In summary, our analysis for the first time showed that hypomethylation-mediated high expression of CASK in hepatocellular carcinoma is associated with poor prognosis for hepatocellular carcinoma patients, and depletion of CASK enhances the sorafenib sensitivity in vitro and in vivo through activating apoptosis and autophagic cell death. Here, CASK is linked to hepatocellular carcinoma.