【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.