Hepatocellular Carcinoma (HCC) is the sixth most common type of cancer and the second leading cause of cancer-related deaths worldwide. Currently, Sorafenib is the only approved first-line treatment option for unresectable advanced HCC patients. Although Sorafenib can be beneficial for some patients, overall survival can only be extended for 4 months. One of the main reasons is the development of Sorafenib resistance. Many studies have been conducted to decipher the mechanisms underlying this drug resistance, yet much more still awaits for elucidation. This study suggests a novel involvement of a player, an antiviral kinase, which was previously described as an oncogenic protein. Strikingly in our investigation, Sorafenib resistance seems to be caused by the loss of this interferon related kinase. This protein expression is ablated in Sorafenib resistant Hep3B cell line. Loss of this protein by shRNA confers Sorafenib resistance to naïve Hep3B cells. Reversely, protein rescue can re-sensitize these resistant cells to Sorafenib. We also report in this work for the first time that this Sorafenib resistant Hep3B cell line exhibits partial EMT signature. Over all, this study paves way for further studies investigating the implication of this antiviral protein in Sorafenib resistance mechanism in HCC.