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Highlights • IL-2 promotes sorafenib-mediated apoptosis in Huh7 cells. • IL-2 in combination with sorafenib interrupts mitochondrial metabolism. • Mitochondrial fragmentation is augmented by IL-2 in the presence of sorafenib. Abstract Sorafenib is a standard targeted drug used to treat hepatocellular carcinoma (HCC). Notably, cytokine has been found to further enhance the therapeutic effectiveness of the targeted drug. Thereby, the aim of this study is to verify whether cytokine IL-2 could increase the anti-cancer effects of sorafenib on liver cancer in vitro. Huh7 cells were used in the present study and the cell apoptosis and migration were determined in response to sorafenib treatment. Then, siRNA and pathway blocker were used to determine the molecular mechanisms by which IL-2 enhance the therapeutic effectiveness of Huh7 liver cancer cell in vitro. The data in our study illustrated that sorafenib treatment induced apoptosis in Huh7 liver cancer cell in vitro, an effect that was accompanied with a drop in cell proliferation and migration. Biological investigation demonstrated that IL-2 supplementation further augmented the pro-apoptotic effects of sorafenib in vitro. At the molecular levels, the combination of IL-2 and sorafenib impaired mitochondrial respiratory function, reduced mitochondrial potential, promoted mitochondrial ROS overloading and activated mitochondrial apoptotic pathway. Meanwhile, we found that IL-2 supplementation induced mitochondrial stress via activating mitochondrial fragmentation in a manner dependent on MAPK-JNK signalling pathway and TAZ protein. Blockade of the JNK signalling pathway and/or knockdown of TAZ could abrogate the inhibitor effects of IL-2/sorafenib on liver cancer survival, growth and mobility. Collectively, these data indicated that IL-2 supplementation could further augment the anti-cancer effectiveness of sorafenib via activating mitochondrial fragmentation in a manner dependent on MAPK-JNK signalling pathway and TAZ protein. This finding identifies mitochondrial stress and the JNK-Hippo pathway as the potential targets to treat liver cancer. [ABSTRACT FROM AUTHOR]