{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T20:27:26Z","timestamp":1789244846623,"version":"build-2803163510"},"reference-count":42,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T00:00:00Z","timestamp":1769558400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T00:00:00Z","timestamp":1769558400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100001424","name":"American Liver Foundation","doi-asserted-by":"publisher","award":["2018"],"award-info":[{"award-number":["2018"]}],"id":[{"id":"10.13039\/100001424","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["RO1 DK123262"],"award-info":[{"award-number":["RO1 DK123262"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82202000"],"award-info":[{"award-number":["82202000"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Liver International"],"published-print":{"date-parts":[[2026,3]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background and Aims<\/jats:title>\n                    <jats:p>Immune\u2010mediated bile duct injury is the primary histological feature of autoimmune cholestatic liver diseases. Macrophages, the most abundant immune cell population in the liver, have been postulated to play a critical role in biliary repair. However, it is unclear whether activated macrophages interact with injured biliary epithelial cells.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We evaluated the expression of insulin\u2010like growth factor\u2010binding protein 4 (IGFBP4) in primary monocytes, MDM\u03a6, serum, and liver tissue sections from a total of 292 samples from PBC, PSC, and healthy controls using RNA\u2010sequencing, ELISA, and immunohistochemistry analysis. The signal pathways involved in the effect of IGFBP4 in human intrahepatic biliary epithelial cells were examined by phospho\u2010kinase arrays.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Herein we demonstrate a role for insulin\u2010like growth factor binding protein 4 (IGFBP4) in the interaction of macrophages and biliary cells. Importantly, the serum levels of IGFBP4 are significantly increased in PBC and negatively correlate with bilirubin levels. Furthermore, immunohistochemistry revealed an increase in IGFBP4 positive cells located not only in the periductal area but also around the portal tract in the PBC liver. In\u00a0vitro study indicated that IGFBP4 protected biliary cells from bile salt\u2010induced cell injury and promoted biliary cell proliferation, which was associated with reduced expression of the bile acid receptor TGR5, bile acid efflux transporter SLCO3A1, and activation of the GSK\u20103\u03b2\/\u03b2\u2010catenin signalling pathway.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These data highlight that IGFBP4 not only serves as a potential biomarker for PBC but also plays a protective role against bile duct injury.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/liv.70525","type":"journal-article","created":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T10:52:36Z","timestamp":1769597556000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["<scp>IGFBP4<\/scp>\n                    is a Metric for Primary Biliary Cholangitis and Attenuates Biliary Epithelial Cell Injury"],"prefix":"10.1111","volume":"46","author":[{"given":"Xing","family":"Zhou","sequence":"first","affiliation":[{"name":"Department of Hepatobiliary Surgery Union Hospital, Tongji Medical College, Huazhong University of Science and Technology  Wuhan China"},{"name":"Division of Rheumatology, Allergy, and Clinical Immunology, School of Medicine University of California Davis  Davis California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuyu","family":"Shao","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary Surgery Union Hospital, Tongji Medical College, Huazhong University of Science and Technology  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danning","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary Surgery Union Hospital, Tongji Medical College, Huazhong University of Science and Technology  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziyan","family":"Cheng","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Allergy, and Clinical Immunology, School of Medicine University of California Davis  Davis California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshihiro","family":"Tanaka","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Allergy, and Clinical Immunology, School of Medicine University of California Davis  Davis California USA"},{"name":"Division of Gastroenterology and Hepatology, The Third Department of Internal Medicine Kansai Medical University  Osaka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick S. C.","family":"Leung","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Allergy, and Clinical Immunology, School of Medicine University of California Davis  Davis California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koichi","family":"Tsuneyama","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine Institute of Biomedical Sciences, Tokushima University Graduate School  Tokushima Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aftab A.","family":"Ansari","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Allergy, and Clinical Immunology, School of Medicine University of California Davis  Davis California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William M.","family":"Ridgway","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Allergy, and Clinical Immunology, School of Medicine University of California Davis  Davis California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3262-1998","authenticated-orcid":false,"given":"Pietro","family":"Invernizzi","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology Center for Autoimmune Liver Diseases, European Reference Network on Hepatological Diseases (ERN RARE\u2010LIVER), IRCCS Fondazione San Gerardo Dei Tintori  Monza Italy"},{"name":"Department of Medicine and Surgery University of Milano\u2010Bicocca  Monza Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher L.","family":"Bowlus","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology University of California  Davis California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. Eric","family":"Gershwin","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Allergy, and Clinical Immunology, School of Medicine University of California Davis  Davis California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weici","family":"Zhang","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Allergy, and Clinical Immunology, School of Medicine University of California Davis  Davis California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,1,28]]},"reference":[{"key":"e_1_2_13_2_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-pathol-020712-164014"},{"key":"e_1_2_13_3_1","doi-asserted-by":"publisher","DOI":"10.1097\/MOG.0000000000000814"},{"key":"e_1_2_13_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.23783"},{"key":"e_1_2_13_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaut.2008.04.017"},{"key":"e_1_2_13_6_1","doi-asserted-by":"publisher","DOI":"10.1023\/A:1020511002025"},{"key":"e_1_2_13_7_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.177.10.7303"},{"key":"e_1_2_13_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2020.03.013"},{"key":"e_1_2_13_9_1","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2018.00499"},{"key":"e_1_2_13_10_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0151491"},{"key":"e_1_2_13_11_1","doi-asserted-by":"publisher","DOI":"10.1159\/000185444"},{"key":"e_1_2_13_12_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2015-2196"},{"key":"e_1_2_13_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(20)31607-X"},{"key":"e_1_2_13_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(18)30300-3"},{"issue":"8","key":"e_1_2_13_15_1","article-title":"Utility of Ethylene\u2010Diamine\u2010Tetraacetic Acid Buffer Solution With Boric Acid for Immunostaining of Specimens Stored for an Extended Period","volume":"13","author":"Hatta H.","year":"2021","journal-title":"Cureus"},{"key":"e_1_2_13_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.22736"},{"key":"e_1_2_13_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaut.2022.102897"},{"key":"e_1_2_13_18_1","doi-asserted-by":"publisher","DOI":"10.1093\/biomet\/70.1.41"},{"key":"e_1_2_13_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaut.2020.102515"},{"key":"e_1_2_13_20_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0705964104"},{"key":"e_1_2_13_21_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2018.11.018"},{"key":"e_1_2_13_22_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2004.08.056"},{"key":"e_1_2_13_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1063-4584(05)80104-9"},{"key":"e_1_2_13_24_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.28273"},{"key":"e_1_2_13_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature07027"},{"key":"e_1_2_13_26_1","doi-asserted-by":"publisher","DOI":"10.1111\/jcmm.15516"},{"key":"e_1_2_13_27_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.116.024441"},{"key":"e_1_2_13_28_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12035-019-1629-8"},{"key":"e_1_2_13_29_1","doi-asserted-by":"publisher","DOI":"10.1210\/en.2017-00248"},{"key":"e_1_2_13_30_1","doi-asserted-by":"publisher","DOI":"10.1038\/cddis.2013.445"},{"key":"e_1_2_13_31_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gky589"},{"key":"e_1_2_13_32_1","doi-asserted-by":"publisher","DOI":"10.1210\/en.2014-1829"},{"key":"e_1_2_13_33_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpgi.00349.2017"},{"key":"e_1_2_13_34_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.31494"},{"key":"e_1_2_13_35_1","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2018-316670"},{"key":"e_1_2_13_36_1","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2015-309458"},{"key":"e_1_2_13_37_1","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2018-316975"},{"key":"e_1_2_13_38_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12016-014-8443-x"},{"key":"e_1_2_13_39_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2018.07.031"},{"key":"e_1_2_13_40_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.25899"},{"key":"e_1_2_13_41_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.30927"},{"key":"e_1_2_13_42_1","doi-asserted-by":"publisher","DOI":"10.2353\/ajpath.2010.100173"},{"key":"e_1_2_13_43_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.01140"}],"container-title":["Liver International"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/liv.70525","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/liv.70525","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/liv.70525","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T13:55:47Z","timestamp":1774274147000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/liv.70525"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,28]]},"references-count":42,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2026,3]]}},"alternative-id":["10.1111\/liv.70525"],"URL":"https:\/\/doi.org\/10.1111\/liv.70525","archive":["Portico"],"relation":{},"ISSN":["1478-3223","1478-3231"],"issn-type":[{"value":"1478-3223","type":"print"},{"value":"1478-3231","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,28]]},"assertion":[{"value":"2025-03-17","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-01-10","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-01-28","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70525"}}