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

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.

The MASTL/YBX1/PAK4 axis regulated by stress-activated STK24 triggers lenvatinib resistance and tumor progression in HCC.

Background And Aims: Many patients with HCC present inadequate responses to lenvatinib therapy. Therefore, it is important to elucidate the underlying mechanisms of resistance and to formulate effective reversal strategies.

Approach And Results: We conducted transcriptome and proteome sequencing analyses of lenvatinib-resistant cell lines and patient-derived tissues, identifying microtubule-associated serine/threonine kinase-like (MASTL) as a critical factor associated with lenvatinib resistance in HCC.

FMO2 cancer-associated fibroblasts sensitize anti-PD-1 therapy in patients with hepatocellular carcinoma.

Background: The efficacy of immune checkpoint inhibitors (ICIs) for hepatocellular carcinoma (HCC) is limited by heterogeneity in individual responses to therapy. The heterogeneous phenotypes and crucial roles of cancer-associated fibroblasts (CAFs) in immunotherapy resistance remain largely unclear.

Methods: A specific CAF subset was identified by integrating comprehensive single-cell RNA sequencing, spatial transcriptomics and transcriptome profiling of patients with HCC with different responses to antiprogrammed cell death protein 1 (anti-PD-1) therapy.

Cordycepin mediates pyroptosis in HCC through the upregulation of TXNIP and synergizes with anti-PD-L1 immunotherapy.

Background: Immune checkpoint inhibitors are effective treatments for HCC; however, their therapeutic efficacy is often limited by the development of drug resistance. Therefore, investigating new combination therapeutics involving immune checkpoint inhibitors is critical to improving patient prognosis. In this study, we investigated the therapeutic effect of cordycepin (COR) in HCC and its synergistic effect with anti-programmed cell death ligand 1 (anti-PD-L1) immunotherapy.

Deubiquitination of CIB1 by USP14 promotes lenvatinib resistance via the PAK1-ERK1/2 axis in hepatocellular carcinoma.

Lenvatinib is the most common multitarget receptor tyrosine kinase inhibitor for the treatment of advanced hepatocellular carcinoma (HCC). Acquired resistance to lenvatinib is one of the major factors leading to the failure of HCC treatment, but the underlying mechanism has not been fully characterized. We established lenvatinib-resistant cell lines, cell-derived xenografts (CDXs) and patient-derived xenografts (PDXs) and obtained lenvatinib-resistant HCC tumor tissues for further study.