Related Experiment Video

Updated: Sep 19, 2025

Identification of Transcription Factor Regulators using Medium-Throughput Screening of Arrayed Libraries and a Dual-Luciferase-Based Reporter
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The MASTL/YBX1/PAK4 axis regulated by stress-activated STK24 triggers lenvatinib resistance and tumor progression in

Bu-Gang Liang1, Yi-Min Zheng1, Ming-Hao Xu1

  • 1Department of Hepatobiliary Surgery and Liver Transplantation, Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China.

Hepatology (Baltimore, Md.)
|June 2, 2025
PubMed
Abstract

Insights

Microtubule-associated serine/threonine kinase-like (MASTL) drives lenvatinib resistance in hepatocellular carcinoma (HCC) by activating the YBX1/PAK4 pathway. Targeting MASTL overcomes this resistance, offering a new therapeutic strategy for HCC patients.

Area of Science:

  • Hepatocellular Carcinoma Research
  • Molecular Oncology
  • Drug Resistance Mechanisms

Background:

  • Hepatocellular carcinoma (HCC) patients often show poor responses to lenvatinib treatment.
  • Understanding lenvatinib resistance mechanisms is crucial for developing effective therapies.

Purpose of the Study:

  • To identify key factors and pathways involved in lenvatinib resistance in HCC.
  • To explore strategies for overcoming lenvatinib resistance.

Main Methods:

  • Transcriptome and proteome sequencing of resistant HCC cell lines and tissues.
  • In vivo mouse models and in vitro assays (IC50, colony formation) to assess MASTL function.
  • Co-immunoprecipitation, mass spectrometry, and chromatin immunoprecipitation assays to elucidate signaling pathways.

Main Results:

  • Microtubule-associated serine/threonine kinase-like (MASTL) was identified as a critical factor in lenvatinib resistance.
  • MASTL promotes HCC growth and lenvatinib resistance by phosphorylating Y-box binding protein-1 (YBX1).
  • Phosphorylated YBX1 activates PAK4 transcriptionally, forming the MASTL/YBX1/PAK4 axis.
  • Stress-induced STK24 activates MASTL in HCC under lenvatinib exposure.
  • Disrupting the MASTL/YBX1/PAK4 axis restored sensitivity to lenvatinib.

Conclusions:

  • The MASTL/YBX1/PAK4 axis, activated by STK24, is a key driver of lenvatinib resistance in HCC.
  • Targeting MASTL effectively overcomes lenvatinib resistance, presenting a promising therapeutic approach.
Keywords:
HCCMASTLcombination therapylenvatinib resistancephosphorylation modification

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