Extracellular matrix protein 1 (ECM1) As a dual regulator of liver regeneration via HGF/c-MET and TGF-β signaling pathways

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Introduction: Extracellular matrix protein 1 (ECM1) is crucial for liver homeostasis and negatively correlates with chronic liver disease progression. However, its role in acute liver injury and regeneration (LR) remains unclear. Objective: This study investigates ECM1's impact on LR and its underlying mechanisms. Methodology: Ecm1-tdTomato mice were administered adeno-associated virus 8 (AAV8)-ECM1 seven days before 70% partial hepatectomy (PHx). Hepatic gene expression was analyzed with RNA sequencing. Functional assays were done with hepatocytes, mouse liver tissue and patient samples. Results: ECM1 is downregulated during LR after PHx. Interference with ECM1 downregulation by AAV8-ECM1 delays proliferation and liver mass gain at days 2 and 4, but catches up by day 8, as indicated by the liver-to-body weight ratio and immunostaining of BrdU and PCNA. Mechanistically, in early-stages of LR (days 0–4), downregulation of ECM1 is required for efficient HGF/c-MET/ERK/MYC signaling to mediate cell cycle progression, including CyclinA2, B1, B2, and Birc5 expression. In the late stage (days 4–8), overexpression of ECM1 inhibits latent TGF-β activation, therefore interfering with TGF-β-induced cell cycle kinase inhibitors p15, p16, p18, and p19, required for regeneration termination, which finally restores the liver mass. Additionally, Myc overexpression in hepatocytes rescues ECM1 mediated proliferation inhibition. In the liver of patients, ECM1-negative tissues display increased nuclear expression of MYC and PCNA. Conclusion: ECM1 regulates liver regeneration by modulating HGF/c-MET/ERK/MYC and TGF-β/SMAD pathways. We hypothesize that for patients requiring liver regeneration, ECM1 downregulation benefits hepatocyte proliferation and liver function restoration. However, its inhibitory effect on TGF-β signaling should also be considered. Publication History Article published online: 04 September 2025 © 2025. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany

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