In summary, this work demonstrates that elevated FGF19 expression or hyperactivation of FGF19/FGFR4 signaling in HCC cells is one of the main mechanisms of sorafenib resistance, and blocking FGF19/FGFR4 axis by ponatinib can overcome the resistance of HCC cells to sorafenib through enhancing ROS-associated apoptosis. The gene discussed is FGF19; the disease is hepatocellular carcinoma.