METTL14-dependent m 6 A modification restrains interferon signaling to prevent myocarditis and dilated Cardiomyopathy

Abstract The impact of inflammation on heart failure is increasingly recognized; but how cardiomyocyte restrains innate immune activation remains poorly defined, and nor does the role of N⁶-methyladenosine (m⁶A) modification in maintaining cardiac immune homeostasis. Here, we demonstrate that cardiomyocyte-specific deletion of the m⁶A methyltransferase METTL14 triggers myocarditis, dilated cardiomyopathy, and premature lethality. Meanwhile, widespread hypomethylation and upregulation of innate immune and necroptosis-related transcripts in Mettl14-deficient hearts exemplified by IFN-1 and STAT1. Mechanistically, METTL14 deficiency promotes RIPK1 accumulation thereby priming cardiomyocytes for necroptosis and inflammatory cell death. Genetic ablation of IFN-I receptor Ifnar1 can largely rescue the processes and improve cardiac function and survival. Furthermore, METTL14 loss disrupts mitochondrial integrity and autophagy/mitophagy flux, suggesting mitochondrial dysfunction–driven innate immune activation upstream of IFN-I signaling. Collectively, these findings identify METTL14-mediated m⁶A modification as a critical safeguard against cardiomyocyte-intrinsic IFN-I signaling and necroptosis and establish an epitranscriptomic–innate immune axis that drives inflammatory heart failure. Competing Interest Statement The authors have declared no competing interest.