{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,2]],"date-time":"2026-01-02T12:34:44Z","timestamp":1767357284345,"version":"3.48.0"},"reference-count":115,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2026,1,2]],"date-time":"2026-01-02T00:00:00Z","timestamp":1767312000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>The insulin-like growth factor (IGF) axis orchestrates hepatic development, regeneration, and metabolism, yet the roles of individual IGF-binding proteins (IGFBPs) remain incompletely defined. IGFBP-6, a high-affinity, IGF-II-preferring binding protein, has emerged as a context-dependent modulator of IGF bioavailability and cell signaling with additional IGF-independent actions. This review synthesizes current evidence on IGFBP-6 in liver biology and disease. We first outline hepatic expression, regulation, and post-translational processing of IGFBP-6 across development, homeostasis, and injury, and summarize its effects on canonical IGF-II\/IGF1R signaling and downstream phosphatidylinositol 3-kinase\u2014protein kinase B (PI3K\u2013AKT) and rat sarcoma\u2014mitogen-activated protein kinase (RAS\u2013MAPK) pathways. We then evaluate experimental and clinical data linking IGFBP-6 to steatotic liver disease, inflammation, and fibrogenesis, including putative roles in hepatocyte stress responses, stellate cell activation, and extracellular matrix remodeling. Finally, we examine IGFBP-6 in primary liver cancers\u2014hepatocellular carcinoma and cholangiocarcinoma\u2014highlighting evidence for tumor-suppressive versus pro-migratory activities, potential crosstalk with hypoxia, Wnt\/\u03b2-catenin and TGF-\u03b2 signaling, and interactions with the tumor immune microenvironment. Across conditions, we assess the translational potential of IGFBP-6 as a circulating or tissue biomarker, its utility for patient stratification, and prospects for therapeutic targeting\u2014either by modulating IGF-II sequestration or exploiting IGF-independent mechanisms. We conclude by identifying key knowledge gaps, methodological limitations, and priorities for future studies, including standardized measurement, cell-type-resolved profiling, and in vivo perturbation in clinically relevant models. Collectively, the review positions IGFBP-6 as a nuanced regulator of liver pathophysiology and a promising, yet underexplored, lever for diagnosis and therapy.<\/jats:p>","DOI":"10.3390\/cells15010077","type":"journal-article","created":{"date-parts":[[2026,1,2]],"date-time":"2026-01-02T12:23:44Z","timestamp":1767356624000},"page":"77","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Insulin Growth Factor Binding Protein-6 and the Liver"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0204-1872","authenticated-orcid":false,"given":"Anna Rita Daniela","family":"Coda","sequence":"first","affiliation":[{"name":"C.R.E.A.T.E.\u2014Center for Research and Innovation in Medicine, Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8974-5786","authenticated-orcid":false,"given":"S\u0142awomir","family":"Kasperczyk","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 41-808 Katowice, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8399-7624","authenticated-orcid":false,"given":"Micha\u0142","family":"Dobrakowski","sequence":"additional","affiliation":[{"name":"Department of Radiology and Radiodiagnostics, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 41-808 Katowice, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aleksandra","family":"Kasperczyk","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 41-808 Katowice, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-2122-1478","authenticated-orcid":false,"given":"Maria Incoronata","family":"Trecca","sequence":"additional","affiliation":[{"name":"C.R.E.A.T.E.\u2014Center for Research and Innovation in Medicine, Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5638-227X","authenticated-orcid":false,"given":"Arcangelo","family":"Liso","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, University of Perugia, 06123 Perugia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6424-7841","authenticated-orcid":false,"given":"Gaetano","family":"Serviddio","sequence":"additional","affiliation":[{"name":"C.R.E.A.T.E.\u2014Center for Research and Innovation in Medicine, Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8196-7373","authenticated-orcid":false,"given":"Francesco","family":"Bellanti","sequence":"additional","affiliation":[{"name":"C.R.E.A.T.E.\u2014Center for Research and Innovation in Medicine, Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s00592-010-0227-z","article-title":"The IGF System","volume":"48","author":"Annunziata","year":"2011","journal-title":"Acta Diabetol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1038\/nrc3215","article-title":"The Insulin and Insulin-like Growth Factor Receptor Family in Neoplasia: An Update","volume":"1","author":"Pollak","year":"2012","journal-title":"Nat. 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