These results suggested that mito-COX-2-dependent mitochondrial fission accelerated HCC growth via the regulatory mechanism underlying the PINK1-activated p-Drp1Ser616 mitochondrial translocation and mito-COX-2/p-Drp1Ser616 interaction, and targeting the intervention to mito-COX-2 could inhibit p-Drp1Ser616-driven HCC growth in vivo. Here, PTGS2 is linked to hepatocellular carcinoma.