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BACKGROUND & AIMS: Activation of TGFB (transforming growth factor b) promotes liver fibrosis by activating hepatic stellate cells (HSCs), but the mechanisms of TGFB activation are not clear. We investigated the role of ECM1 (extracellular matrix protein 1), which interacts with extracellular and structural proteins, in TGFB activation in mouse livers. METHODS:We performed studies with C57BL/6J mice (controls), ECM1-knockout (ECM1-KO) mice, and mice with hepatocyte-specific knockout of EMC1 (ECM1 Dhep ). ECM1 or soluble TGFBR2 (TGFB receptor 2) were expressed in livers of mice after injection of an adeno-associated virus vector. Liver fibrosis was induced by carbon tetrachloride (CCl 4 ) administration. Livers were collected from mice and analyzed by histology, immunohistochemistry, in situ hybridization, and immunofluorescence analyses. Hepatocytes and HSCs were isolated from livers of mice and incubated with ECM1; production of cytokines and activation of reporter genes were quantified. Liver tissues from patients with viral or alcohol-induced hepatitis (with different stages of fibrosis) and individuals with healthy livers were analyzed by immunohistochemistry and in situ hybridization. RESULTS: ECM1-KO mice spontaneously developed liver fibrosis and died by 2 months of age without significant hepatocyte damage or inflammation. In liver tissues of mice, we found that ECM1 stabilized extracellular matrix-deposited TGFB in its inactive form by interacting with av integrins Gastroenterology 2019;157:1352-1367 BASIC AND TRANSLATIONAL LIVER * Authors share co-first authorship.Abbreviations used in this paper: AAV, adeno-associated virus; CLD, chronic liver disease; CCl 4 , carbon tetrachloride; ECM1, extracellular matrix protein 1; ECM1 D;hep , hepatocyte-specific deletion of extracellular matrix protein 1; GAPDH, glyceraldehyde 3-phosphate dehydrogenase;