In the present study, we aimed to investigate the role of the SIRT3-modulated mito-COX-2/p-Drp1Ser616 axis in mitochondrial dynamics and apoptosis of HCC cells, and elucidate the mechanisms of PINK1-dependent mito-COX-2/p-Drp1Ser616 interaction implicating the mitochondrial protein machinery. Here, SIRT3 is linked to hepatocellular carcinoma.