死亡原因，尽管再灌注治疗对于挽救心肌至关重要，但它常常导致缺血-再灌注（I/R）损伤，这在很大程度上导致了心肌细胞坏死。虽然心肌细胞坏死的机制尚不清楚，但我们确定ACSS2是心肌I/R损伤中的关键调节因子。在氧化应激和I/R条件下，ACSS2表达上调。敲低ACSS2可减少坏死，而过表达则会加重坏死。从机制上讲，ACSS2的核转位增强了组蛋白H3赖氨酸9（H3K9）的乙酰化并激活了与坏死相关的基因。在体内，沉默ACSS2可减轻心肌损伤并改善心脏功能。这些发现表明，ACSS2通过核乙酰辅酶A的产生和表观遗传调控促进坏死，为I/R损伤提供了一个潜在的治疗靶点。
