【】? Objective To investigate the effects and underlying mechanisms of RNF130 (Ring Finger Protein 130) in myocardial ischemia-reperfusion injury (MI/RI). Methods? Male C57BL/6J mice were randomly assigned to four groups (n=6): sham-operated (Sham), myocardial ischemia-reperfusion (IR), myocardial ischemia-reperfusion with empty vector plasmid (IR+Vector), and myocardial ischemia-reperfusion with RNF130 overexpression (IR+RNF130 OE). Mice underwent 24 hours of myocardial ischemia-reperfusion, after which cardiac function was assessed using echocardiography. Cardiac tissues and serum were subsequently collected. Histopathological examination was performed using immunohistochemistry (IHC), dihydroethidium (DHE) staining for oxidative stress, and TUNEL staining to evaluate apoptosis. Protein expression levels were analyzed by Western blotting, [①]immunofluorescence, and IHC. Proteomic analysis was conducted to identify downstream targets of RNF130, and protein-protein interactions were assessed via immunoprecipitation (IP). Results? Compared to the control group mice given an empty vector plasmid, the overexpression of RNF130 in mouse cardiac myocytes led to a significant increase in RNF130 protein expression and a marked improvement in cardiac function, as evidenced by increased values of left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS), as well as a significant reduction in the area of myocardial infarction. Additionally, the expression levels of NOX-2 and BAX proteins were observed to decrease significantly. HE staining revealed that the arrangement of myocardial fibers in the RNF130 overexpression group was more orderly compared to the Vector group, with a reduction in the areas of myocardial cell destruction and necrosis, and an improvement in inflammatory cell infiltration. DHE and TUNEL staining indicated that, compared to the Vector group, the rate of myocardial cell oxidative damage and apoptosis in RNF130 overexpression mice was significantly reduced. Proteomic analysis showed that, compared to the RNF130 overexpression group, there were 75 proteins significantly upregulated and 49 proteins significantly downregulated in the model group mice. We selected the top five proteins with the most significant increase in expression for IP experiments and found that protein PARP1 interacted notably with RNF130. Western blot (WB) experiments revealed that, contrary to the expression changes of RNF130 protein, the expression of RNF130 protein was significantly increased in I/R mice compared to Sham mice, and after overexpressing RNF130, the expression of PARP1 protein was further reduced, and the ubiquitination level of PARP1 was significantly enhanced. ?Conclusions? RNF130 overexpression provides a protective effect against ischemia-reperfusion injury, likely by promoting the ubiquitination and degradation of PARP1. This mechanism may mitigate DNA damage and apoptosis in cardiomyocytes, offering potential therapeutic insights for ischemic heart disease.