Related Experiment Video

Updated: Apr 12, 2026

Drug-Induced Senescence in Liver Cells Promotes M2 Macrophage Polarization: Implications for Tyrosine Kinase Inhibitor-Associated Hepatotoxicity
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Drug-Induced Senescence in Liver Cells Promotes M2 Macrophage Polarization: Implications for Tyrosine Kinase Inhibitor-Associated Hepatotoxicity

Published on: October 17, 2025

646

YEATS2/TAK1 axis mediates TGF-β1 driven adaptive resistance to sorafenib in hepatocellular carcinoma

Lizhi Bai1, Yu Wang2, Guanyi Li1

  • 1Department of Thoracic Surgery, Affiliated Zhongshan Hospital of Dalian University, Dalian, 115007, China.

Biochemical and Biophysical Research Communications
|April 10, 2026
PubMed

Insights

Hepatocellular carcinoma (HCC) patients developing sorafenib resistance can be treated by targeting the YEATS2-TAK1 pathway. This pathway mediates resistance driven by TGF-β1, offering new therapeutic strategies for HCC.

Area of Science:

  • Hepatocellular Carcinoma Research
  • Molecular Oncology
  • Drug Resistance Mechanisms

Background:

  • Sorafenib is a standard treatment for hepatocellular carcinoma (HCC), but drug resistance limits its efficacy.
  • The transforming growth factor-beta 1 (TGF-β1) pathway is implicated in HCC development, and its role in sorafenib resistance requires further investigation.

Purpose of the Study:

  • To elucidate the mechanism of TGF-β1-mediated sorafenib resistance in HCC.
  • To identify novel therapeutic targets for overcoming sorafenib resistance in HCC.

Main Methods:

  • Analysis of gene expression data from TGF-β1-treated and sorafenib-resistant HCC cell lines (GEO database).
  • Gene silencing of YEATS2 and assessment of sorafenib sensitivity.
  • Investigating the interaction between YEATS2 and TGF-β-activated kinase 1 (TAK1) using structural modeling, molecular dynamics simulation, and co-immunoprecipitation.
  • Inhibition of TAK1 activity to evaluate its role in resistance.

Main Results:

  • YEATS2 was identified as a TGF-β1-responsive gene upregulated in sorafenib-resistant HCC models, correlating with poor prognosis.
  • Silencing YEATS2 restored sorafenib sensitivity in HCC cells under TGF-β1 stimulation.
  • YEATS2 physically interacts with TAK1, enhancing its activation and downstream signaling.
  • Inhibition of TAK1 abrogated YEATS2-mediated adaptive resistance to sorafenib.

Conclusions:

  • YEATS2 acts as a key mediator of TGF-β1-driven adaptive resistance to sorafenib in HCC.
  • The YEATS2-TAK1 signaling axis represents a novel therapeutic target for overcoming sorafenib resistance in HCC.
Keywords:
Hepatocellular carcinomaResistanceSorafenibTAK1TGF-β1YEATS2

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