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Wharton's jelly\u2010derived MSCs (WJ\u2010MSCs) have immunomodulatory and antifibrotic potential. Hypoxia preconditioning enhances MSC survival and paracrine activity, but its effects in liver fibrosis remain unclear. This study compares hypoxia and normoxia WJ\u2010MSCs in a CCl<jats:sub>4<\/jats:sub>\u2010induced liver fibrosis rat model. Sprague\u2013Dawley rats received chronic CCl<jats:sub>4<\/jats:sub> to induce fibrosis. At Week 8, normoxia or hypoxia WJ\u2010MSCs were injected via the portal vein. Liver function was assessed using biochemical markers (ALT, AST, T\u2010Bil, albumin), PET\/MR imaging, and qPCR for IL\u20101\u03b2 and IL\u20106. Fibrosis regression was evaluated via ultrasound, histology, and collagen quantification. Regeneration was analyzed through Ki67 immunostaining and qPCR for Ki67 and HGF. MSC engraftment was determined by hNA immunohistochemistry. Both normoxia and hypoxia WJ\u2010MSCs improved liver function, with hypoxia WJ\u2010MSCs showing greater AST and T\u2010Bil reductions. PET\/MR imaging demonstrated superior metabolic recovery in the hypoxia group, with greater <jats:sup>18<\/jats:sup>F\u2010FDG uptake reduction. Histological analysis confirmed more significant fibrosis regression and collagen reduction in the hypoxia group. Gene expression analysis showed stronger suppression of TGF\u2010\u03b2, \u03b1\u2010SMA, and collagen I. Liver regeneration markers Ki67 and HGF were significantly upregulated with a greater HGF increase in the hypoxia group. Additionally, hypoxia WJ\u2010MSCs exhibited higher engraftment and reduced pulmonary entrapment, indicating improved liver homing. Both normoxia and hypoxia WJ\u2010MSCs improved liver fibrosis, but hypoxia preconditioning further enhanced liver function, fibrosis regression, and metabolic recovery, supporting its therapeutic superiority.<\/jats:p>","DOI":"10.1002\/kjm2.70053","type":"journal-article","created":{"date-parts":[[2025,7,13]],"date-time":"2025-07-13T12:37:07Z","timestamp":1752410227000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Hypoxia\u2010Enhanced Wharton's Jelly Mesenchymal Stem Cell Therapy for Liver Fibrosis: A Comparative Study in a Rat Model"],"prefix":"10.1002","volume":"41","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-7709-8544","authenticated-orcid":false,"given":"Wei\u2010Ting","family":"Kuo","sequence":"first","affiliation":[{"name":"Institute of Clinical Medicine National Yang Ming Chiao Tung University  Taipei Taiwan"},{"name":"Department of Surgery Chiayi Christian Hospital  Chiayi 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