The Effect of Malonate as a Succinate Dehydrogenase Inhibitor on Myocardial Ischemia/Reperfusion Injury

Myocardial ischemia-reperfusion injury (MIRI) continues to provide a serious therapeutic challenge, substantially influencing myocardial infarct size and negative cardiovascular outcomes. Recent research underscores the critical significance of succinate accumulation and its rapid oxidation during reperfusion, initiating the generation of reactive oxygen species (ROS) and mitochondrial impairment. Malonate, a competitive inhibitor of succinate dehydrogenase (SDH), has attracted interest as a cardioprotective drug by reducing ROS production and cellular damage during the first reperfusion. Malonate preferentially accumulates in ischemic tissues via monocarboxylate transporter 1 (MCT1), driven by the acidic conditions of ischemia. This specific dosing prevents SDH, which in turn reduces succinate oxidation and ROS production, protecting mitochondrial integrity and heart function. The effects of malonate on infarct size reduction, left ventricular ejection fraction enhancement, and pro-inflammatory and fibrotic marker mitigation have been demonstrated in preclinical research conducted on animal models. Additionally, acidified malonate formulations improve therapeutic selectivity, providing significant cardioprotection at lower dosages. Notwithstanding encouraging experimental results, clinical validation is crucial to ascertain malonate's translational potential for the treatment of acute myocardial infarction (MI) and post-reperfusion heart failure. This review discusses the pathophysiology of MIRI, the function of SDH, and the mechanism of action of malonate, highlighting its potential as a targeted intervention for MIRI.