In the current study, we presented evidence that COX-2 was frequently overexpressed in HCC, and more importantly, that the PINK1-mediated mito-COX-2/p-Drp1Ser616 interaction played a multifaceted role by promoting mitochondrial fission-driven functional outcomes and anti-tumor sensitivity of HCC cells in vitro and in vivo. Here, PTGS2 is linked to hepatocellular carcinoma.