2. Academic Validation
  3. MCM7 promotes liver fibrosis by transcriptionally regulating IL11 via the SHCBP1-RACGAP1-STAT3 axis

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

  • Cell Death Dis. 2025 Aug 11;16(1):608. doi: 10.1038/s41419-025-07937-x.
Cheng Wang 1 2,  Mengling Ye 3,  Tian Xu 1 2 4,  Jiayi Feng 1 2,  Jiaxi Zhang 2,  Wenjuan Yang 1 2,  Qian Fang 2,  Guangbo Mei 1 2,  Xuejun Zhao 2 5,  Kejun Liu 2,  Huiqin Zhou 2,  Yaru Yu 2,  Yujun Peng 2,  Na Kuang 6,  Xuebing Qiu 7,  Qinping Zhong 8,  Hongying Zong 8,  Huifen Dong 2,  Zhenping Ming 9,  Yan Xiong 10,  Rui Zhou 11 12
Affiliations

Affiliations

  • 1 Hubei Province Key Laboratory of Allergy and Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan, Hubei, China.
  • 2 Department of Medical Parasitology, School of Basic Medical Sciences, Wuhan University, Wuhan, Hubei, China.
  • 3 Department of Research, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, China.
  • 4 Department of Clinical Laboratory, Fuwai Yunnan Cardiovascular Hospital, Kunming, Yunnan, China.
  • 5 Department of Clinical Laboratory, Guizhou Provincial People's Hospital, Guiyang, Guizhou, China.
  • 6 Ecological Station of Oncomelania hupensis in Gong'an County, Jingzhou, Hubei, China.
  • 7 Kindstar Diagnostics, Wuhan, Hubei, China.
  • 8 Teaching Center for Basic Medical Experiments, School of Basic Medical Sciences, Wuhan University, Wuhan, Hubei, China.
  • 9 Department of Medical Parasitology, School of Basic Medical Sciences, Wuhan University, Wuhan, Hubei, China. mingzp@whu.edu.cn.
  • 10 Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, National Quality Control Center for Donated Organ Procurement, Hubei Key Laboratory of Medical Technology on Transplantation, Hubei Provincial Clinical Research Center for Natural Polymer Biological Liver, Wuhan, Hubei, China. yanaxiong@whu.edu.cn.
  • 11 Hubei Province Key Laboratory of Allergy and Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan, Hubei, China. ruizhou@whu.edu.cn.
  • 12 Department of Medical Parasitology, School of Basic Medical Sciences, Wuhan University, Wuhan, Hubei, China. ruizhou@whu.edu.cn.
PMID: 40789837 DOI: 10.1038/s41419-025-07937-x
Abstract

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. Liver fibrosis conditions induce upregulation of MCM7 and SHCBP1 in hepatocytes. Elevated MCM7 promotes the interaction between SHCBP1 and RACGAP1, which in turn facilitates the binding of RACGAP1 to STAT3 and induces its phosphorylation. Phosphorylated STAT3 translocates to the nucleus, activating transcription of the IL11 gene. Secreted IL11 acts in a paracrine manner to enhance hepatic stellate cell activation, further exacerbating liver fibrosis.

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