<scp>FTO</scp> Regulates Autophagy and Energy Metabolism in Sepsis‐Induced Cardiomyopathy: Insights From Integrated Transcriptome and Proteome Analysis

ABSTRACT Sepsis‐induced cardiomyopathy (SCM) is a severe complication of sepsis, characterized by profound cardiac dysfunction and high mortality, but its molecular mechanisms remain poorly defined. RNA epigenetic regulation, particularly by the m 6 A demethylase FTO, has been implicated in cardiovascular disease, yet its role in SCM is unclear. This study aimed to elucidate the function of FTO in SCM by integrating transcriptomic and proteomic analyses. A cecal ligation and puncture (CLP) mouse model was used for in vivo experiments, while lipopolysaccharide (LPS)‐stimulated H9c2 cardiomyocytes were employed for in vitro studies to assess the expression and function of FTO. Transcriptomic and proteomic profiling of FTO‐overexpressing cardiomyocytes was performed, followed by multi‐omics integration analysis to identify key regulatory pathways and genes. The role of FTO in SCM was further validated using molecular and functional assays. CLP‐induced septic mice exhibited progressive cardiac dysfunction. m 6 A modification was increased while the expression of FTO was markedly reduced in vivo and in vitro. Multi‐omics analysis of FTO‐overexpressing cells revealed enrichment of autophagy and energy metabolism pathways. The integrated transcriptomic and proteomic profiling, coupled with MeRIP‐qPCR validation, identified key FTO‐regulated genes. Functionally, FTO overexpression restored autophagic flux and ATP production, whereas FTO knockdown exacerbated autophagic blockade and energy failure, establishing FTO as a central regulator of SCM pathogenesis. FTO acts as a critical regulator of autophagy and energy metabolism, conferring cardioprotection in SCM. This epitranscriptomic pathway adds a new layer of potential therapeutic targets for precision treatment in SCM.