Objective:To observe the effects of sacubitril/valsartan (LCZ696) on viral replication and cardiomyocyte apoptosis in mice with coxsackievirus B3 (CVB3)-induced viral myocarditis (VMC) and to analyze the underlying mechanisms.Methods:Forty BALB/c mice were randomly divided into four groups with 10 in each group: Sham, Sham+ LCZ696, VMC, and VMC+ LCZ696 groups. VMC model was established by intraperitoneal injection of 0.1 ml of CVB3 with a concentration of 10 6 TCID 50/ml into BALB/c mice, while the sham intervention was an equal volume of saline. The day of virus injection was defined as day 0. LCZ696 was administered by gavage at a dose of 60 mg/kg every day for seven consecutive days starting from day 1. Mouse survival rates were calculated. Echocardiography was used to evaluate the cardiac function of mice. The level of creatine kinase-MB (CK-MB) was detected by ELISA. Western blot was used to detect the levels of inflammatory cytokines (IL-6, TNF-α), apoptosis-related proteins (caspase-3, cleaved-caspase-3, Bax, Bcl-2), CVB3 surface protein (VP-1) and p-AKT/AKT in the hearts of mice. CVB3 mRNA in mouse hearts was measured by PCR. Inflammatory cell infiltration and cell apoptosis in mouse hearts were observed by HE staining and TUNEL staining, respectively. Results:Compared with the Sham group, the mice in the VMC group had a decreased survival rate and impaired cardiac function ( P<0.05). The levels of CK-MB, IL-6, TNF-α, cleaved-caspase-3/caspase-3, Bax/Bcl-2, VP-1, and CVB3 mRNA in the hearts of VMC mice increased significantly ( P<0.05), accompanied by increased expression of AKT, decreased phosphorylation of AKT ( P<0.05) and increased cell apoptosis. LCZ696 reversed the above changes. It could increase the survival rate, improve the cardiac function ( P<0.05), decrease cardiac inflammation, cell apoptosis and viral replication ( P<0.05), and increase the phosphorylation of AKT ( P<0.05). LCZ696 had no significant effects on the survival rate, cardiac function, myocardial injury, cardiac inflammation, cell apoptosis, viral replication or the expression of PI3K/AKT signaling pathway-related proteins in normal mice. Conclusions:LCZ696 could significantly inhibit cardiomyocyte apoptosis and reduce CVB3 replication in the hearts of VMC mice by regulating the PI3K/AKT pathway, thereby improving mouse cardiac function and survival rate.