Diabetic cardiomyopathy (DCM) is a prevalent myocardial microvascular complication of the myocardium with a complex pathogenesis. Investigating the pathogenesis of DCM can significantly contribute to enhancing its prevention and treatment strategies. Our study revealed an upregulation of lysine acetyltransferase 2 A (Kat2a) expression in DCM, accompanied by a decrease in N6-methyladenosine (m6A) modified Kat2a mRNA levels. Our study revealed an upregulation of lysine acetyltransferase 2 A (Kat2a) expression in DCM, accompanied by a decrease in N6-methyladenosine (m6A) modified Kat2a mRNA levels. Functionally, inhibition of Kat2a effectively ameliorated high glucose-induced cardiomyocyte injury both in vitro and in vivo by suppressing ferroptosis. Mechanistically, Demethylase alkB homolog 5 (Alkbh5) was found to reduce m6A methylation levels on Kat2a mRNA, leading to its upregulation. YTH domain family 2 (Ythdf2) played a crucial role as an m6A reader protein mediating the degradation of Kat2a mRNA. Furthermore, Kat2a promoted ferroptosis by increasing Tfrc and Hmox1 expression via enhancing the enrichment of H3K27ac and H3K9ac on their promoter regions. In conclusion, our findings unveil a novel role for the Kat2a-ferroptosis axis in DCM pathogenesis, providing valuable insights for potential clinical interventions.

糖尿病心肌病（DCM）是一种常见的心肌微血管并发症，发病机制复杂。研究 DCM 的发病机制可以极大地有助于增强其预防和治疗策略。我们的研究揭示了 DCM 中赖氨酸乙酰转移酶 2 A (Kat2a) 表达的上调，同时伴随着 N6-甲基腺苷 (m6A) 修饰的 Kat2a mRNA 水平的降低。我们的研究揭示了 DCM 中赖氨酸乙酰转移酶 2 A (Kat2a) 表达的上调，同时伴随着 N6-甲基腺苷 (m6A) 修饰的 Kat2a mRNA 水平的降低。从功能上来说，抑制 Kat2a 可以通过抑制铁死亡，有效改善体外和体内高葡萄糖诱导的心肌细胞损伤。从机制上讲，去甲基化酶 alkB 同源物 5 (Alkbh5) 可降低 Kat2a mRNA 上的 m6A 甲基化水平，从而导致其上调。 YTH 结构域家族 2 (Ythdf2) 作为 m6A 读取蛋白在介导 Kat2a mRNA 降解中发挥着至关重要的作用。此外，Kat2a 通过增强 H3K27ac 和 H3K9ac 在其启动子区域的富集来增加 Tfrc 和 Hmox1 的表达，从而促进铁死亡。总之，我们的研究结果揭示了 Kat2a-铁死亡轴在 DCM 发病机制中的新作用，为潜在的临床干预提供了宝贵的见解。