In this study, using established Sleeping Beauty hydrodynamic tail vein injection (SB-HDTVI)-mediated murine liver cancer models, we demonstrate that SALL4 is selectively required for myristoylated Akt (myrAkt)-YAP1S127A(AY)-driven HC-to-CCA transformation and regenerative HC-to-CC reprogramming in the 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet cholestasis model. Here, SALL4 is linked to cholangiocarcinoma.