Alleviation of liver fibrosis by inhibiting a non-canonical ATF4-regulated enhancer program in hepatic stellate cells
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 stres...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-55738-1 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Li-Xian Yang |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-a9e7e767ade542d4932fd2e4a3918231 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-a9e7e767ade542d4932fd2e4a39182312025-01-12T12:31:57ZengNature PortfolioNature Communications2041-17232025-01-0116111510.1038/s41467-024-55738-1Alleviation of liver fibrosis by inhibiting a non-canonical ATF4-regulated enhancer program in hepatic stellate cellsLi-Xian Yang0Chuangye Qi1Si Lu2Xiang-Shi Ye3Parnaz Merikhian4Du-Yu Zhang5Tao Yao6Jiang-Sha Zhao7Ying Wu8Yongshi Jia9Bo Shan10Jinghai Chen11Xiaozhou Mou12Jia You13Wenbo Li14Yu-Xiong Feng15Zhejiang 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 MedicineDepartment of Biochemistry and Molecular Biology, McGovern Medical School, University of Texas Health Science CenterZhejiang 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 MedicineZhejiang 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 MedicineDepartment of Biochemistry and Molecular Biology, McGovern Medical School, University of Texas Health Science CenterZhejiang 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 MedicineZhejiang 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 MedicineZhejiang 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 MedicineCollege of Life Sciences, Zhejiang Chinese Medical UniversityCancer Center, Department of Radiation Oncology, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical CollegeZhejiang 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 MedicineDepartment 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 MedicineClinical Research Institute, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical CollegeSchool of Life Sciences, Westlake UniversityDepartment of Biochemistry and Molecular Biology, McGovern Medical School, University of Texas Health Science CenterZhejiang 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 MedicineAbstract 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.https://doi.org/10.1038/s41467-024-55738-1 |
| spellingShingle | 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 Alleviation of liver fibrosis by inhibiting a non-canonical ATF4-regulated enhancer program in hepatic stellate cells Nature Communications |
| title | Alleviation of liver fibrosis by inhibiting a non-canonical ATF4-regulated enhancer program in hepatic stellate cells |
| title_full | Alleviation of liver fibrosis by inhibiting a non-canonical ATF4-regulated enhancer program in hepatic stellate cells |
| title_fullStr | Alleviation of liver fibrosis by inhibiting a non-canonical ATF4-regulated enhancer program in hepatic stellate cells |
| title_full_unstemmed | Alleviation of liver fibrosis by inhibiting a non-canonical ATF4-regulated enhancer program in hepatic stellate cells |
| title_short | Alleviation of liver fibrosis by inhibiting a non-canonical ATF4-regulated enhancer program in hepatic stellate cells |
| title_sort | alleviation of liver fibrosis by inhibiting a non canonical atf4 regulated enhancer program in hepatic stellate cells |
| url | https://doi.org/10.1038/s41467-024-55738-1 |
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