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<p>Hepatocellular carcinoma (HCC) is frequently linked to compensatory proliferating hepatocytes in damaged livers, yet the underlying molecular mechanisms remain elusive. The Mediator complex precisely coordinates multiple transcription factors and cofactors to regulate diverse physiological and pathological processes. Here, we discovered that Mediator subunit MED23 is involved in the progression of HCC. Both constitutive and inducible liver-specific ablation of Med23 effectively inhibited HCC development in diethylnitrosamine (DEN)-induced HCC mouse models. Mechanistically, MED23 deficiency significantly compromised hepatocyte cell viability by reducing the stability of the NQO1 protein, thereby leading to an increase in reactive oxygen species (ROS) production. Furthermore, MED23 collaborates with the transcription factor RFX5 to regulate a novel enhancer function for IGF2 expression, which thus influences hepatocyte viability and HCC development. Consistently, overexpression of IGF2 in MED23-deficient HCC cells stabilizes NQO1 and partially restores cell growth and reduces apoptosis. Collectively, our findings underscore the significance of the MED23-IGF2-NQO1 axis in HCC progression and propose a novel therapeutic strategy for the treatment of HCC.</p>

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Targeting MED23 inhibits hepatocellular carcinoma development by suppressing compensatory proliferation and facilitating ROS-mediated cell death

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月24日

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  • Xiaying Zhao,
  • Zhichao Wang,
  • Lihua Min,
  • Dan Cao,
  • Yajing Chu,
  • Chonghui Li,
  • Jiabin Cai,
  • Gang Wang

摘要

Hepatocellular carcinoma (HCC) is frequently linked to compensatory proliferating hepatocytes in damaged livers, yet the underlying molecular mechanisms remain elusive. The Mediator complex precisely coordinates multiple transcription factors and cofactors to regulate diverse physiological and pathological processes. Here, we discovered that Mediator subunit MED23 is involved in the progression of HCC. Both constitutive and inducible liver-specific ablation of Med23 effectively inhibited HCC development in diethylnitrosamine (DEN)-induced HCC mouse models. Mechanistically, MED23 deficiency significantly compromised hepatocyte cell viability by reducing the stability of the NQO1 protein, thereby leading to an increase in reactive oxygen species (ROS) production. Furthermore, MED23 collaborates with the transcription factor RFX5 to regulate a novel enhancer function for IGF2 expression, which thus influences hepatocyte viability and HCC development. Consistently, overexpression of IGF2 in MED23-deficient HCC cells stabilizes NQO1 and partially restores cell growth and reduces apoptosis. Collectively, our findings underscore the significance of the MED23-IGF2-NQO1 axis in HCC progression and propose a novel therapeutic strategy for the treatment of HCC.