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As\u00a0HSCs are identified as the principal collagen\u2010producing cells in the injured liver, several experimental and clinical studies have targeted HSCs to treat liver fibrosis. However, HSCs also play a critical role in developing nonfibrotic liver diseases such as cholestasis, portal hypertension, and hepatocellular carcinoma (HCC). Therefore, this review exclusively focuses on the role of activated HSCs beyond hepatic fibrosis. In cholestasis conditions, elevated bile salts and bile acids activate HSCs to secrete collagen and other extracellular matrix products, which cause biliary fibrosis and cholangitis. In the chronically injured liver, autocrine and paracrine signaling from liver sinusoidal endothelial cells activates HSCs to induce portal hypertension via endothelin\u20101 release. In the tumor microenvironment (TME), activated HSCs are the major source of cancer\u2010associated fibroblasts (CAF). The crosstalk between activated HSC\/CAF and tumor cells is\u00a0associated with tumor cell proliferation, migration, metastasis, and chemoresistance. In TME, activated HSCs convert macrophages to tumor\u2010associated macrophages and induce the differentiation of dendritic cells (DCs) and monocytes to regulatory DCs and myeloid\u2010derived suppressor cells, respectively. This differentiation, in turn, increases T cells proliferation and induces their apoptosis leading to reduced immune surveillance in TME. Thus, HSCs activation in chronically injured liver is a critical process involved in the progression of cholestasis, portal hypertension, and liver cancer.<\/jats:p>","DOI":"10.1002\/jcp.30582","type":"journal-article","created":{"date-parts":[[2021,9,13]],"date-time":"2021-09-13T05:08:52Z","timestamp":1631509732000},"page":"436-449","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":74,"title":["Hepatic stellate cells in the injured liver: Perspectives beyond hepatic fibrosis"],"prefix":"10.1002","volume":"237","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5068-2383","authenticated-orcid":false,"given":"Devaraj","family":"Ezhilarasan","sequence":"first","affiliation":[{"name":"Department of Pharmacology, The Blue Lab, Molecular Medicine and Toxicology Division, Saveetha Dental College Saveetha Institute of Medical and Technical Sciences  Chennai Tamil Nadu 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