The Role of HINT3 in Myocardial Ischemia‐Reperfusion Injury in Male Mice: Mechanisms Involving SDHA and its Acetylation

Abstract Myocardial ischemia‐reperfusion (I/R) injury is characterized by oxidative stress, mitochondrial dysfunction, and cardiomyocyte apoptosis. During I/R, the accumulation and oxidation of succinate contribute to reactive oxygen species (ROS) production, worsening tissue damage. Histidine triad nucleotide‐binding protein 3 (HINT3) is identified as a regulator of mitochondrial function and cardiomyocyte survival during I/R. In a mouse I/R model and an oxygen‐glucose deprivation/reoxygenation (OGD/R) model, it shows that HINT3 expression is downregulated after I/R. Cardiomyocyte‐specific knockout of HINT3 exacerbates myocardial injury, impairs cardiac function, and promotes mitochondrial dysfunction and apoptosis, whereas HINT3 overexpression mitigates these effects. Mechanistically, HINT3 interacts with succinate dehydrogenase subunit A (SDHA), suppresses HDAC1 expression, and prevents SDHA deacetylation at K335, reducing SDH activity and mitochondrial ROS production. These findings highlight the HINT3‐HDAC1‐SDHA axis as a key pathway in mitochondrial regulation, offering new insights and therapeutic targets for myocardial reperfusion injury.