MYC promotes myocardial fibrosis via METTL1-mediated m7G modification of HILPDA.

backgroundPost-infarction myocardial fibrosis is a pivotal pathological process leading to heart failure; however, its epitranscriptional regulatory mechanisms remain poorly defined. The role of the MYC-METTL1-HILPDA axis in this process remains unexplored.

methodsMyocardial infarction (MI) models were established in mice, and hypoxia-induced mouse cardiac fibroblasts were used. A range of molecular techniques, including qRT-PCR, Western blot, immunohistochemistry, RNA immunoprecipitation, chromatin immunoprecipitation, and dual-luciferase reporter assays, were employed to investigate the MYC-METTL1-HILPDA axis.

resultsFollowing MI, METTL1 and HILPDA were significantly upregulated in cardiac tissue. METTL1 stabilized HILPDA mRNA via m7G modification, thereby enhancing its protein expression. Functional studies demonstrated that HILPDA overexpression induced mitochondrial dysfunction and fibroblast activation, whereas HILPDA knockdown attenuated these effects. Furthermore, the transcription factor MYC was identified as an upstream regulator that directly binds the METTL1 promoter to activate its transcription. Crucially, HILPDA knockdown improved cardiac function, attenuated fibrosis, and reduced infarct size in mice.

conclusionThis study identifies the MYC-METTL1-HILPDA axis as a novel driver of post-infarction myocardial fibrosis, which promotes mitochondrial dysfunction and fibroblast activation through m7G-mediated stabilization of HILPDA mRNA. These findings provide new mechanistic insights and reveal potential therapeutic targets for preventing heart failure.