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Ruscogenin (RUS), a natural steroidal sapogenin, exerts various biological activities. However, its effectiveness for preventing myocardial ischemia (MI) and its molecular mechanisms need further clarification. The model of MI mice and oxygen-glucose deprivation-induced cardiomyocytes injury was performed. RUS significantly alleviated MI, as evidenced by decreased infarct size, ameliorated biochemical indicators and cardiac pathological features, and markedly inhibited ferroptosis by means of the up-regulation of GPX4 and down-regulatio