Objective To explore the possible mechanism of apoptosis induced by SARS-CoV-2 targeting cyclophilin A(CypA)/CD147 receptor pathway.Methods The pEncmv-SARS-CoV-2 S-3xflag recombinant plasmid was constructed and transfected into H9C2 cells.Apoptosis was analyzed by TUNEL assay,flow cytometry and DNA ladder.The interaction between CD147 and SARS-CoV-2 S protein was verified by CoIP.The expressions of apoptosis-related proteins were detected by Western blotting.Results Compared with the control group,TUNEL assay and flow cytometry showed that apoptosis was significantly increased in transfection group(P＜0.05),and DNA ladder analysis showed that DNA degradation was obvious.The expression levels of Caspase12 and DR3 were significantly increased(P＜0.001),the expression level of FAS was slightly increased(P＜0.01),while the expression levels of TRF1 and DR4 were decreased(P＜0.01).Conclusion SARS-CoV-2 S protein targets CypA/CD147 receptor to invade host cells,activate endoplasmic network pathway(Caspase12)and death receptor pathway(DR3,FAS),and induce apoptosis of cardiomyocytes through endogenous and exogenous apoptotic pathways.