{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T20:58:56Z","timestamp":1790629136092,"version":"4.1.0"},"reference-count":136,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,6,11]],"date-time":"2025-06-11T00:00:00Z","timestamp":1749600000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Non-neoplastic chronic liver diseases (CLDs), including alcoholic liver disease, metabolic-associated fatty liver disease, viral hepatitis, fibrosis, and cirrhosis, pose a global health challenge due to progressive fibro-inflammatory remodeling. Emerging evidence highlights the pivotal roles of non-parenchymal cells (NPCs)\u2014liver sinusoidal endothelial cells (LSECs), hepatic stellate cells (HSCs), Kupffer cells (KCs), and innate immune lymphocytes such as natural killer (NK) and natural killer T (NKT) cells\u2014in driving disease progression. Chronic liver injury triggers LSEC capillarization, HSC transdifferentiation into collagen-producing myofibroblasts, and KC polarization toward pro-inflammatory phenotypes, collectively exacerbating extracellular matrix deposition and immune dysregulation. Dysfunctional NK\/NKT cells play dual roles in antiviral defense and fibrosis amplification through excessive cytokine production. This review summarizes recent advances in understanding NPC-driven mechanisms underlying chronic liver injury and fibrosis, with a focus on LSEC dysfunction, HSC activation, and inflammation mediated by KCs and NK\/NKT cells. Furthermore, we delve into emerging therapeutic strategies aimed at targeting NPC-specific pathways, including mechanotransduction modulation in LSECs, metabolic reprogramming of HSCs, and regulation of KC polarization. These approaches provide valuable insights into halting CLD progression and advancing the development of innovative antifibrotic therapies.<\/jats:p>","DOI":"10.3389\/fimmu.2025.1576739","type":"journal-article","created":{"date-parts":[[2025,6,11]],"date-time":"2025-06-11T01:15:13Z","timestamp":1749604513000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":16,"title":["Non-parenchymal cells: key targets for modulating chronic liver diseases"],"prefix":"10.3389","volume":"16","author":[{"given":"Tongwang","family":"Yang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiyun","family":"Gu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"Feng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juanjuan","family":"Shan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng","family":"Qian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Na","family":"Zhuang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,6,11]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2018.09.014","article-title":"Burden of liver diseases in the world","volume":"70","author":"Asrani","year":"2019","journal-title":"J Hepatol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1002\/hep.27406","article-title":"The global burden of liver disease: The major impact of China","volume":"60","author":"Wang","year":"2014","journal-title":"Hepatology"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.7150\/thno.106597","article-title":"Metabolism of hepatic stellate cells in chronic liver diseases: emerging molecular and therapeutic interventions","volume":"15","author":"Yan","year":"2025","journal-title":"Theranostics"},{"key":"B4","doi-asserted-by":"publisher","first-page":"1945","DOI":"10.3390\/cells10081945","article-title":"Circular RNA as an epigenetic regulator in chronic liver diseases","volume":"10","author":"Zeng","year":"2021","journal-title":"Cells"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1093\/ije\/dyad100","article-title":"Proportion of liver cancer cases and deaths attributable to potentially modifiable risk factors in China","volume":"52","author":"Lin","year":"2023","journal-title":"Int J Epidemiol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.v122.11","article-title":"Population attributable fractions of risk factors for hepatocellular carcinoma in the United States","volume":"122","author":"Makarova-Rusher","year":"2016","journal-title":"Cancer"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1289\/ehp.0901388","article-title":"Global burden of aflatoxin-induced hepatocellular carcinoma: A risk assessment","volume":"118","author":"Liu","year":"2010","journal-title":"Environ Health Perspect"},{"key":"B8","doi-asserted-by":"publisher","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 201510.1001\/jamaoncol.2017.3055","volume":"3","author":"Akinyemiju","year":"2017","journal-title":"JAMA Oncol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2018.12.001","article-title":"The trends in incidence of primary liver cancer caused by specific etiologies: Results from the Global Burden of Disease Study 2016 and implications for liver cancer prevention","volume":"70","author":"Liu","year":"2019","journal-title":"J Hepatol"},{"key":"B10","doi-asserted-by":"publisher","first-page":"997","DOI":"10.1002\/hep.32434","article-title":"Risk factors for HCC in contemporary cohorts of patients with cirrhosis","volume":"77","author":"Kanwal","year":"2023","journal-title":"Hepatology"},{"key":"B11","doi-asserted-by":"publisher","first-page":"938","DOI":"10.1016\/j.cgh.2007.02.039","article-title":"Incidence and predictors of hepatocellular carcinoma in patients with cirrhosis","volume":"5","author":"Ioannou","year":"2007","journal-title":"Clin Gastroenterol Hepatol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1002\/hep.22034","article-title":"Liver: An organ with predominant innate immunity","volume":"47","author":"Gao","year":"2008","journal-title":"Hepatology"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.72.2.441","article-title":"Distribution of organelles and membranes between hepatocytes and nonhepatocytes in the rat liver parenchyma","volume":"72","author":"Blouin","year":"1977","journal-title":"A stereological study. 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