2. Academic Validation
  3. CLDN4 palmitoylation promotes hepatic-to-biliary lineage transition and lenvatinib resistance in hepatocellular carcinoma

CLDN4 palmitoylation promotes hepatic-to-biliary lineage transition and lenvatinib resistance in hepatocellular carcinoma

  • Cell Rep Med. 2025 Jul 15;6(7):102208. doi: 10.1016/j.xcrm.2025.102208.
Minghao Xu 1,  Yimin Zheng 1,  Junbo Chen 1,  Chao Gao 2,  Miao Zhu 3,  Aying Ma 2,  Bugang Liang 1,  Wenxin Xu 1,  Jia Fan 4,  Haibo Zhou 5,  Aiwu Ke 6,  Yinghao Shen 7
Affiliations

Affiliations

  • 1 Department of Hepatobiliary Surgery and Liver Transplantation, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
  • 2 Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education of the People's Republic of China, Shanghai 200032, China.
  • 3 Department of Physiology and Pathophysiology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
  • 4 Department of Hepatobiliary Surgery and Liver Transplantation, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education of the People's Republic of China, Shanghai 200032, China. Electronic address: fan.jia@zs-hospital.sh.cn.
  • 5 College of Pharmacy, Jinan University, Guangzhou 510632, China. Electronic address: haibo.zhou@jnu.edu.cn.
  • 6 Department of Hepatobiliary Surgery and Liver Transplantation, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education of the People's Republic of China, Shanghai 200032, China. Electronic address: ke.aiwu@zs-hospital.sh.cn.
  • 7 Department of Hepatobiliary Surgery and Liver Transplantation, Zhongshan Hospital, Fudan University, Shanghai 200032, China. Electronic address: syh12268@163.com.
PMID: 40592346 DOI: 10.1016/j.xcrm.2025.102208
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.

Keywords

Claudin4; hepatic-to-biliary transition; hepatocellular carcinoma; lenvatinib resistance; palmitoylation.

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