Combined administration of the TLR4 inhibitor TAK-242 and PTK2 inhibitor defactinib or genetic ablation of KLF7 in hepatocytes significantly impeded the HMGB1-KLF7 axis-mediated HCC progression and metastasis, which represented promising therapeutic strategies for KLF7-positive HCC patients. Here, TLR4 is linked to hepatocellular carcinoma.