Nuclear factor erythroid 2-related factor 2 (NRF2) is a redox-sensitive transcriptional factor that enables cells to resist oxidant responses, ferroptosis and inflammation. Here, we set out to probe the effects of NRF2 on cardiomyocyte injury under acute myocardial infarction (AMI) condition and its potential mechanism. Human cardiomyocytes were exposed to hypoxia/reoxygenation (H/R) to induce cell injury. qRT-PCR and western blot assays were used to detect the levels of mRNAs and proteins. Cardiomyocyte injury was determined by detecting the levels of lactate dehydrogenase and creatine Kinase MB (CK-MB). Cell apoptosis was investigated by flow cytometry and related markers. Levels of IL-6, IL-10, and TNF-α were measured by ELISA. Cell ferroptosis was assessed by detecting the production of reactive oxygen species (ROS), malonaldehyde (MDA), reduced glutathione/oxidized glutathione disulfide (GSH/GSSG) ratio, Fe + content, and related regulators. The interaction between NRF2 and the suppressor of zest 12 (SUZ12) was analyzed by using dual-luciferase reporter and RNA immunoprecipitation assays. AMI rat models were established for in vivo analysis. NRF2 was lowly expressed in AMI patients and H/R-induced cardiomyocytes. Forced expression of NRF2 reduced H/R-induced cardiomyocyte injury, apoptosis, inflammation, and ferroptosis. Moreover, NRF2 overexpression improved cardiac function and injury in vivo. Mechanistically, SUZ12 bound to the promoter of NRF2 and promoted its expression. Further functional analyses showed that SUZ12 overexpression reduced H/R-induced cardiomyocyte injury, apoptosis, inflammation, and ferroptosis, which were reversed by NRF2 silencing. SUZ12-increased NRF2 suppressed H/R-induced cardiomyocyte injury, apoptosis, inflammation, and ferroptosis in vitro and improved cardiac functions in rats with I/R injury, suggesting the potential cardioprotective effect of NRF2 in cardiac injury during AMI.© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.