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<p>Liver fibrosis is driven by the persistent activation of hepatic stellate cells (HSCs) through inflammatory factors released from various cell types, including stressed hepatocytes, yet the underlying mechanisms are not fully understood. Here, we show that minichromosome maintenance complex component 7 (MCM7) is predominantly upregulated in hepatocytes of liver fibrosis mouse models and in liver cirrhosis patients. Hepatocyte-specific overexpression of MCM7 accelerates fibrosis progression, while its knockdown mitigates it in <i>Schistosoma japonicum</i>- and CCl4-induced fibrosis models. Mechanistically, MCM7 interacts with SHCBP1, promoting <i>IL11</i> transcription via the SHCBP1-RACGAP1-STAT3 axis. Moreover, neutralizing IL11 significantly attenuated the enhanced activation of HSCs induced by MCM7 overexpression in vitro. Additionally, recombinant human IL11 (rhIL11), which effectively inhibits endogenous IL11 signaling, significantly attenuated the exacerbation of liver fibrosis driven by MCM7 overexpression in vivo. These findings identify MCM7 in hepatocytes as a key regulator of HSC activation through IL11 and highlight its potential as a therapeutic target for liver fibrosis treatment.</p><p></p>

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MCM7 promotes liver fibrosis by transcriptionally regulating IL11 via the SHCBP1-RACGAP1-STAT3 axis

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年8月11日

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  • Cheng Wang,
  • Mengling Ye,
  • Tian Xu,
  • Jiayi Feng,
  • Jiaxi Zhang,
  • Wenjuan Yang,
  • Qian Fang,
  • Guangbo Mei,
  • Xuejun Zhao,
  • Kejun Liu,
  • Huiqin Zhou,
  • Yaru Yu,
  • Yujun Peng,
  • Na Kuang,
  • Xuebing Qiu,
  • Qinping Zhong,
  • Hongying Zong,
  • Huifen Dong,
  • Zhenping Ming,
  • Yan Xiong,
  • Rui Zhou

摘要

Liver fibrosis is driven by the persistent activation of hepatic stellate cells (HSCs) through inflammatory factors released from various cell types, including stressed hepatocytes, yet the underlying mechanisms are not fully understood. Here, we show that minichromosome maintenance complex component 7 (MCM7) is predominantly upregulated in hepatocytes of liver fibrosis mouse models and in liver cirrhosis patients. Hepatocyte-specific overexpression of MCM7 accelerates fibrosis progression, while its knockdown mitigates it in Schistosoma japonicum- and CCl4-induced fibrosis models. Mechanistically, MCM7 interacts with SHCBP1, promoting IL11 transcription via the SHCBP1-RACGAP1-STAT3 axis. Moreover, neutralizing IL11 significantly attenuated the enhanced activation of HSCs induced by MCM7 overexpression in vitro. Additionally, recombinant human IL11 (rhIL11), which effectively inhibits endogenous IL11 signaling, significantly attenuated the exacerbation of liver fibrosis driven by MCM7 overexpression in vivo. These findings identify MCM7 in hepatocytes as a key regulator of HSC activation through IL11 and highlight its potential as a therapeutic target for liver fibrosis treatment.