ArticleHepatology (Baltimore, Md.)2026
The MASTL/YBX1/PAK4 axis regulated by stress-activated STK24 triggers lenvatinib resistance and tumor progression in HCC.
Article in Hepatology (Baltimore, Md.), 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.
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Who cites it
4 citing papers in PubMed.
- Activation of Nerve Growth Factor signaling limits the response to lenvatinib in hepatocellular carcinoma.Signal transduction and targeted therapy · 2026Article
- YBX1 as an adaptive RNA hub in cancer: linking state-dependent RNA regulation to tumor immunity, metabolic reprogramming, and therapy resistance.Frontiers in immunology · 2026Review
- Identification of a Prognostic Gene Signature Based on Lenvatinib Resistance in Hepatocellular Carcinoma with Functional Validation of the Key Gene CPB2.Journal of hepatocellular carcinoma · 2026Article
- Exploring the Proteomic Landscape of Cochlear Implant Trauma: An iTRAQ-Based Quantitative Analysis Utilizing an Ex Vivo Model.Journal of clinical medicine · 2025Article
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16 authors.
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Abstract
BACKGROUND AND
aimsMany 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
resultsWe 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. Then, we utilized subcutaneous mouse models, half maximal inhibitory concentration (IC 50 ) measurements, and colony formation assays to determine the biological function of MASTL in promoting tumor growth and mediating resistance to lenvatinib. To further elucidate the underlying mechanisms, we performed co-immunoprecipitation and mass spectrometry analyses, revealing that MASTL facilitates the phosphorylation of Y-box binding protein-1 (YBX1). Using chromatin immunoprecipitation assays, we subsequently confirmed that phosphorylated YBX1 transcriptionally activates PAK4, identifying PAK4 as a downstream effector of the MASTL pathway. Moreover, mass spectrometry and phosphorylation analysis indicated that serine/threonine protein kinase 24 (STK24), a stress-responsive kinase, can activate MASTL in HCC under lenvatinib exposure. Notably, disruption of the MASTL/YBX1/PAK4 signaling axis restored HCC sensitivity to lenvatinib.
conclusionsWe propose that the MASTL/YBX1/PAK4 axis, which is activated by stress-induced STK24, plays a crucial role in lenvatinib resistance. Inhibiting this axis by targeting MASTL effectively overcomes lenvatinib resistance in HCC.
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