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The HLF/IL-6/STAT3 feedforward circuit drives hepatic stellate cell activation to promote liver fibrosis
  1. Dai-Min Xiang1,2,3,
  2. Wen Sun1,
  3. Bei-Fang Ning4,
  4. Teng-Fei Zhou1,
  5. Xiao-Feng Li1,
  6. Wei Zhong5,
  7. Zhuo Cheng1,
  8. Ming-Yang Xia1,
  9. Xue Wang1,
  10. Xing Deng4,
  11. Wei Wang4,6,
  12. Heng-Yu Li1,
  13. Xiu-Liang Cui1,
  14. Shi-Chao Li1,
  15. Bin Wu7,
  16. Wei-Fen Xie4,
  17. Hong-Yang Wang1,3,
  18. Jin Ding1,3
  1. 1 The International Cooperation Laboratory on Signal Transduction, Shanghai Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
  2. 2 Nelson Institute of Environmental Medicine, New York University School of Medicine, New York, USA
  3. 3 National Center for Liver Cancer, Shanghai, China
  4. 4 Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai, China
  5. 5 Department of Gastroenterology, Renji Hospital, Shanghai Jiaotong University, Shanghai, China
  6. 6 Department of Gastroenterology, Lanzhou General Hospital of Lanzhou Military Command, Lanzhou, China
  7. 7 Department of Gastroenterology and Endoscopy, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, China
  1. Correspondence to Hong-Yang Wang and Jin Ding, The International Cooperation Laboratory on Signal Transduction, Shanghai Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, 225 Changhai Road, 200438 Shanghai, China; hywangk{at}, dingjin1103{at}


Background and aims Liver fibrosis is a wound-healing response that disrupts the liver architecture and function by replacing functional parenchyma with scar tissue. Recent progress has advanced our knowledge of this scarring process, but the detailed mechanism of liver fibrosis is far from clear.

Methods The fibrotic specimens of patients and HLF (hepatic leukemia factor)PB/PB mice were used to assess the expression and role of HLF in liver fibrosis. Primary murine hepatic stellate cells (HSCs) and human HSC line Lx2 were used to investigate the impact of HLF on HSC activation and the underlying mechanism.

Results Expression of HLF was detected in fibrotic livers of patients, but it was absent in the livers of healthy individuals. Intriguingly, HLF expression was confined to activated HSCs rather than other cell types in the liver. The loss of HLF impaired primary HSC activation and attenuated liver fibrosis in HLFPB/PB mice. Consistently, ectopic HLF expression significantly facilitated the activation of human HSCs. Mechanistic studies revealed that upregulated HLF transcriptionally enhanced interleukin 6 (IL-6) expression and intensified signal transducer and activator of transcription 3 (STAT3) phosphorylation, thus promoting HSC activation. Coincidentally, IL-6/STAT3 signalling in turn activated HLF expression in HSCs, thus completing a feedforward regulatory circuit in HSC activation. Moreover, correlation between HLF expression and alpha-smooth muscle actin, IL-6 and p-STAT3 levels was observed in patient fibrotic livers, supporting the role of HLF/IL-6/STAT3 cascade in liver fibrosis.

Conclusions In aggregate, we delineate a paradigm of HLF/IL-6/STAT3 regulatory circuit in liver fibrosis and propose that HLF is a novel biomarker for activated HSCs and a potential target for antifibrotic therapy.

  • Liver fibrosis
  • Hepatic stellate cell
  • Hepatic leukemia factor
  • IL-6
  • STAT3

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  • D-MX, WS and B-FN contributed equally.

  • Contributors Study concept and design: JD and H-YW. Acquisition of data: D-MX, WS, B-FN, X-FL, WZ, ZC, M-YX and XW. Analysis and interpretation of data: D-MX and WS. Statistical analysis: D-MX. Drafting of the manuscript: WS. Critical revision of the manuscript: JD. Obtained funding: JD and H-YW. Administrative, technical support: XD, WW, H-YL, T-FZ, X-LC, S-CL, BW and W-FX. Study supervision: JD and H-YW. D-MX, WS and B-FN contributed equally to this work.

  • Funding Supported by grants from the National Key Research and Development Program of China 2017YFA0504503, National Natural Science Foundation of China 81572412, 81372329, 81572897 and 81670546.

  • Competing interests None declared.

  • Patient consent Detail has been removed from this case description/these case descriptions to ensure anonymity. The editors and reviewers have seen the detailed information available and are satisfied that the information backs up the case the authors are making.

  • Ethics approval The Ethical Committee of Eastern Hepatobiliary Surgery Hospital.

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