Alleviation of liver fibrosis by inhibiting a non-canonical ATF4-regulated enhancer program in hepatic stellate cells
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.
Authors
- Lu Si (ORCID: https://orcid.org/0000-0002-2123-9761)
- Yongshi Jia
- Chuangye Qi
- Jiang‐Sha Zhao
- Bo Shan (ORCID: https://orcid.org/0000-0002-1675-5809)
- Parnaz Merikhian (ORCID: https://orcid.org/0000-0001-7482-836X)
- Jinghai Chen (ORCID: https://orcid.org/0000-0002-5401-047X)
- Yuxiong Feng (ORCID: https://orcid.org/0000-0002-9086-4448)
- Du-Yu Zhang
- Tao Yao
- Xiaozhou Mou (ORCID: https://orcid.org/0000-0002-3234-1737)
- Wenbo Li (ORCID: https://orcid.org/0000-0002-9042-5664)
- Jia Emil You (ORCID: https://orcid.org/0009-0001-2931-0905)
- Ying Wu (ORCID: https://orcid.org/0009-0008-1808-3349)
- Lixian Yang
- Xiang-Shi Ye
Institutions
- Zhejiang Chinese Medical University (CN)
- The University of Texas MD Anderson Cancer Center (US)
- Sir Run Run Shaw Hospital (CN)
- Westlake University (CN)
- Tongde Hospital of Zhejiang Province (CN)
- Zhejiang Provincial People's Hospital (CN)
- Second Affiliated Hospital of Zhejiang University (CN)
- Zhejiang University-University of Edinburgh Institute (CN)
- The University of Texas Health Science Center (US)
- Hangzhou Medical College (CN)
- First Affiliated Hospital Zhejiang University (CN)
- Zhejiang University (CN)
- The University of Texas Health Science Center at Houston (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-01-09
- DOI
- https://doi.org/10.1038/s41467-024-55738-1
- Citations
- 32
- Primary Topic
- Liver physiology and pathology
- Type
- article
- Field-Weighted Citation Impact
- 42.30
Funders
- National Natural Science Foundation of China
- Ministry of Science and Technology of the People's Republic of China
- Zhejiang University
- Peking University