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Aims To observe the effect of electro-acupuncture (EA) on cardiomyocytes ferroptosis induced by myocardial ischemia/reperfusion injury (MIRI) in mice and to investigate whether this effect occurs via the nuclear factor-E2-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1) signalling pathway. Materials and methods Firstly, Fe 2+ in the hearts and serum of mice from both the sham-operated (SO) group and MIRI group was measured to ascertain whether ferroptosis had occurred in the cardiomyocytes of mice in MIRI group. In the second phase, EA was administered, with sham acupuncture (SA) group as the comparator, to investigate the protective effects of EA on ferroptosis in MIRI cardiomyocytes and cardiac function. Additionally, we studied the levels of Nrf2 and HO-1 within the myocardium. In the third phase, Nrf2 inhibitor ML385 and agonist DMF were applied to observe the impact of inhibiting Nrf2 on the therapeutic efficacy of EA. Results Compared with SO group, MIRI group showed increased iron deposition, along with a significant decrease in Nrf2 and HO-1 levels. Compared with MIRI group, MIRI + EA group exhibited significantly improved cardiac function and reduced cardiac iron deposition, accompanied by increased Nrf2 and HO-1 levels. Furthermore, the therapeutic effect of MIRI + EA group was superior to that of MIRI + SA group. Administration of ML385 partially blocked the anti-ferroptotic and cardioprotective effects of EA, while EA treatment exhibited similar effects to dimethyl fumarate (DMF) intervention. Conclusion EA alleviates ferroptosis-induced damage in MIRI in mice via the Nrf2/HO-1 pathway, providing modern scientific evidence for the application of acupuncture in the treatment of cardiovascular diseases.