Taken together, our findings indicate the functional role of HBx in regulating the stem-like properties of OV6+ CSCs in HCC through the MDM2/CXCL12/CXCR4/β-catenin signaling axis, and identify HBx, MDM2, CXCR4 and OV6 as a novel prognostic pathway and potential therapeutic targets for patients with HBV-related HCC patients. Here, CXCL12 is linked to hepatocellular carcinoma.