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Our previous research discovered that cinnamamide derivatives are a new type of potential cardioprotective agents myocardial ischemia-reperfusion (MIR) injury, among which Compound 10 exhibits wonderful beneficial action in vitro. However, the exact mechanism of Compound 10 still needs to be elucidated. The protective effect of Compound 10 was determined by detecting the cell viability and LDH leakage rate in H9c2 cells subjected to H 2 O 2. Alterations of electrocardiogram, echocardiography, cardiac infarct area, histopathology and serum myocardial zymogram were tested in MIR rats. Additionally, the potential mechanism of Compound 10 was explored through PCR. Network pharmacology and Western blotting was conducted to monitor levels of proteins related to autophagic flux and mTOR, autophagy regulatory substrate, induced by Compound 10 both in vitro and in vivo , as well as expressions of Sirtuins family members. Compound 10 significantly ameliorated myocardial injury, as demonstrated by increased cell viability, decreased LDH leakage in vitro , and declined serum myocardial zymogram, ST elevation, cardiac infarct area and improved cardiac function and microstructure of heart tissue in vivo. Importantly, Compound 10 markedly enhanced the obstruction of autophagic flux and inhibited excessive autophagy initiation against MIR by decreased ATG5, Rab7 and increased P-mTOR and LAMP2. Furthermore, Sirt1 knockdown hindered Compound 10 's regulation on mTOR, leading to interrupted cardiac autophagic flux. Compound 10 exerted cardioprotective effects on MIR by reducing excessive autophagy and improving autophgic flux blockage. Our work would take a novel insight in seeking effective prevention and treatment strategies against MIR injury. [Display omitted] • Cinnamamide derivative compound 10 had beneficial effects against MIR in vitro and in vivo. • Compound 10 improved cardiac autophagic flux blockage against MIR. • Compound 10 inhibited excessive cardiac autophagy initiation in vitro and in vivo. [ABSTRACT FROM AUTHOR]