{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T03:13:03Z","timestamp":1783566783106,"version":"3.55.0"},"reference-count":48,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,2,24]],"date-time":"2026-02-24T00:00:00Z","timestamp":1771891200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R01HL125877"],"award-info":[{"award-number":["R01HL125877"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R01HL160927"],"award-info":[{"award-number":["R01HL160927"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R01HL174922"],"award-info":[{"award-number":["R01HL174922"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R01DK131442"],"award-info":[{"award-number":["R01DK131442"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R01DK115406"],"award-info":[{"award-number":["R01DK115406"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["P30ES030328"],"award-info":[{"award-number":["P30ES030328"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Kentucky Pediatric Cancer Research Trust Fund","award":["FY 24\/25"],"award-info":[{"award-number":["FY 24\/25"]}]},{"name":"Jewish Heritage Fund for Excellence Research Enhancement Grant Program at the University of Louisville School of Medicine"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>The prevalence of metabolic dysfunction-associated steatohepatitis (MASH) is rising worldwide. hFGF1\u0394HBS, a variant of human fibroblast growth factor 1 with three substitutions in its heparin-binding sites, was previously shown by our group to ameliorate fatty liver. However, hFGF1\u0394HBS also significantly modulates systemic metabolism, making it unclear whether its hepatic benefits arise from direct liver-specific actions. Additionally, its poor pharmacokinetic profile underscores the need for alternative delivery strategies. Here, we employed adeno-associated virus serotype 8 under the thyroxine-binding globulin promoter (AAV8-TBG) to achieve sustained, hepatocyte-specific expression of hFGF1\u0394HBS. In high-fat-, high-cholesterol-diet-fed apolipoprotein E knockout mice, liver-directed hFGF1\u0394HBS expression markedly reduced hepatic steatosis, inflammation, and fibrosis, independent of changes in body weight, blood glucose, insulin sensitivity, body composition, or circulating triglyceride and cholesterol levels. Mechanistically, hFGF1\u0394HBS gene transfer normalized fatty acid synthesis and suppressed fatty acid uptake by downregulation of stearoyl-CoA desaturase-1 and cluster of differentiation 36. Importantly, these therapeutic effects were achieved without inducing hepatic hyperproliferation, as evidenced by unchanged expression of proliferating cell nuclear antigen and antigen Kiel 67. Collectively, our findings demonstrate that hFGF1\u0394HBS exerts direct hepatoprotective effects and that AAV8-TBG-mediated liver-directed hFGF1\u0394HBS delivery represents a safe and effective strategy for treating MASH.<\/jats:p>","DOI":"10.3390\/cells15050387","type":"journal-article","created":{"date-parts":[[2026,2,24]],"date-time":"2026-02-24T08:54:56Z","timestamp":1771923296000},"page":"387","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Human FGF1\u0394HBS Gene Therapy as Treatment for Metabolic Dysfunction-Associated Steatohepatitis in ApoE-KO Mice"],"prefix":"10.3390","volume":"15","author":[{"given":"Yingjian","family":"Li","sequence":"first","affiliation":[{"name":"Pediatric Research Institute, Department of Pediatrics, School of Medicine, University of Louisville, Louisville, KY 40202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaodan","family":"Hui","sequence":"additional","affiliation":[{"name":"Pediatric Research Institute, Department of Pediatrics, School of Medicine, University of Louisville, Louisville, KY 40202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunjie","family":"Gu","sequence":"additional","affiliation":[{"name":"Pediatric Research Institute, Department of Pediatrics, School of Medicine, University of Louisville, Louisville, KY 40202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6712-7431","authenticated-orcid":false,"given":"Qian","family":"Lin","sequence":"additional","affiliation":[{"name":"Touchstone Diabetes Center, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmed","family":"Abdelbaset-Ismail","sequence":"additional","affiliation":[{"name":"Pediatric Research Institute, Department of Pediatrics, School of Medicine, University of Louisville, Louisville, KY 40202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zixuan","family":"Xu","sequence":"additional","affiliation":[{"name":"Pediatric Research Institute, Department of Pediatrics, School of Medicine, University of Louisville, Louisville, KY 40202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0517-9527","authenticated-orcid":false,"given":"Suchen","family":"Yadav","sequence":"additional","affiliation":[{"name":"Pediatric Research Institute, Department of Pediatrics, School of Medicine, University of Louisville, Louisville, KY 40202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongbiao","family":"Huang","sequence":"additional","affiliation":[{"name":"Pediatric Research Institute, Department of Pediatrics, School of Medicine, University of Louisville, Louisville, KY 40202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason","family":"Xu","sequence":"additional","affiliation":[{"name":"Pediatric Research Institute, Department of Pediatrics, School of Medicine, University of Louisville, Louisville, KY 40202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara E.","family":"Watson","sequence":"additional","affiliation":[{"name":"Wendy Novak Diabetes Institute, Norton Children\u2019s Hospital, Louisville, KY 40202, USA"},{"name":"Norton Children\u2019s Endocrinology, Department of Pediatrics, University of Louisville, Norton Children\u2019s Hospital, Louisville, KY 40202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8373-061X","authenticated-orcid":false,"given":"Kupper A.","family":"Wintergerst","sequence":"additional","affiliation":[{"name":"Wendy Novak Diabetes Institute, Norton Children\u2019s Hospital, Louisville, KY 40202, USA"},{"name":"Norton Children\u2019s Endocrinology, Department of Pediatrics, University of Louisville, Norton Children\u2019s Hospital, Louisville, KY 40202, USA"},{"name":"The Center for Integrative Environmental Health Sciences, School of Medicine, University of Louisville, Louisville, KY 40202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3048-1135","authenticated-orcid":false,"given":"Lu","family":"Cai","sequence":"additional","affiliation":[{"name":"Pediatric Research Institute, Department of Pediatrics, School of Medicine, University of Louisville, Louisville, KY 40202, USA"},{"name":"Wendy Novak Diabetes Institute, Norton Children\u2019s Hospital, Louisville, KY 40202, USA"},{"name":"The Center for Integrative Environmental Health Sciences, School of Medicine, University of Louisville, Louisville, KY 40202, USA"},{"name":"Department of Pharmacology and Toxicology, School of Medicine, University of Louisville, Louisville, KY 40202, USA"},{"name":"Department of Radiation Oncology, School of Medicine, University of Louisville, Louisville, KY 40202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhongbin","family":"Deng","sequence":"additional","affiliation":[{"name":"Division of Immunotherapy, Department of Surgery, School of Medicine, University of Louisville, Louisville, KY 40202, USA"},{"name":"Brown Cancer Center, School of Medicine, University of Louisville, Louisville, KY 40202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Tan","sequence":"additional","affiliation":[{"name":"Pediatric Research Institute, Department of Pediatrics, School of Medicine, University of Louisville, Louisville, KY 40202, USA"},{"name":"Wendy Novak Diabetes Institute, Norton Children\u2019s Hospital, Louisville, KY 40202, USA"},{"name":"Department of Pharmacology and Toxicology, School of Medicine, University of Louisville, Louisville, KY 40202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Wang, J., Du, J., Wang, M., Jin, M., Tang, Z., and Mao, Y. 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