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Simple Summary: Liver fibrosis and/or cirrhosis is a major risk factor for hepatocellular carcinoma. Hepatic Fibrogenesis is the result of an excessive production and deposition of extracellular matrix by hepatic myofibroblasts, which are primarily formed from hepatic stellate cells. The heparan sulfate editing enzyme sulfatase-2 is known to be elevated in cirrhotic liver and hepatocellular carcinoma. Our aim in this study was to delineate the mechanistic role of sulfatase-2 in fibrotic liver disease using mouse and in vitro cell culture models of liver fibrosis. Our data here demonstrates that mice deficient in sulfatase-2 have reduced liver fibrosis. We also show that sulfatase-2 promotes cell proliferation, cell viability, the production of collagen, migration, and activation of hepatic stellate cells. Our findings highlight sulfatase-2 as a potential target for therapeutic intervention geared at reversing liver fibrosis. Transforming growth factor-β (TGF-β) activates hepatic stellate cells (HSCs), which drive liver fibrosis via the production and deposition of extracellular matrix (ECM). We aimed to elucidate the mechanistic role of sulfatase-2 (SULF2) in liver fibrosis. To this end, we induced liver fibrosis in wild-type (WT) and SULF2 knockout (Sulf2-KO) mice (6–8 weeks-old) via bile duct ligation (BDL), intraperitoneal injection of carbon tetrachloride (CCl4) or thioacetamide (TAA). The levels of fibrosis in the liver sections were assessed via Sirius red and Masson's trichrome staining, immunohistochemistry and immunoblotting for α-smooth muscle actin (α-SMA) and hydroxyproline. To evaluate the interaction between TGF-β and SULF2, we transfected human HSCs with scrambled control shRNA and shRNA constructs targeting SULF2 and measured α-SMA expression following treatment with TGF-β1 ligand. We show here that knockout of SULF2 significantly decreases collagen content, as well as bands of bridging fibrosis, as demonstrated by Sirius red, Masson's trichrome and α-SMA staining after BDL, CCl4 and TAA injection in Sulf2-KO versus WT mice. In all three models of liver fibrosis, we observed significantly lower levels of hydroxyproline in the Sulf2-KO mice compared to the WT mice. HSCs with reduced levels of SULF2 failed to significantly express α-SMA and collagen type I following treatment with TGF-β1. Furthermore, SULF2 co-localizes with TGFBR3 and the in vitro knockdown of SULF2 in HSCs decreases the release of TGF-β1 from TGFBR3. Together, these data suggest that SULF2 regulates liver fibrosis via the TGF-β signaling pathway. Pharmacologic inhibition of SULF2 may represent a novel therapeutic approach to improve liver fibrosis. [ABSTRACT FROM AUTHOR]