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 () and Yu-Xiong Feng ()
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Li-Xian Yang: Zhejiang University School of Medicine
Chuangye Qi: University of Texas Health Science Center
Si Lu: Zhejiang University School of Medicine
Xiang-Shi Ye: Zhejiang University School of Medicine
Parnaz Merikhian: University of Texas Health Science Center
Du-Yu Zhang: Zhejiang University School of Medicine
Tao Yao: Zhejiang University School of Medicine
Jiang-Sha Zhao: Zhejiang University School of Medicine
Ying Wu: Zhejiang Chinese Medical University
Yongshi Jia: Hangzhou Medical College
Bo Shan: Zhejiang University School of Medicine
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
Yu-Xiong Feng: Zhejiang University School of Medicine

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-024-55738-1

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