Abstract: Abstract: Objective　To explore the protective mechanism of dimethyl fumarate (DMF) on myocardial ischemia/reperfusion (I/R) injury based on the iron death pathway mediated by nuclear factor E2 related factor 2 (Nrf2) -glutathione peroxidase 4 (GPX4). Methods　A total of 72 SD rats were randomly divided into the sham operation group, the I/R group, the Ferrostatin-1 group (2 mg/kg), the DMF low-dose group (25 mg/kg), the DMF high-dose group (50 mg/kg) and the DMF+ML385 group (50 mg/kg DMF+30 mg/kg ML385), with 12 rats in each group. Rats were given corresponding drug intervention once a day for 7 consecutive days. At the same time, the rat model of myocardial I/R was established by ligating the left anterior descending coronary artery. After 12 h of reperfusion, the serum levels of lactate dehydrogenase (LDH), troponin I (cTnI) and creatine kinase isoenzyme MB (CK-MB) were detected by ELISA. HE staining was used to observe the pathological changes of myocardium. Cardiomyocyte apoptosis was detected by TUNEL staining. The level of reactive oxygen species (ROS) in myocardial tissue was detected by DHE fluorescence staining. Malondialdehyde, glutathione content and superoxide dismutase activity in myocardial tissue homogenate were detected by biochemical method. Fe2+ content in myocardial tissue was detected by colorimetry. The protein levels of Nrf2, GPX4, ferritin heavy chain 1 (FTH1) and transferrin receptor 1 (TfR1) in myocardial tissue were detected by Western blot assay. Results　Compared with the sham group, the serum levels of CK-MB, cTnI, LDH, cardiomyocyte apoptosis rate, ROS and MDA, Fe2+ content, TfR1 protein level were significantly increased in the I/R group (P＜0.05 ). GSH content, SOD activity and Nrf2, GPX4, FTH1 protein level were significantly decreased (P＜0.05). Compared with the I/R group, the serum levels of CK-MB, cTnI, LDH, myocardial cell apoptosis rate, ROS, MDA, Fe2+ content and TfR1 protein were significantly decreased in the Fer-1 group, the DMF-L group and the DMF-H group (P＜0.05), while GSH and SOD activities, and Nrf2, GPX4, and FTH1 protein levels were significantly increased (P＜0.05). Compared with the DMF-H group, the serum levels of CK-MB, cTnI, LDH, cardiomyocyte apoptosis rate, ROS and MDA, Fe2+ content and TfR1 protein level were significantly increased in the DMF+ML385 group (P＜0.05). GSH and SOD and protein levels of Nrf2, GPX4 and FTH1 were significantly decreased (P＜0.05). The Nrf2 inhibitor ML385 could significantly attenuate the inhibition of DMF on ferroptosis and the protective effect of myocardial I/R injury. Conclusion　DMF may alleviate myocardial I/R injury by inhibiting iron death, and its mechanism may be related to the activation of Nrf2-GPX4 pathway.

Key words: dimethyl fumarate, myocardial reperfusion injury, NF-E2-related factor 2, oxidative stress, receptors, transferrin, glutathione peroxidase, iron death