Subjective: This study aimed to investigate the therapeutic mechanisms of 7-hydroxyflavone (7-HF) in treating myocardial ischemia/reperfusion injury (MI/RI) via network pharmacology, molecular docking, target validation, and experiments at the animal level. Methods: Firstly, the genes of 7-HF were acquired from PharmMapper, TCMSP, and SwissTargetPrediction. At the same time, MI/RI-related genes were obtained from OMIM, GeneCards, and TTD online platforms. Subsequently, string platform and Cytoscape 3.9.2 were used to construct protein-protein interaction network diagrams and 7-HF-targets-signaling pathways-MI/RI network. Then, the Metascape platform was used to conduct functional enrichment analyses. Next, AutoDock Vina and Pymol were used to perform molecular docking. The hub targets were validated in the GSE66360. Lastly, SOD, MDA, transmission electron microscope, quantitative real-time PCR, and western blot were used to validate in MI/RI rats. Results: 139 genes of 7-HF, 4832 genes of MI/RI were obtained. The 47 interact genes between 7-HF and MI/RI targets for MI/RI were likely to act through multiple pathways. And NQO1 was a critical target in the above process. In an animal experiment, 7-HF could relieve the injured interfibrillar mitochondria and myocardial fibers, decrease the expression of MDA and SOD, and increase the expression of Nrf2, NQO1 and HO-1 in the mRNA and protein level in the MI/RI rats. Conclusion: This study preliminarily demonstrated that 7-HF could provide cardioprotection by inhibiting the oxidative stress and up-regulating Nrf2/NQO1/HO-1 signaling pathway based on network pharmacology, molecular docking, target validation, and animal experiments.
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