{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,25]],"date-time":"2026-02-25T15:27:56Z","timestamp":1772033276256,"version":"3.50.1"},"reference-count":210,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2023,2,18]],"date-time":"2023-02-18T00:00:00Z","timestamp":1676678400000},"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>Hepatocellular carcinoma (HCC) in the setting of non-alcoholic fatty liver disease (NAFLD)-related cirrhosis and even in the pre-cirrhotic state is increasing in incidence. NAFLD-related HCC has a poor clinical outcome as it is often advanced at diagnosis due to late diagnosis and systemic treatment response is poor due to reduced immune surveillance. Much of the focus of molecular research has been on the pathological changes in hepatocytes; however, immune cells, hepatic stellate cells, liver sinusoidal endothelial cells and the extracellular matrix may play important roles in the pathogenesis of NAFLD-related HCC as well. Here, we review the role of non-parenchymal cells in the liver in the pathogenesis of HCC in the context of NAFLD-NASH, with a particular focus on the innate and the adaptive immune system, fibrogenesis and angiogenesis. We review the key roles of macrophages, hepatic stellate cells (HSCs), T cells, natural killer (NK) cells, NKT cells and liver sinusoidal endothelial cells (LSECs) and the role of the extracellular matrix in hepatocarcinogenesis within the steatotic milieu.<\/jats:p>","DOI":"10.3390\/cancers15041308","type":"journal-article","created":{"date-parts":[[2023,2,20]],"date-time":"2023-02-20T01:36:37Z","timestamp":1676856997000},"page":"1308","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Non-Parenchymal Cells and the Extracellular Matrix in Hepatocellular Carcinoma in Non-Alcoholic Fatty Liver Disease"],"prefix":"10.3390","volume":"15","author":[{"given":"Koen C.","family":"van Son","sequence":"first","affiliation":[{"name":"Department of Vascular and Internal Medicine, Amsterdam University Medical Center, 1105 AZ Amsterdam, The Netherlands"},{"name":"Department of Gastroenterology and Hepatology, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7847-9037","authenticated-orcid":false,"given":"Lars","family":"Verschuren","sequence":"additional","affiliation":[{"name":"Department of Metabolic Health Research, Netherlands Organization for Applied Scientific Research, 2333 BE Leiden, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roeland","family":"Hanemaaijer","sequence":"additional","affiliation":[{"name":"Department of Metabolic Health Research, Netherlands Organization for Applied Scientific Research, 2333 BE Leiden, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0359-9795","authenticated-orcid":false,"given":"Helen","family":"Reeves","sequence":"additional","affiliation":[{"name":"Newcastle University Translational and Clinical Research Institute, Newcastle upon Tyne NE2 4HH, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"R. Bart","family":"Takkenberg","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Amsterdam University Medical Center, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joost P. H.","family":"Drenth","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maarten E.","family":"Tushuizen","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adriaan G.","family":"Holleboom","sequence":"additional","affiliation":[{"name":"Department of Vascular and Internal Medicine, Amsterdam University Medical Center, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1683","DOI":"10.1001\/jamaoncol.2017.3055","article-title":"The Burden of Primary Liver Cancer and Underlying Etiologies from 1990 to 2015 at the Global, Regional, and National Level: Results from the Global Burden of Disease Study 2015","volume":"3","author":"Akinyemiju","year":"2017","journal-title":"JAMA Oncol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1301","DOI":"10.1016\/S0140-6736(18)30010-2","article-title":"Hepatocellular carcinoma","volume":"391","author":"Forner","year":"2018","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/bs.acr.2020.10.001","article-title":"Hepatocellular carcinoma (HCC): Epidemiology, etiology and molecular classification","volume":"149","author":"Fisher","year":"2021","journal-title":"Adv. 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