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This study aimed to investigate the therapeutic effect and underlying mechanism of Guizhi Tongluo Tablets in myocardial ischemia-reperfusion injury(MIRI) by regulating the phosphoinositide 3-kinase(PI3K)/protein kinase B(Akt) signaling pathway and inhibiting inflammatory response. Sixty healthy SPF-grade male C57BL/6J mice were randomly divided into sham group, model group, low-dose Guizhi Tongluo Tablets group, medium-dose Guizhi Tongluo Tablets group, high-dose Guizhi Tongluo Tablets group, and nicorandil group. The MIRI model was established by ligating the left anterior descending coronary artery for 30 min followed by reperfusion. Beginning on day 1 after the operation, the mice in the low-, medium-, and high-dose Guizhi Tongluo Tablets groups received 0.51, 1.03, and 2.06 g·kg~(-1)·d~(-1) by gavage, respectively. Mice in the nicorandil group were administered 2.28 mg·kg~(-1)·d~(-1) by gavage. Mice in the sham group and the model group received an equal volume of normal saline once daily by gavage for four consecutive weeks. Cardiac function was assessed via echocardiography. Laser speckle contrast analysis(LASCA) was used to evaluate the microvascular reperfusion in each group. Hematoxylin-eosin(HE) staining was used to observe pathological changes in cardiac tissue, while TUNEL staining was used to detect the apoptosis of cardiomyocytes. The expression levels of inflammatory cytokines interleukin-1β(IL-1β), interleukin-6(IL-6), and tumor necrosis factor-α(TNF-α) in the myocardium were measured by qPCR and enzyme-linked immunosorbent assay(ELISA). Transcriptomic sequencing was conducted to identify differentially expressed genes, and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment analysis was used to determine the related pathways. The protein expression levels of PI3K, phosphorylated PI3K(p-PI3K), Akt, and phosphorylated Akt(p-Akt) were analyzed using the Jess automated protein analysis system. The results showed that compared with the sham group, the model group exhibited significantly reduced left ventricular ejection fraction(LVEF) and left ventricular fractional shortening(LVFS), increased infiltration of inflammatory cells in the heart tissue, disorganized cardiomyocyte arrangement, and significantly increased cardiomyocyte apoptosis. Expression levels of IL-1β, IL-6, and TNF-α were markedly upregulated, while the ratios of p-PI3K/PI3K and p-Akt/Akt were significantly decreased. Compared with the model group, mice in the Guizhi Tongluo Tablets groups showed significantly improved cardiac function, reduced inflammatory cell infiltration, partially restored cardiac structure, significantly decreased cardiomyocyte apoptosis and levels of IL-1β, IL-6, and TNF-α, along with significantly increased p-PI3K/PI3K and p-Akt/Akt levels. These findings suggest that Guizhi Tongluo Tablets can effectively prevent and treat MIRI, possibly by activating the PI3K/Akt signaling pathway and alleviating cardiac inflammation.