Objective To investigate the effect of ring finger protein 130 (RNF130) on myocardial ischemia-reperfusion injury (MI/RI) and its potential mechanism. Methods Male C57BL/6J mice were divided into four groups (n=6): Sham, MI/RI, MI/RI+Vector, and MI/RI+RNF130 overexpression (MI/RI+RNF130OE). Cardiac function was evaluated by echocardiography 24 hours after ischemia-reperfusion. Pathological changes, oxidative damage, and apoptosis in myocardial tissues were observed via IHC, DHE, and TUNEL staining. Protein expression was detected using Western blot, immunofluorescence, and immunohistochemistry. Proteomic analysis was performed to identify downstream proteins regulated by RNF130, and protein-protein interactions were validated by immunoprecipitation (IP) assay. Results Compared with the MI/RI+Vector group, RNF130 overexpression significantly improved cardiac function, as indicated by increased left ventricular ejection fraction (EF) and fractional shortening (FS), reduced myocardial infarction area, and decreased expression of NOX-2 and BAX proteins(P<0.05). DHE and TUNEL staining showed that RNF130 overexpression alleviated myocardial oxidative damage and apoptosis(P<0.05). Proteomic analysis and IP assays revealed a significant interaction between RNF130 and PARP1, with PARP1 expression inversely correlated with RNF130. Conclusions RNF130 may mitigate MI/RI injury by regulating the PARP1 ubiquitination pathway, providing a new target for therapeutic intervention.