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

IF 11.7 1区医学 Q1 CELL BIOLOGY

Cell Reports Medicine Pub Date : 2025-07-15 Epub Date: 2025-06-30 DOI:10.1016/j.xcrm.2025.102208

Minghao Xu, Yimin Zheng, Junbo Chen, Chao Gao, Miao Zhu, Aying Ma, Bugang Liang, Wenxin Xu, Jia Fan, Haibo Zhou, Aiwu Ke, Yinghao Shen

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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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CLDN4棕榈酰化促进肝细胞癌向胆道谱系的转变和lenvatinib耐药性。

肝细胞癌（HCC）表现出显著的可塑性，使表型转换促进耐药状态并规避药物诱导的细胞毒性。在这项研究中，我们确定了与紧密连接蛋白Claudin 4 （CLDN4）相关的肝-胆道谱系转变（HBT），作为减轻lenvatinib耐药的潜在靶点。CLDN4表达在lenvatinib耐药患者中更为普遍。CLDN4在半胱氨酸残基C104和C107上的棕榈酰化调节赖氨酸残基K103上的泛素化，抑制网格蛋白介导的内吞作用，并维持CLDN4在脂筏内的锚定。锚定的CLDN4促进了HCC细胞的表型转变，通过驱动接触蛋白-1向脂筏的动员和激活Notch信号通路，导致对lenvatinib的抗性增加。丹酚酸B是一种CLDN4抑制剂，被证明可以降低HCC患者的HBT和lenvatinib耐药性。此外，联合化疗似乎是HCC患者接受HBT的有效治疗策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cell Reports Medicine Biochemistry, Genetics and Molecular Biology-Biochemistry, Genetics and Molecular Biology (all)

CiteScore

15.00

自引率

1.40%

发文量

231

审稿时长

40 days

期刊介绍： Cell Reports Medicine is an esteemed open-access journal by Cell Press that publishes groundbreaking research in translational and clinical biomedical sciences, influencing human health and medicine. Our journal ensures wide visibility and accessibility, reaching scientists and clinicians across various medical disciplines. We publish original research that spans from intriguing human biology concepts to all aspects of clinical work. We encourage submissions that introduce innovative ideas, forging new paths in clinical research and practice. We also welcome studies that provide vital information, enhancing our understanding of current standards of care in diagnosis, treatment, and prognosis. This encompasses translational studies, clinical trials (including long-term follow-ups), genomics, biomarker discovery, and technological advancements that contribute to diagnostics, treatment, and healthcare. Additionally, studies based on vertebrate model organisms are within the scope of the journal, as long as they directly relate to human health and disease.