Furthermore, combination strategies sensitize tumors to chemo/targeted therapies: the PPT1 inhibitor DC661 reverses sorafenib adaptive resistance in HCC cells by disrupting lysosomal acidification and autophagic flux, while inducing mitochondrial apoptosis (208); salvianolic acid B, targeting CLDN4, inhibits hepatic-to-biliary transition (HBT) and restores lenvatinib sensitivity in HCC (226). This evidence concerns the gene CLDN4 and hepatocellular carcinoma.