Abstract
Hepatocellular carcinoma (HCC) exhibits significant plasticity, enabling phenotypic switching that promotes a drug-tolerant state and circumvents drug-induced cytotoxicity. In this study, we identify the hepatic-to-biliary lineage transition (HBT), associated with Claudin 4 (CLDN4), a tight junction protein, as a potential target for mitigating lenvatinib resistance in HCC. CLDN4 expression is more prevalent in lenvatinib-resistant patients. Palmitoylation of CLDN4 at cysteine residues C104 and C107 regulates ubiquitination at lysine residue K103, inhibits clathrin-mediated endocytosis, and sustains CLDN4 anchoring within lipid rafts. Anchored CLDN4 facilitates the phenotypic transition of HCC cells, resulting in increased resistance to lenvatinib by driving the mobilization of contactin-1 to lipid rafts and activating the Notch signaling pathway. Salvianolic acid B, an inhibitor of CLDN4, is demonstrated to reduce both HBT and lenvatinib resistance in HCC. Additionally, combination chemotherapy appears to be an effective therapeutic strategy for HCC patients undergoing HBT.