{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T04:08:24Z","timestamp":1791518904017,"version":"4.3.4"},"reference-count":46,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T00:00:00Z","timestamp":1778803200000},"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. Physiol."],"abstract":"<jats:p>\n                    Insulin-like growth factor binding proteins (IGFBPs) are critical regulators of hepatic metabolic homeostasis, and accumulating evidence implicates them in liver disease progression. However, their precise roles and regulatory mechanisms in alcoholic liver disease (ALD) remain elusive. In this study, we performed comprehensive analyses of the expression of IGF system proteins both\n                    <jats:italic>in vitro<\/jats:italic>\n                    and\n                    <jats:italic>in vivo<\/jats:italic>\n                    , and identified a significant downregulation of IGFBP3 in ALD. Subsequently, we overexpressed IGFBP3 or its mutant IGFBP3\n                    <jats:sup>GGG<\/jats:sup>\n                    with an IGF1-binding site mutation in AML12 cells to evaluate its effect on alcohol-induced hepatocyte injury. Our findings revealed that IGFBP3 overexpression exacerbated alcohol-induced lipid accumulation, reactive oxygen species (ROS) generation, and apoptosis in hepatocytes. Compared with the IGFBP3-overexpressing group, the IGFBP3\n                    <jats:sup>GGG<\/jats:sup>\n                    -overexpressing group showed no significant difference in lipid accumulation, whereas the levels of ROS and apoptosis were significantly lower. Furthermore, we generated liver-specific IGFBP3 knockout mice (\n                    <jats:italic>\n                      Alb-cre;Igfbp3\n                      <jats:sup>f\/f<\/jats:sup>\n                    <\/jats:italic>\n                    ), which exhibited significantly attenuated alcoholic liver injury compared to their\n                    <jats:italic>\n                      Igfbp3\n                      <jats:sup>f\/f<\/jats:sup>\n                    <\/jats:italic>\n                    littermates following chronic ethanol exposure. Mechanistically, IGFBP3 overexpression activates the Akt\/GSK3\u03b2 and TMEM219\/Caspase8 signaling pathways, driving hepatic lipid accumulation and hepatocyte apoptosis. Paradoxically, knockout of IGFBP3 also promotes the phosphorylation of Akt\/GSK3\u03b2 in liver. Collectively, these findings suggest a potential cross-talk between the Akt\/GSK3\u03b2 and TMEM219\/Caspase8 signaling pathways, and the downregulation of IGFBP3 in chronic liver disease may represent a self-regulatory mechanism of hepatocytes to resist adversity.\n                  <\/jats:p>","DOI":"10.3389\/fphys.2026.1775461","type":"journal-article","created":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T04:27:44Z","timestamp":1778819264000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Knockout of IGFBP3 improves alcohol-induced liver injury via Akt\/GSK3\u03b2 and TMEM219\/caspase 8 pathways"],"prefix":"10.3389","volume":"17","author":[{"given":"Huimei","family":"Cai","sequence":"first","affiliation":[{"name":"Department of Gastroenterology, Affiliated Fuzhou First Hospital of Fujian Medical University","place":["Fuzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenyu","family":"Zhu","sequence":"additional","affiliation":[{"name":"First Affiliated Hospital of Dalian Medical University","place":["Dalian, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xi","family":"Zheng","sequence":"additional","affiliation":[{"name":"Clinical Research Center for Oral Tissue Deficiency Diseases of Fujian Province, Fujian Key Laboratory of Oral Diseases, Fujian Provincial Engineering Research Center of Oral Biomaterial, School and Hospital of Stomatology, Fujian Medical University","place":["Fuzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiqi","family":"Lian","sequence":"additional","affiliation":[{"name":"Fujian Key Laboratory of Developmental and Neural Biology, College of Life Science, Fujian Normal University","place":["Fuzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enqi","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Affiliated Fuzhou First Hospital of Fujian Medical University","place":["Fuzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yushan","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Affiliated Fuzhou First Hospital of Fujian Medical University","place":["Fuzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenyu","family":"Cao","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Affiliated Fuzhou First Hospital of Fujian Medical University","place":["Fuzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Affiliated Fuzhou First Hospital of Fujian Medical University","place":["Fuzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Lv","sequence":"additional","affiliation":[{"name":"Fujian Key Laboratory of Developmental and Neural Biology, College of Life Science, Fujian Normal University","place":["Fuzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,5,15]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2025.107901","article-title":"Targeting of the IGFBP3\/TMEM219 pathway restores intestinal stem cells capability of healing mucosa in gastrointestinal autoimmune disorders","volume":"219","author":"Amabile","year":"2025","journal-title":"Pharmacol. 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