Ferroptosis is a nonapoptotic form of regulated cell death that has been reported to play a central role in cardiac ischemia‒reperfusion (I/R) injury. N-acetyltransferase 10 (NAT10) contributes to cardiomyocyte apoptosis by functioning as an RNA ac4c acetyltransferase, but its role in cardiomyocyte ferroptosis during I/R injury has not been determined. This study aimed to elucidate the role of NAT10 in cardiac ferroptosis as well as the underlying mechanism. The mRNA and protein levels of NAT10 were increased in mouse hearts after I/R and in cardiomyocytes that were exposed to hypoxia/reoxygenation. P53 acted as an endogenous activator of NAT10 during I/R in a transcription-dependent manner. Cardiac overexpression of NAT10 caused cardiomyocyte ferroptosis to exacerbate I/R injury, while cardiomyocyte-specific knockout of NAT10 or pharmacological inhibition of NAT10 with Remodelin had the opposite effects. The inhibition of cardiomyocyte ferroptosis by Fer-1 exerted superior cardioprotective effects against the NAT10-induced exacerbation of post-I/R cardiac damage than the inhibition of apoptosis by emricasan. Mechanistically, NAT10 induced the ac4C modification of Mybbp1a, increasing its stability, which in turn activated p53 and subsequently repressed the transcription of the anti-ferroptotic gene SLC7A11. Moreover, knockdown of Mybbp1a partially abolished the detrimental effects of NAT10 overexpression on cardiomyocyte ferroptosis and cardiac I/R injury. Collectively, our study revealed that p53 and NAT10 interdependently cooperate to form a positive feedback loop that promotes cardiomyocyte ferroptosis to exacerbate cardiac I/R injury, suggesting that targeting the NAT10/Mybbp1a/p53 axis may be a novel approach for treating cardiac I/R.

中文翻译：

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NAT10/Mybbp1a/p53轴的正反馈环促进心肌细胞铁死亡，加剧心脏I/R损伤


铁死亡是一种非凋亡形式的调节性细胞死亡，据报道在心脏缺血再灌注（I/R）损伤中发挥核心作用。 N-乙酰转移酶 10 (NAT10) 通过作为 RNA ac4c 乙酰转移酶发挥作用，促进心肌细胞凋亡，但其在 I/R 损伤期间心肌细胞铁死亡中的作用尚未确定。本研究旨在阐明NAT10在心脏铁死亡中的作用及其潜在机制。缺血再灌注后的小鼠心脏以及暴露于缺氧/复氧的心肌细胞中 NAT10 的 mRNA 和蛋白质水平增加。 P53 在 I/R 过程中以转录依赖性方式充当 NAT10 的内源激活剂。心脏过度表达NAT10会导致心肌细胞铁死亡，加剧I/R损伤，而心肌细胞特异性敲除NAT10或用Remodelin药理抑制NAT10则产生相反的效果。与 emricasan 抑制细胞凋亡相比，Fer-1 抑制心肌细胞铁死亡对 NAT10 诱导的 I/R 后心脏损伤恶化具有更好的心脏保护作用。从机制上讲，NAT10 诱导 Mybbp1a 的 ac4C 修饰，增加其稳定性，进而激活 p53，随后抑制抗铁死亡基因 SLC7A11 的转录。此外，Mybbp1a 的敲低部分消除了 NAT10 过度表达对心肌细胞铁死亡和心脏 I/R 损伤的不利影响。总的来说，我们的研究表明，p53 和 NAT10 相互依赖地合作形成正反馈环，促进心肌细胞铁死亡，加剧心脏 I/R 损伤，这表明靶向 NAT10/Mybbp1a/p53 轴可能是治疗心脏 I/R 的新方法。