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Alleviation of liver fibrosis by inhibiting a non-canonical ATF4-regulated enhancer program in hepatic stellate cells

Author

Listed:
  • Li-Xian Yang

    (Zhejiang University School of Medicine
    Zhejiang University
    Hangzhou Medical College)

  • Chuangye Qi

    (University of Texas Health Science Center)

  • Si Lu

    (Zhejiang University School of Medicine
    Zhejiang University School of Medicine)

  • Xiang-Shi Ye

    (Zhejiang University School of Medicine
    Zhejiang University)

  • Parnaz Merikhian

    (University of Texas Health Science Center
    University of Texas MD Anderson Cancer Center and UTHealth)

  • Du-Yu Zhang

    (Zhejiang University School of Medicine
    Zhejiang University)

  • Tao Yao

    (Zhejiang University School of Medicine
    Zhejiang University
    Zhejiang Chinese Medical University)

  • Jiang-Sha Zhao

    (Zhejiang University School of Medicine
    Zhejiang University)

  • Ying Wu

    (Zhejiang Chinese Medical University
    Tongde Hospital of Zhejiang Province)

  • Yongshi Jia

    (Hangzhou Medical College)

  • Bo Shan

    (Zhejiang University School of Medicine
    Zhejiang University)

  • Jinghai Chen

    (Zhejiang University School of Medicine)

  • Xiaozhou Mou

    (People’s Hospital of Hangzhou Medical College)

  • Jia You

    (Westlake University)

  • Wenbo Li

    (University of Texas Health Science Center
    University of Texas MD Anderson Cancer Center and UTHealth)

  • Yu-Xiong Feng

    (Zhejiang University School of Medicine
    Zhejiang University)

Abstract

Liver fibrosis is a critical liver disease that can progress to more severe manifestations, such as cirrhosis, yet no effective targeted therapies are available. Here, we identify that ATF4, a master transcription factor in ER stress response, promotes liver fibrosis by facilitating a stress response-independent epigenetic program in hepatic stellate cells (HSCs). Unlike its canonical role in regulating UPR genes during ER stress, ATF4 activates epithelial-mesenchymal transition (EMT) gene transcription under fibrogenic conditions. HSC-specific depletion of ATF4 suppresses liver fibrosis in vivo. Mechanistically, TGFβ resets ATF4 to orchestrate a unique enhancer program for the transcriptional activation of pro-fibrotic EMT genes. Analysis of human data confirms a strong correlation between HSC ATF4 expression and liver fibrosis progression. Importantly, a small molecule inhibitor targeting ATF4 translation effectively mitigates liver fibrosis. Together, our findings identify a mechanism promoting liver fibrosis and reveal new opportunities for treating this otherwise non-targetable disease.

Suggested Citation

  • Li-Xian Yang & Chuangye Qi & Si Lu & Xiang-Shi Ye & Parnaz Merikhian & Du-Yu Zhang & Tao Yao & Jiang-Sha Zhao & Ying Wu & Yongshi Jia & Bo Shan & Jinghai Chen & Xiaozhou Mou & Jia You & Wenbo Li & Yu-, 2025. "Alleviation of liver fibrosis by inhibiting a non-canonical ATF4-regulated enhancer program in hepatic stellate cells," Nature Communications, Nature, vol. 16(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-024-55738-1
    DOI: 10.1038/s41467-024-55738-1
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    References listed on IDEAS

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    1. P. Ramachandran & R. Dobie & J. R. Wilson-Kanamori & E. F. Dora & B. E. P. Henderson & N. T. Luu & J. R. Portman & K. P. Matchett & M. Brice & J. A. Marwick & R. S. Taylor & M. Efremova & R. Vento-Tor, 2019. "Resolving the fibrotic niche of human liver cirrhosis at single-cell level," Nature, Nature, vol. 575(7783), pages 512-518, November.
    2. Gioele La Manno & Ruslan Soldatov & Amit Zeisel & Emelie Braun & Hannah Hochgerner & Viktor Petukhov & Katja Lidschreiber & Maria E. Kastriti & Peter Lönnerberg & Alessandro Furlan & Jean Fan & Lars E, 2018. "RNA velocity of single cells," Nature, Nature, vol. 560(7719), pages 494-498, August.
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