ArticleCell reports. Medicine2025
CLDN4 palmitoylation promotes hepatic-to-biliary lineage transition and lenvatinib resistance in hepatocellular carcinoma.
Article in Cell reports. Medicine, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed.
- CCT2 defines a highly cisplatin-resistant and poor-prognosis subtype of lung adenocarcinoma.Oncology letters · 2026Article
- Targeting the Notch signaling pathway in digestive system cancers: from bench to bedside.Cancer cell international · 2026Review
- Palmitoylation of CLDN12 regulated by ZDHHC7 and APT1/2 promotes hepatitis C virus entry.Journal of virology · 2026Article
- Protein expression profiling of lenvatinib-resistant liver cancer cells and identify B4GALT4 as a critical drug resistance molecule.Discover oncology · 2026Article
- From lipid modification to cell death: the diverse roles of S-palmitoylation in cell fate decisions.Cell communication and signaling : CCS · 2026Review
- Activation of Nerve Growth Factor signaling limits the response to lenvatinib in hepatocellular carcinoma.Signal transduction and targeted therapy · 2026Article
- Targeting the ZDHHC9-mediated STAT1 palmitoylation-phosphorylation conversion inhibits gastric cancer progression.Journal of gastroenterology · 2026Article
- Notch signaling in liver diseases: mechanistic insights and therapeutic implications.Frontiers in cell and developmental biology · 2026Review
- ZDHHC-Mediated Protein S-Palmitoylation in Cancer: Epigenetic Interfaces, Structural Logic and Therapeutic Targeting.International journal of medical sciences · 2026Review
- Nanodelivery of Traditional Chinese Medicine Monomers: An Emerging Strategy to Reprogram the Immunosuppressive Tumor Microenvironment.International journal of nanomedicine · 2026Review
- ZDHHC14-Mediated TEAD4 Palmitoylation Drives Th17 Cell Recruitment in Renal Immunopathology.Research (Washington, D.C.) · 2025Article
- Palmitoylation in cancer: decoding its roles in signal transduction, tumor immunity, and emerging therapeutic opportunities.Frontiers in immunology · 2025Review
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Authors and funding
12 authors.
Funding
No grant is acknowledged in the PubMed record.
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.
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