ECM1 expression in chronic liver disease: Regulation by EGF/STAT1 and IFNγ/NRF2 signalling
Background & Aims: The extracellular matrix protein 1 (ECM1) is essential for liver homeostasis by keeping latent transforming growth factor-beta quiescent. Upon hepatocyte damage, ECM1 is significantly downregulated, facilitating fibrosis and chronic liver disease (CLD) progression. We inve...
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2025-08-01
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| author | Yujia Li Chenjun Huang Weiguo Fan Seddik Hammad Cyrill Géraud Lea Berger Shanshan Wang Ye Yao Chenhao Tong Claudia Rubie Laura Kim Feiner Zeribe C. Nwosu Frederik Link Pia Erdösi Weronika Piorońska Kerry Gould Christoph Meyer Rilu Feng Hui Liu Chen Shao Bing Sun Huiguo Ding Roman Liebe Matthias P.A. Ebert Honglei Weng Matthias Glanemann Chunfang Gao Peter ten Dijke Steven Dooley Sai Wang |
| author_facet | Yujia Li Chenjun Huang Weiguo Fan Seddik Hammad Cyrill Géraud Lea Berger Shanshan Wang Ye Yao Chenhao Tong Claudia Rubie Laura Kim Feiner Zeribe C. Nwosu Frederik Link Pia Erdösi Weronika Piorońska Kerry Gould Christoph Meyer Rilu Feng Hui Liu Chen Shao Bing Sun Huiguo Ding Roman Liebe Matthias P.A. Ebert Honglei Weng Matthias Glanemann Chunfang Gao Peter ten Dijke Steven Dooley Sai Wang |
| author_sort | Yujia Li |
| collection | DOAJ |
| description | Background & Aims: The extracellular matrix protein 1 (ECM1) is essential for liver homeostasis by keeping latent transforming growth factor-beta quiescent. Upon hepatocyte damage, ECM1 is significantly downregulated, facilitating fibrosis and chronic liver disease (CLD) progression. We investigated the mechanism of ECM1 regulation in hepatocytes under pathophysiological conditions. Methods: We used promoter analysis to predict Ecm1 transcriptional regulators and assessed the expression of Ecm1-related genes by single-cell RNA sequencing (scRNA-seq) and bulk RNA-seq. Functional assays were performed with AML12 cells, mouse and human primary hepatocytes, and liver tissue from mice and patients. Results: In healthy hepatocytes, epidermal growth factor (EGF)/EGF receptor (EGFR) signalling sustains ECM1 expression through phosphorylating signal transducer and activator of transcription 1 (STAT1) at serine727 (S727), thus enhancing its binding to the ECM1 promoter and boosting gene transcription. This process is disrupted during liver inflammation by interferon gamma (IFNγ), which downregulates EGFR and inhibits EGF/EGFR/STAT1-mediated ECM1 promoter binding. Mechanistically, IFNγ-induced STAT1 phosphorylation at tyrosine701 (Y701) impairs the binding of p-STAT1 S727 to the ECM1 promoter. Additionally, IFNγ induces nuclear factor erythroid 2-related factor 2 (NRF2) nuclear translocation, which repressively binds to the promoter of ECM1, further reducing its expression. These findings are confirmed in several CLD mouse models (n = 2–6). Moreover, AAV8-ECM1 attenuates liver fibrosis and injury in Western diet-fed mice (n = 8–10), counteracting the effects of EGF signalling inhibition and IFNγ/NRF2 activation. In CLD patients (n = 22), ECM1 levels correlate positively with EGFR expression (p <0.0001) and negatively with IFNγ/NRF2 activation (p <0.0001). Conclusions: EGF/STAT1 signalling promotes whereas IFNγ/NRF2 inhibits ECM1 expression in hepatocytes in health or disease, respectively. ECM1 has the potential to be developed as an antifibrotic agent, particularly in inflammation- or reactive oxygen species-driven CLD. Impact and implications: This study reveals the regulatory mechanism of ECM1 in hepatocytes, demonstrating that EGF/STAT1 maintains ECM1 expression to prevent fibrosis, whereas IFNγ/NRF2 signalling inhibits ECM1 during chronic liver inflammation, thereby accelerating disease progression. These findings are important for researchers and clinicians to understand the pathogenesis of liver fibrosis, especially in CLD driven by inflammation or oxidative stress. Clinically, ECM1 levels correlate positively with EGFR expression and negatively with IFNγ/NRF2 activation, providing potential antifibrotic targets for CLD patients. |
| format | Article |
| id | doaj-art-2ac51d680e104cff961a647f00a9ca7c |
| institution | Kabale University |
| issn | 2589-5559 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | JHEP Reports |
| spelling | doaj-art-2ac51d680e104cff961a647f00a9ca7c2025-08-20T03:28:13ZengElsevierJHEP Reports2589-55592025-08-017810142310.1016/j.jhepr.2025.101423ECM1 expression in chronic liver disease: Regulation by EGF/STAT1 and IFNγ/NRF2 signallingYujia Li0Chenjun Huang1Weiguo Fan2Seddik Hammad3Cyrill Géraud4Lea Berger5Shanshan Wang6Ye Yao7Chenhao Tong8Claudia Rubie9Laura Kim Feiner10Zeribe C. Nwosu11Frederik Link12Pia Erdösi13Weronika Piorońska14Kerry Gould15Christoph Meyer16Rilu Feng17Hui Liu18Chen Shao19Bing Sun20Huiguo Ding21Roman Liebe22Matthias P.A. Ebert23Honglei Weng24Matthias Glanemann25Chunfang Gao26Peter ten Dijke27Steven Dooley28Sai Wang29Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, GermanyDepartment of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Department of Clinical Laboratory Medicine Center, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, ChinaKey Laboratory of Multi-Cell Systems, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, ChinaDepartment of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, GermanySection of Clinical and Molecular Dermatology, Department of Dermatology, Venereology, and Allergology, University Medical Center and Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; DKFZ Hector Cancer Institute at the University Medical Center Mannheim, Mannheim, GermanySection of Clinical and Molecular Dermatology, Department of Dermatology, Venereology, and Allergology, University Medical Center and Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, GermanyBeijing Institute of Hepatology, Beijing You’an Hospital, Capital Medical University, Beijing, ChinaDepartment of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, GermanyDepartment of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, GermanyDepartment of General-, Visceral-, Vascular- and Pediatric Surgery, Saarland University, Homburg/Saar, GermanyDepartment of General-, Visceral-, Vascular- and Pediatric Surgery, Saarland University, Homburg/Saar, GermanyDepartment of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY, USADepartment of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, GermanyDepartment of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, GermanyDepartment of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, GermanyDepartment of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, GermanyDepartment of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, GermanyDepartment of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Department of Endocrinology and Metabolism, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, ChinaDepartment of Pathology, Beijing You’an Hospital, Affiliated with Capital Medical University, Beijing, ChinaDepartment of Pathology, Beijing You’an Hospital, Affiliated with Capital Medical University, Beijing, ChinaState Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, ChinaDepartment of Gastroenterology and Hepatology, Beijing You’an Hospital, Affiliated with Capital Medical University, Beijing, ChinaKlinik für Gastroenterologie, Hepatologie und Transplantationsmedizin, Universitätsklinikum Essen, Essen, GermanyDepartment of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; DKFZ Hector Cancer Institute at the University Medical Center Mannheim, Mannheim, Germany; Molecular Medicine Partnership Unit, European Molecular Biology Laboratory, Heidelberg, GermanyDepartment of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, GermanyDepartment of General-, Visceral-, Vascular- and Pediatric Surgery, Saarland University, Homburg/Saar, GermanyDepartment of Clinical Laboratory Medicine Center, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, ChinaOncode Institute and Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, The NetherlandsDepartment of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Corresponding authors. Address: Department of Medicine II, Section Molecular Hepatology, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany. Tel.: +49-621-383-3768 (S. Dooley), +49-621-383-5595 (S. Wang).Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Corresponding authors. Address: Department of Medicine II, Section Molecular Hepatology, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany. Tel.: +49-621-383-3768 (S. Dooley), +49-621-383-5595 (S. Wang).Background & Aims: The extracellular matrix protein 1 (ECM1) is essential for liver homeostasis by keeping latent transforming growth factor-beta quiescent. Upon hepatocyte damage, ECM1 is significantly downregulated, facilitating fibrosis and chronic liver disease (CLD) progression. We investigated the mechanism of ECM1 regulation in hepatocytes under pathophysiological conditions. Methods: We used promoter analysis to predict Ecm1 transcriptional regulators and assessed the expression of Ecm1-related genes by single-cell RNA sequencing (scRNA-seq) and bulk RNA-seq. Functional assays were performed with AML12 cells, mouse and human primary hepatocytes, and liver tissue from mice and patients. Results: In healthy hepatocytes, epidermal growth factor (EGF)/EGF receptor (EGFR) signalling sustains ECM1 expression through phosphorylating signal transducer and activator of transcription 1 (STAT1) at serine727 (S727), thus enhancing its binding to the ECM1 promoter and boosting gene transcription. This process is disrupted during liver inflammation by interferon gamma (IFNγ), which downregulates EGFR and inhibits EGF/EGFR/STAT1-mediated ECM1 promoter binding. Mechanistically, IFNγ-induced STAT1 phosphorylation at tyrosine701 (Y701) impairs the binding of p-STAT1 S727 to the ECM1 promoter. Additionally, IFNγ induces nuclear factor erythroid 2-related factor 2 (NRF2) nuclear translocation, which repressively binds to the promoter of ECM1, further reducing its expression. These findings are confirmed in several CLD mouse models (n = 2–6). Moreover, AAV8-ECM1 attenuates liver fibrosis and injury in Western diet-fed mice (n = 8–10), counteracting the effects of EGF signalling inhibition and IFNγ/NRF2 activation. In CLD patients (n = 22), ECM1 levels correlate positively with EGFR expression (p <0.0001) and negatively with IFNγ/NRF2 activation (p <0.0001). Conclusions: EGF/STAT1 signalling promotes whereas IFNγ/NRF2 inhibits ECM1 expression in hepatocytes in health or disease, respectively. ECM1 has the potential to be developed as an antifibrotic agent, particularly in inflammation- or reactive oxygen species-driven CLD. Impact and implications: This study reveals the regulatory mechanism of ECM1 in hepatocytes, demonstrating that EGF/STAT1 maintains ECM1 expression to prevent fibrosis, whereas IFNγ/NRF2 signalling inhibits ECM1 during chronic liver inflammation, thereby accelerating disease progression. These findings are important for researchers and clinicians to understand the pathogenesis of liver fibrosis, especially in CLD driven by inflammation or oxidative stress. Clinically, ECM1 levels correlate positively with EGFR expression and negatively with IFNγ/NRF2 activation, providing potential antifibrotic targets for CLD patients.http://www.sciencedirect.com/science/article/pii/S2589555925001004Extracellular matrixGrowth factorIFNγTGF-βLiver fibrosis |
| spellingShingle | Yujia Li Chenjun Huang Weiguo Fan Seddik Hammad Cyrill Géraud Lea Berger Shanshan Wang Ye Yao Chenhao Tong Claudia Rubie Laura Kim Feiner Zeribe C. Nwosu Frederik Link Pia Erdösi Weronika Piorońska Kerry Gould Christoph Meyer Rilu Feng Hui Liu Chen Shao Bing Sun Huiguo Ding Roman Liebe Matthias P.A. Ebert Honglei Weng Matthias Glanemann Chunfang Gao Peter ten Dijke Steven Dooley Sai Wang ECM1 expression in chronic liver disease: Regulation by EGF/STAT1 and IFNγ/NRF2 signalling JHEP Reports Extracellular matrix Growth factor IFNγ TGF-β Liver fibrosis |
| title | ECM1 expression in chronic liver disease: Regulation by EGF/STAT1 and IFNγ/NRF2 signalling |
| title_full | ECM1 expression in chronic liver disease: Regulation by EGF/STAT1 and IFNγ/NRF2 signalling |
| title_fullStr | ECM1 expression in chronic liver disease: Regulation by EGF/STAT1 and IFNγ/NRF2 signalling |
| title_full_unstemmed | ECM1 expression in chronic liver disease: Regulation by EGF/STAT1 and IFNγ/NRF2 signalling |
| title_short | ECM1 expression in chronic liver disease: Regulation by EGF/STAT1 and IFNγ/NRF2 signalling |
| title_sort | ecm1 expression in chronic liver disease regulation by egf stat1 and ifnγ nrf2 signalling |
| topic | Extracellular matrix Growth factor IFNγ TGF-β Liver fibrosis |
| url | http://www.sciencedirect.com/science/article/pii/S2589555925001004 |
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