In this study, we provided the first evidence that B56γ specifically targeted p‐AKT as a substrate to regulate the dephosphorylation of p‐AKTThr308 and p‐AKTSer473 and inhibit the MMP2/9‐associated metastasis phenotype of HBx‐expressing HCC cells in vitro and in vivo. Here, PPP2R5C is linked to hepatocellular carcinoma.