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Updated: Sep 15, 2025
06:46
3D Imaging of the Liver Extracellular Matrix in a Mouse Model of Non-Alcoholic Steatohepatitis
Published on: February 25, 2022
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ECM1 expression in chronic liver disease: Regulation by EGF/STAT1 and IFNγ/NRF2 signalling
Yujia Li1, Chenjun Huang1,2, Weiguo Fan3
1Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
JHEP Reports : Innovation in Hepatology
|July 17, 2025
Summary
Epidermal Growth Factor (EGF)/Signal Transducer and Activator of Transcription 1 (STAT1) signaling promotes extracellular matrix protein 1 (ECM1) expression, preventing liver fibrosis. Interferon gamma (IFNγ)/Nuclear Factor erythroid 2-related Factor 2 (NRF2) signaling inhibits ECM1, accelerating chronic liver disease (CLD).
Area of Science:
- Hepatology and Molecular Biology
- Extracellular Matrix and Fibrosis Research
Background:
- Extracellular matrix protein 1 (ECM1) is crucial for liver homeostasis, maintaining latent transforming growth factor-beta quiescence.
- ECM1 downregulation upon hepatocyte damage accelerates fibrosis and chronic liver disease (CLD) progression.
Purpose of the Study:
- To elucidate the regulatory mechanisms of ECM1 expression in hepatocytes under pathophysiological conditions.
- To investigate the role of ECM1 in the context of liver inflammation and fibrosis.
Main Methods:
- Promoter analysis to identify ECM1 transcriptional regulators.
- Single-cell and bulk RNA sequencing to assess ECM1-related gene expression.
- Functional assays using cell lines, primary hepatocytes, and clinical/preclinical liver tissues.
Main Results:
- Epidermal Growth Factor (EGF)/EGF Receptor (EGFR) signaling, via STAT1 phosphorylation at S727, enhances ECM1 transcription in healthy hepatocytes.
- Interferon gamma (IFNγ) disrupts this pathway by downregulating EGFR and promoting STAT1 phosphorylation at Y701, impairing ECM1 promoter binding.
- IFNγ also induces Nuclear Factor erythroid 2-related Factor 2 (NRF2) nuclear translocation, repressing ECM1 expression; AAV8-ECM1 therapy attenuated fibrosis in mice, and ECM1 levels correlated with EGFR and IFNγ/NRF2 in CLD patients.
Conclusions:
- EGF/STAT1 signaling promotes ECM1 expression, while IFNγ/NRF2 signaling inhibits it in hepatocytes during health and disease, respectively.
- ECM1 demonstrates potential as an antifibrotic agent, particularly for CLD driven by inflammation or oxidative stress.
- Understanding these regulatory pathways offers potential therapeutic targets for CLD patients.
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