N4-acetylcytidine-mediated SOAT1 upregulation aggravates heart failure by inducing NCOA4-dependent ferroautophagy and ferroptosis in cardiomyocytes.

Heart failure (HF) remains a critical global health challenge, with accumulating evidence implicating iron metabolism dysregulation through ferritinophagy activation in disease progression. Our study focused on sterol O-acyltransferase 1 (SOAT1), an established regulator of hypoxia-induced cardiomyocyte dysfunction, investigating its role in HF pathogenesis through ferritinophagy and ferroptosis regulation. Here, mouse HF models were generated via transverse aortic constriction (TAC), while primary cardiomyocyte injury was induced by isoproterenol (ISO) exposure. We demonstrated that SOAT1 knockdown alleviated pressure overload-induced left ventricular hypertrophy and enhanced systolic function in vivo, while attenuating ISO-induced cardiomyocyte death in vitro. Mechanistically, SOAT1 deficiency suppressed ferritinophagy-mediated ferroptosis by blocking autophagy-dependent ferritin degradation, consequently reducing intracellular iron accumulation and lipid peroxidation in both cardiac tissues and isolated cardiomyocytes. Molecular analyses revealed that SOAT1 enhanced NCOA4 protein stability through acetylation modification, while the RNA acetyltransferase NAT10 maintained SOAT1 expression via N4-acetylcytidine (ac4C)-dependent mRNA modification, enhancing transcript stability and translation. Crucially, NCOA4 overexpression reversed the cardioprotective effects of SOAT1 knockdown, and NAT10 silencing attenuated ISO-induced ferritinophagy and ferroptosis. Collectively, our findings establish that ac4C-modified SOAT1 exacerbates HF by acetylating NCOA4 and promoting NCOA4-dependent ferroautophagy and ferroptosis.