{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T21:31:54Z","timestamp":1790803914282,"version":"4.1.0"},"reference-count":45,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2021,10,21]],"date-time":"2021-10-21T00:00:00Z","timestamp":1634774400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Transforming growth factor-\u03b2 (TGF-\u03b2) 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\u20138 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\u2019s trichrome staining, immunohistochemistry and immunoblotting for \u03b1-smooth muscle actin (\u03b1-SMA) and hydroxyproline. To evaluate the interaction between TGF-\u03b2 and SULF2, we transfected human HSCs with scrambled control shRNA and shRNA constructs targeting SULF2 and measured \u03b1-SMA expression following treatment with TGF-\u03b21 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\u2019s trichrome and \u03b1-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 \u03b1-SMA and collagen type I following treatment with TGF-\u03b21. Furthermore, SULF2 co-localizes with TGFBR3 and the in vitro knockdown of SULF2 in HSCs decreases the release of TGF-\u03b21 from TGFBR3. Together, these data suggest that SULF2 regulates liver fibrosis via the TGF-\u03b2 signaling pathway. Pharmacologic inhibition of SULF2 may represent a novel therapeutic approach to improve liver fibrosis.<\/jats:p>","DOI":"10.3390\/cancers13215279","type":"journal-article","created":{"date-parts":[[2021,10,21]],"date-time":"2021-10-21T14:37:48Z","timestamp":1634827068000},"page":"5279","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Sulfatase-2 Regulates Liver Fibrosis through the TGF-\u03b2 Signaling Pathway"],"prefix":"10.3390","volume":"13","author":[{"given":"Ikuo","family":"Nakamura","sequence":"first","affiliation":[{"name":"Division of Gastroenterology and Hepatology, College of Medicine, Mayo Clinic and Mayo Clinic Cancer Center, Rochester, MN 55905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Faizal Z.","family":"Asumda","sequence":"additional","affiliation":[{"name":"Department of Clinical Genomics, Mayo Clinic, Rochester, MN 55905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine D.","family":"Moser","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology, College of Medicine, Mayo Clinic and Mayo Clinic Cancer Center, Rochester, MN 55905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoo Na N.","family":"Kang","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology, College of Medicine, Mayo Clinic and Mayo Clinic Cancer Center, Rochester, MN 55905, USA"},{"name":"Department of Pathology, Keimyung University School of Medicine, Daegu 42601, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin-Ping","family":"Lai","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology, College of Medicine, Mayo Clinic and Mayo Clinic Cancer Center, Rochester, MN 55905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7885-8574","authenticated-orcid":false,"given":"Lewis R.","family":"Roberts","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology, College of Medicine, Mayo Clinic and Mayo Clinic Cancer Center, Rochester, MN 55905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,10,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"S51","DOI":"10.1016\/j.clinre.2015.05.005","article-title":"Liver fibrosis: Common mechanisms and antifibrotic therapies","volume":"1","author":"Schuppan","year":"2015","journal-title":"Clin. 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