Methadone, a metabolite of RU486 and a cancer metastasis preventive agent, targets the SDF-1/CXCR4 axis. When combined with sorafenib, it enhances the delivery of both drugs to hepatocellular carcinoma (HCC) cells by specifically recognizing and binding to CXCR4. This combination not only increases cytotoxicity but also modulates the Akt/ERK/p38 MAPK/caspase signaling pathway. Consequently, it inhibits cell proliferation and suppresses potential resistance to sorafenib. This evidence concerns the gene CXCL12 and hepatocellular carcinoma.