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An Oncogenic Hepatocyte-Induced Orthotopic Mouse Model of Hepatocellular Cancer Arising in the Setting of Hepatic Inflammation and Fibrosis
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EZH2: From Oncogenic Driver to Therapeutic Target for Overcoming Drug Resistance in Hepatocellular Carcinoma

Weijing Tang1, Jianzhong Cao1, Nan Wang2

  • 1School of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, People's Republic of China.

Journal of Hepatocellular Carcinoma
|January 7, 2026
PubMed

Insights

Enhancer of Zeste Homolog 2 (EZH2) drives drug resistance in hepatocellular carcinoma (HCC). Targeting EZH2 with inhibitors or PROTACs may re-sensitize HCC to therapies, offering new treatment avenues.

Area of Science:

  • Oncology
  • Epigenetics
  • Molecular Biology

Background:

  • Hepatocellular carcinoma (HCC) presents significant therapeutic challenges due to widespread drug resistance.
  • Enhancer of Zeste Homolog 2 (EZH2), a key epigenetic regulator, is overexpressed in HCC and contributes to treatment failure.

Purpose of the Study:

  • To review the mechanisms by which EZH2 promotes resistance to various HCC therapies.
  • To evaluate current and emerging EZH2 inhibitors for HCC treatment.
  • To identify future research directions for EZH2-targeted therapies in HCC.

Main Methods:

  • Literature review of studies investigating EZH2 function in HCC drug resistance.
  • Analysis of EZH2's role in modulating cell survival pathways (cell cycle, apoptosis, DNA repair).
  • Assessment of EZH2's impact on the tumor microenvironment and immunotherapy response.
  • Evaluation of EZH2 inhibitors, including small molecules and PROTACs.

Main Results:

  • EZH2 promotes resistance by enhancing cell survival pathways and DNA repair.
  • EZH2 contributes to an immunosuppressive tumor microenvironment, hindering immunotherapy.
  • Various EZH2 inhibitors, including novel modalities like PROTACs, show promise in preclinical models.
  • Combination strategies involving EZH2 inhibition may overcome resistance.

Conclusions:

  • EZH2 is a critical mediator of drug resistance in hepatocellular carcinoma.
  • Targeting EZH2 offers a promising strategy to re-sensitize HCC to chemotherapy, targeted therapy, and immunotherapy.
  • Further research into combination therapies and biomarker development is essential for advancing EZH2-targeted treatments.
Keywords:
EZH2epigeneticshepatocellular carcinomamechanisms of drug resistance

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