Objective Extracellular matrix protein 1 (ECM1) serves as a gatekeeper of hepatic fibrosis by maintaining transforming growth factor-β1 (TGF-β1) in its latent form. ECM1 knockout (KO) causes latent (L) TGF-β1 activation, resulting in hepatic fibrosis with rapid mortality. In chronic liver disease (CLD), ECM1 decreases with increasing CLD severity. We investigate the regulatory role of ECM1 in TGF-β1 bioavailability and its impact on CLD progression. Design RNAseq was performed to analyse hepatic gene expression. Functional assays were performed using hepatic stellate cells (HSCs), Ecm1 -KO and Fxr -KO mice, patient liver tissue and computer simulations. Results Expression of LTGF-β1 activators, including thrombospondins (TSPs), ADAMTS proteases and matrix metalloproteinases (MMPs), increased along with profibrotic gene expression in liver tissue of Ecm1 -KO mice. In HSCs, overexpression of ECM1 prevented LTGF-β1 activation mediated by TSP-1, ADAMTS1, and MMP-2/9. In vitro interaction a