{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T02:00:31Z","timestamp":1785117631877,"version":"3.55.0"},"reference-count":99,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,7,25]],"date-time":"2026-07-25T00:00:00Z","timestamp":1784937600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Hepatic fibrosis is a pathological process involving the systemic reconfiguration of the liver microenvironment under chronic liver injury. It is a pathological wound healing response characterized by the excessive deposition of extracellular matrix (ECM) driven by the activation of hepatic stellate cells (HSCs), starting with the capillarization of liver sinusoidal endothelial cells (LSECs). This process can lead to liver structure destruction, portal hypertension, and even liver dysfunction, and is a major driving factor for death related to liver diseases. During this process, hypoxia initiates the transcriptional upregulation of effector molecules such as vascular endothelial growth factor (VEGF) and Lysyl oxidase (LOX) by stabilizing hypoxia-inducible factors (HIFs), inducing changes in LSEC phenotype and activation of HSCs, thus becoming a core driving factor. Activated HSCs not only exacerbate the capillarization of LSECs and tissue hypoxia but also strengthen the transcriptional activity of HIFs through autocrine\/paracrine signaling, establishing a positive feedback loop linking hypoxia to HIFs and HSC activation, continuously driving the progression of liver fibrosis and significantly increasing the probability of chronic liver diseases evolving into cirrhosis and the risk of death. This review will analyze the mechanism of liver fibrosis driven by hypoxia, integrate the current treatment landscape, focus on exploring the therapeutic targets related to hypoxia-induced activation of hepatic stellate cells leading to liver fibrosis, and evaluate their translational potential. It is expected to provide information for future effective anti-fibrotic intervention strategies.<\/jats:p>","DOI":"10.3390\/biom16081089","type":"journal-article","created":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T01:26:23Z","timestamp":1785115583000},"page":"1089","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Therapeutic Targets for Hepatic Fibrosis Driven by Hypoxia-Mediated Hepatic Stellate Cell Activation"],"prefix":"10.3390","volume":"16","author":[{"given":"Wenteng","family":"Li","sequence":"first","affiliation":[{"name":"Department of Gastroenterology, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4471-4035","authenticated-orcid":false,"given":"Tong","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1896-1988","authenticated-orcid":false,"given":"Jingwei","family":"Mao","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"918","DOI":"10.1053\/j.gastro.2011.12.017","article-title":"Role of Differentiation of Liver Sinusoidal Endothelial Cells in Progression and Regression of Hepatic Fibrosis in Rats","volume":"142","author":"Xie","year":"2012","journal-title":"Gastroenterology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1326","DOI":"10.1097\/HEP.0000000000001608","article-title":"Semaglutide Therapy for Metabolic Dysfunction\u2013Associated Steatohepatitis: November 2025 Updates to AASLD Practice Guidance","volume":"83","author":"Bansal","year":"2026","journal-title":"Hepatology"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2956","DOI":"10.1111\/bph.14341","article-title":"The Selective Mineralocorticoid Receptor Antagonist Eplerenone Prevents Decompensation of the Liver in Cirrhosis","volume":"175","author":"Schreier","year":"2018","journal-title":"Br. 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