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HCC therapy remains a challenge, primarily due to underlying liver disorders such as cirrhosis that determines treatment approach and efficacy. Activated hepatic stellate cells (A\u2010HSCs) are the key cell types involved in hepatic fibrosis\/cirrhosis. A\u2010HSCs are important constituents of HCC tumor microenvironment (TME) and support tumor growth, chemotherapy resistance, cancer cell migration, and escaping immune surveillance. This makes A\u2010HSCs an important therapeutic target in hepatic fibrosis\/cirrhosis as well as in HCC. Although many studies have reported the role of A\u2010HSCs in cancer generation and investigated the therapeutic potential of A\u2010HSCs reversion in cancer arrest, not much is known about inactivated or quiescent HSCs (Q\u2010HSCs) in cancer growth or arrest. Here we report that Q\u2010HSCs resist cancer cell growth by inducing cytotoxicity and enhancing chemotherapy sensitivity. We observed that the conditioned media from Q\u2010HSCs (Q\u2010HSCCM) induces cancer cell death through a caspase\u2010independent mechanism that involves an increase in apoptosis\u2010inducing factor expression, nuclear localization, DNA fragmentation, and cell death. We further observed that Q\u2010HSCCM enhanced the efficiency of doxorubicin, as measured by cell viability assay. Exosomes present in the conditioned media were not involved in the mechanism, which suggests the role of other factors (proteins, metabolites, or microRNA) secreted by the cells. Identification and characterization of these factors are important in the development of effective HCC therapy.<\/jats:p>","DOI":"10.1002\/jcp.29545","type":"journal-article","created":{"date-parts":[[2020,1,24]],"date-time":"2020-01-24T09:35:39Z","timestamp":1579858539000},"page":"6167-6182","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Quiescent hepatic stellate cells induce toxicity and sensitivity to doxorubicin in cancer cells through a caspase\u2010independent cell death pathway: Central role of apoptosis\u2010inducing factor"],"prefix":"10.1002","volume":"235","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9107-1012","authenticated-orcid":false,"given":"Dola","family":"Das","sequence":"first","affiliation":[{"name":"Department of Biomedical Engineering, Lerner Research Institute Cleveland Clinic  Cleveland 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Cleveland Clinic  Cleveland Ohio"},{"name":"Department of Chemical and Biomedical Engineering Cleveland State University  Cleveland Ohio"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Akshay","family":"Wadera","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, Lerner Research Institute Cleveland Clinic  Cleveland Ohio"},{"name":"School of Medicine New York Medical College  Valhalla New York"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Min","family":"Lang","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, Lerner Research Institute Cleveland Clinic  Cleveland Ohio"},{"name":"Department of Radiology, Massachusetts General Hospital Harvard Medical School  Boston Massachusetts"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maximilian","family":"Zernic","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, Lerner Research Institute 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