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Histone methyltransferase Suv39h1 regulates hepatic stellate cell activation and is targetable in liver fibrosis
  1. Ming Kong1,
  2. Junjing Zhou2,
  3. Aoqi Kang3,
  4. Yameng Kuai3,
  5. Huihui Xu3,
  6. Min Li4,
  7. Xiulian Miao5,
  8. Yan Guo5,
  9. Zhiwen Fan6,
  10. Yong Xu1,
  11. Zilong Li1
  1. 1 State Key Laboratory of Natural Medicines, Department of Pharmacology, China Pharmaceutical University, Nanjing, People's Republic of China
  2. 2 Department of Hepatobiliary Surgery, Affiliated Hospital of JiangnanUniversity, Wuxi, People's Republic of China
  3. 3 Key Laboratory of Targeted Intervention of Cardiovascular Disease and Collaborative Innovation Center for Cardiovascular Translational Medicine, Department of Pathophysiology, Nanjing Medical University, Nanjing, People's Republic of China
  4. 4 Department of Pathophysiology, Jiangsu Health Vocational College, Nanjing, People's Republic of China
  5. 5 Institute of Biomedical Research and College of Life Sciences, Liaocheng University, Liaocheng, People's Republic of China
  6. 6 Department of Pathology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, People's Republic of China
  1. Correspondence to Zilong Li, China Pharmaceutical University, Nanjing, People's Republic of China; lzl1114{at}; Dr Yong Xu, China Pharmaceutical University, Nanjing, China; yjxu{at}; Dr Zhiwen Fan, Pathology, Nanjing Drum Tower Hospital, Nanjing, People's Republic of China; fanzhiwenfff{at}


Objective Liver fibrosis is a prelude to a host of end-stage liver diseases. Hepatic stellate cells (HSCs), switching from a quiescent state to myofibroblasts, are the major source for excessive production of extracellular matrix proteins. In the present study, we investigated the role of Suv39h1, a lysine methyltransferase, in HSC-myofibroblast transition and the implication in liver fibrosis.

Design HSC-specific or myofibroblast-specific Suv39h1 deletion was achieved by crossbreeding the Suv39h1 f/f mice to the Lrat-Cre mice or the Postn-CreERT2 mice. Liver fibrosis was induced by CCl4 injection or bile duct ligation.

Results We report that Suv39h1 expression was universally upregulated during HSC-myofibroblast transition in different cell and animal models of liver fibrosis and in human cirrhotic liver tissues. Consistently, Suv39h1 knockdown blocked HSC-myofibroblast transition in vitro. HSC-specific or myofibroblast-specific deletion of Suv39h1 ameliorated liver fibrosis in mice. More importantly, Suv39h1 inhibition by a small-molecule compound chaetocin dampened HSC-myofibroblast transition in cell culture and mitigated liver fibrosis in mice. Mechanistically, Suv39h1 bound to the promoter of heme oxygenase 1 (HMOX1) and repressed HMOX1 transcription. HMOX1 depletion blunted the effects of Suv39h1 inhibition on HSC-myofibroblast transition in vitro and liver fibrosis in vivo. Transcriptomic analysis revealed that HMOX1 might contribute to HSC-myofibroblast transition by modulating retinol homeostasis. Finally, myofibroblast-specific HMOX1 overexpression attenuated liver fibrosis in both a preventive scheme and a therapeutic scheme.

Conclusions Our data demonstrate a previously unrecognised role for Suv39h1 in liver fibrosis and offer proof-of-concept of its targetability in the intervention of cirrhosis.

  • hepatic fibrosis

Data availability statement

Data are available upon reasonable request. The data that support the findings of this study are available upon reasonable request.

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Data availability statement

Data are available upon reasonable request. The data that support the findings of this study are available upon reasonable request.

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  • MK and JZ contributed equally.

  • Contributors ZL, YX and MK conceived the project; MK, ZF and ZL designed experiments; MK, JZ, AK, YK, HX, ML, XM and YG performed experiments, collected data and analysed data; YX wrote the manuscript; all authors edited the manuscript; YX, ZL, ZF and JZ secured funding; YX acts as the gaurantor.

  • Funding Wuxi Taihu Lake Talent Plan, Supports for Leading Talents in Medical and Health Profession (to J Zhou)

  • Competing interests None declared.

  • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting or dissemination plans of this research.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

  • Please re-arrange the order in which the co-corresponding authors appear so that Dr. Zilong Li comes first, followed by Dr. Yong Xu, then by Dr. Zhiwen Fan.

  • This proof was generated prior to the receipt of some last-minute change in authorship. Please send a new version with all the changes incorporated to me for final approval. Thank you.

  • Please delete this funding source.

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