<p>Myocardial ischemia-reperfusion injury (MIRI) is a major clinical challenge, marked by metabolic disruptions and cellular damage following the restoration of blood flow after ischemia. During ischemia, the heart shifts from fatty acid metabolism to glucose metabolism, leading to metabolic abnormalities, including reduced intracellular pH, ion disturbances, cell swelling, and apoptosis. Upon reperfusion, fatty acid β-oxidation resumes, becoming the dominant energy source, which induces excessive oxidative stress and aggravates myocardial injury. To explore the role of FTO (Fat mass and obesity-associated protein) in m6A demethylation of MZF1 and its regulation of DECR1, a key enzyme involved in fatty acid β-oxidation, in the context of MIRI. We investigated the molecular mechanisms by which FTO-mediated m6A modification of MZF1 regulates DECR1 expression, leading to enhanced fatty acid oxidation during reperfusion and its contribution to the exacerbation of MIRI. Our findings suggest that FTO-mediated demethylation of MZF1 promotes the expression of DECR1, thereby enhancing fatty acid oxidation. This process intensifies oxidative stress and worsens myocardial injury during ischemia/reperfusion. The FTO-mediated m6A modification of MZF1 represents a critical mechanism in the regulation of fatty acid oxidation and the exacerbation of MIRI. These insights offer potential therapeutic targets to mitigate the harmful effects of reperfusion injury in myocardial infarction.</p> Graphical Abstract <p></p>