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

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-Xiong Feng

doi:10.1038/s41467-024-55738-1

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

Nat Commun. 2025 Jan 9;16(1):524. doi: 10.1038/s41467-024-55738-1.

Authors

Li-Xian Yang^#^{1

2

3}, Chuangye Qi^#⁴, Si Lu^#^{1

5}, Xiang-Shi Ye^#^{1

2}, Parnaz Merikhian^{4

6}, Du-Yu Zhang^{1

2}, Tao Yao^{1

2

7}, Jiang-Sha Zhao^{1

2}, Ying Wu^{7

8}, Yongshi Jia³, Bo Shan^{1

2}, Jinghai Chen⁹, Xiaozhou Mou¹⁰, Jia You¹¹, Wenbo Li^{12

13}, Yu-Xiong Feng^{14

15}

Affiliations

¹ Zhejiang Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China.
² Institute of Fundamental and Transdisciplinary Research, Cancer Center, Zhejiang University, Hangzhou, China.
³ Cancer Center, Department of Radiation Oncology, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, China.
⁴ Department of Biochemistry and Molecular Biology, McGovern Medical School, University of Texas Health Science Center, Houston, TX, USA.
⁵ Department of Head and Neck Surgery, Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
⁶ Graduate School of Biomedical Sciences, University of Texas MD Anderson Cancer Center and UTHealth, Houston, TX, USA.
⁷ College of Life Sciences, Zhejiang Chinese Medical University, Hangzhou, China.
⁸ Zhejiang Academy of Traditional Chinese Medicine, Tongde Hospital of Zhejiang Province, Hangzhou, China.
⁹ Department of Cardiology of Second Affiliated Hospital, State Key Laboratory of Transvascular Implantation Devices, Heart Regeneration and Repair Key Laboratory of Zhejiang Province, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China.
¹⁰ Clinical Research Institute, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, China.
¹¹ School of Life Sciences, Westlake University, Hangzhou, China. youjia@westlake.edu.cn.
¹² Department of Biochemistry and Molecular Biology, McGovern Medical School, University of Texas Health Science Center, Houston, TX, USA. wenbo.li@uth.tmc.edu.
¹³ Graduate School of Biomedical Sciences, University of Texas MD Anderson Cancer Center and UTHealth, Houston, TX, USA. wenbo.li@uth.tmc.edu.
¹⁴ Zhejiang Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China. yxfeng@zju.edu.cn.
¹⁵ Institute of Fundamental and Transdisciplinary Research, Cancer Center, Zhejiang University, Hangzhou, China. yxfeng@zju.edu.cn.

^# Contributed equally.

PMID: 39789010
DOI: 10.1038/s41467-024-55738-1

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.

MeSH terms

Activating Transcription Factor 4* / genetics
Activating Transcription Factor 4* / metabolism
Animals
Endoplasmic Reticulum Stress / drug effects
Epigenesis, Genetic / drug effects
Epithelial-Mesenchymal Transition* / drug effects
Epithelial-Mesenchymal Transition* / genetics
Hepatic Stellate Cells* / drug effects
Hepatic Stellate Cells* / metabolism
Hepatic Stellate Cells* / pathology
Humans
Liver Cirrhosis* / drug therapy
Liver Cirrhosis* / genetics
Liver Cirrhosis* / metabolism
Liver Cirrhosis* / pathology
Male
Mice
Mice, Inbred C57BL
Transforming Growth Factor beta / metabolism

Substances

Activating Transcription Factor 4
Transforming Growth Factor beta
Atf4 protein, mouse
ATF4 protein, human