{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T12:51:04Z","timestamp":1791204664821,"version":"4.2.0"},"reference-count":134,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T00:00:00Z","timestamp":1784160000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T00:00:00Z","timestamp":1784160000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["R01NS136524"],"award-info":[{"award-number":["R01NS136524"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Medicinal Research Reviews"],"published-print":{"date-parts":[[2026,11]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Chitinase\u20103\u2010like\u20101 (CHI3L1, also known as YKL\u201040) has been recognized as a biomarker of inflammation and tissue remodeling and has now emerged as a pseudoenzymatic immune checkpoint. Recent structural, immunological, and translational studies redefine it as an active regulator of immune suppression rather than a passive disease marker. Despite lacking catalytic activity, CHI3L1's conserved chitinase fold and glycan\u2010decorated surface acts as a modular scaffold linking cytokine, metabolic, and stress signals to immune suppression and fibrotic remodeling. Through its chitinase\u2010like structure it engages with receptor triad complex, including IL\u201013R\u03b12, TMEM219, and Galectin\u20103, activating signaling pathways such as MAPK, PI3K\/AKT, and TGF\u2010\u03b2\/Smad. Through these interactions, CHI3L1 has been reported to promote fibroblast activation, angiogenesis, and immune suppression, creating environments where immune cells are excluded or silenced. These checkpoint\u2010like effects are not limited to cancer; they also appear in fibrosis, infection, and neuroinflammatory diseases, linking CHI3L1 to a broad spectrum of immune\u2010resistant conditions. This review integrates structural glycobiology, receptor pharmacology, and immunometabolic mechanisms to reveal CHI3L1 as a unifying regulator of stromal\u2013immune crosstalk. It further highlights preclinical and clinical evidence demonstrating that antibody, RNA\u2010based, and small\u2010molecule inhibitors of CHI3L1 restore immune surveillance and limit pathological remodeling. Targeting this pseudoenzymatic checkpoint alongside canonical PD\u20101 and CTLA\u20104 blockade represents a promising strategy to overcome immune resistance and normalize pathogenic tissue remodeling across diverse diseases.<\/jats:p>","DOI":"10.1002\/med.70076","type":"journal-article","created":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T10:53:35Z","timestamp":1784199215000},"page":"1897-1921","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Redefining CHI3L1: Therapeutic Opportunities at the Crossroads of Immune Suppression and Disease Progression"],"prefix":"10.1002","volume":"46","author":[{"given":"Kirti","family":"Upmanyu","sequence":"first","affiliation":[{"name":"Department of Radiology, Molecular Imaging Innovations Institute (MI3) Weill Cornell Medicine New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saurabh","family":"Upadhyay","sequence":"additional","affiliation":[{"name":"Department of Radiology, Molecular Imaging Innovations Institute (MI3) Weill Cornell Medicine New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moustafa T.","family":"Gabr","sequence":"additional","affiliation":[{"name":"Department of Radiology, Molecular Imaging Innovations Institute (MI3) Weill Cornell Medicine New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,7,16]]},"reference":[{"key":"e_1_2_16_2_1","doi-asserted-by":"publisher","DOI":"10.1093\/glycob\/cwr092"},{"key":"e_1_2_16_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/jbmr.5650070506"},{"key":"e_1_2_16_4_1","doi-asserted-by":"publisher","DOI":"10.3390\/ph17030307"},{"key":"e_1_2_16_5_1","doi-asserted-by":"publisher","DOI":"10.3390\/biomedicines10051028"},{"key":"e_1_2_16_6_1","doi-asserted-by":"publisher","DOI":"10.4168\/aair.2020.12.6.1012"},{"key":"e_1_2_16_7_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms242216149"},{"key":"e_1_2_16_8_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells13080678"},{"key":"e_1_2_16_9_1","doi-asserted-by":"publisher","DOI":"10.1042\/bsr20182008"},{"key":"e_1_2_16_10_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12890-017-0515-2"},{"key":"e_1_2_16_11_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells14130982"},{"key":"e_1_2_16_12_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.2400035"},{"key":"e_1_2_16_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-020-00303-7"},{"key":"e_1_2_16_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2024.114226"},{"key":"e_1_2_16_15_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms23073529"},{"key":"e_1_2_16_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc3239"},{"key":"e_1_2_16_17_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.1056397"},{"key":"e_1_2_16_18_1","doi-asserted-by":"publisher","DOI":"10.1172\/jci137750"},{"key":"e_1_2_16_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2023.11.002"},{"key":"e_1_2_16_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2023.114520"},{"key":"e_1_2_16_21_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1701442"},{"key":"e_1_2_16_22_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M303371200"},{"key":"e_1_2_16_23_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M303137200"},{"key":"e_1_2_16_24_1","doi-asserted-by":"publisher","DOI":"10.1111\/cas.70028"},{"key":"e_1_2_16_25_1","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2019-0446OC"},{"key":"e_1_2_16_26_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells13080678"},{"key":"e_1_2_16_27_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.3c02255"},{"key":"e_1_2_16_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2025.117960"},{"key":"e_1_2_16_29_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M303371200"},{"key":"e_1_2_16_30_1","doi-asserted-by":"publisher","DOI":"10.3390\/curroncol30100629"},{"key":"e_1_2_16_31_1","doi-asserted-by":"publisher","DOI":"10.1038\/s12276-023-01131-9"},{"key":"e_1_2_16_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2011.05.038"},{"key":"e_1_2_16_33_1","doi-asserted-by":"publisher","DOI":"10.4062\/biomolther.2025.050"},{"key":"e_1_2_16_34_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M510146200"},{"key":"e_1_2_16_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(19)74461-5"},{"key":"e_1_2_16_36_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1349-7006.2005.00026.x"},{"key":"e_1_2_16_37_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13046-018-0876-2"},{"key":"e_1_2_16_38_1","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2014-0366OC"},{"key":"e_1_2_16_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2025.01.014"},{"key":"e_1_2_16_40_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-33239-8"},{"key":"e_1_2_16_41_1","doi-asserted-by":"publisher","DOI":"10.7150\/thno.65522"},{"key":"e_1_2_16_42_1","doi-asserted-by":"publisher","DOI":"10.3390\/pharmaceutics14051046"},{"key":"e_1_2_16_43_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12935-024-03425-y"},{"key":"e_1_2_16_44_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M114.588905"},{"key":"e_1_2_16_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2025.117924"},{"key":"e_1_2_16_46_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep26299"},{"key":"e_1_2_16_47_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.slasd.2025.100281"},{"key":"e_1_2_16_48_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2013.07.032"},{"key":"e_1_2_16_49_1","doi-asserted-by":"publisher","DOI":"10.1172\/jci147552"},{"key":"e_1_2_16_50_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13058-024-01815-8"},{"key":"e_1_2_16_51_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13062-024-00568-w"},{"key":"e_1_2_16_52_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12964-023-01423-7"},{"key":"e_1_2_16_53_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms12752"},{"key":"e_1_2_16_54_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12964-023-01423-7"},{"key":"e_1_2_16_55_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.330803"},{"key":"e_1_2_16_56_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12943-023-01744-8"},{"key":"e_1_2_16_57_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M303371200"},{"key":"e_1_2_16_58_1","doi-asserted-by":"publisher","DOI":"10.11613\/bm.2024.010502"},{"key":"e_1_2_16_59_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.adv1492"},{"key":"e_1_2_16_60_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.Can-21-3629"},{"key":"e_1_2_16_61_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13045-017-0408-0"},{"key":"e_1_2_16_62_1","doi-asserted-by":"publisher","DOI":"10.1101\/2025.06.23.661212"},{"key":"e_1_2_16_63_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12026-014-8517-0"},{"key":"e_1_2_16_64_1","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202310169"},{"key":"e_1_2_16_65_1","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2017.65"},{"key":"e_1_2_16_66_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2013.00122"},{"key":"e_1_2_16_67_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2018.02.050"},{"key":"e_1_2_16_68_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.43356"},{"key":"e_1_2_16_69_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22083912"},{"key":"e_1_2_16_70_1","doi-asserted-by":"publisher","DOI":"10.21037\/tcr.2020.03.80"},{"key":"e_1_2_16_71_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13024-025-00801-8"},{"key":"e_1_2_16_72_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2026.108109"},{"key":"e_1_2_16_73_1","doi-asserted-by":"publisher","DOI":"10.3346\/jkms.2025.40.e254"},{"key":"e_1_2_16_74_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3007096"},{"key":"e_1_2_16_75_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13054-020-03383-7"},{"key":"e_1_2_16_76_1","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.148749"},{"key":"e_1_2_16_77_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.78273"},{"key":"e_1_2_16_78_1","doi-asserted-by":"publisher","DOI":"10.1111\/all.13661"},{"key":"e_1_2_16_79_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1158493"},{"key":"e_1_2_16_80_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00528.2020"},{"key":"e_1_2_16_81_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellsig.2019.109498"},{"key":"e_1_2_16_82_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molimm.2023.02.012"},{"key":"e_1_2_16_83_1","doi-asserted-by":"publisher","DOI":"10.1002\/iub.2156"},{"key":"e_1_2_16_84_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2024.116825"},{"key":"e_1_2_16_85_1","doi-asserted-by":"publisher","DOI":"10.1101\/2025.09.17.676854"},{"key":"e_1_2_16_86_1","doi-asserted-by":"publisher","DOI":"10.1111\/jcmm.12014"},{"key":"e_1_2_16_87_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.rmed.2010.09.012"},{"key":"e_1_2_16_88_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2022.826471"},{"key":"e_1_2_16_89_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.gendis.2025.101653"},{"key":"e_1_2_16_90_1","doi-asserted-by":"publisher","DOI":"10.1002\/1878-0261.13152"},{"key":"e_1_2_16_91_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12272-025-01548-y"},{"key":"e_1_2_16_92_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12967-023-04532-6"},{"key":"e_1_2_16_93_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12974-020-02022-w"},{"key":"e_1_2_16_94_1","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2021-003224"},{"key":"e_1_2_16_95_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tranon.2024.102108"},{"key":"e_1_2_16_96_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1228907"},{"key":"e_1_2_16_97_1","doi-asserted-by":"publisher","DOI":"10.1159\/000438643"},{"key":"e_1_2_16_98_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2021.649876"},{"key":"e_1_2_16_99_1","doi-asserted-by":"publisher","DOI":"10.2174\/1570159x15666170720095240"},{"key":"e_1_2_16_100_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2024.177060"},{"key":"e_1_2_16_101_1","doi-asserted-by":"publisher","DOI":"10.1002\/alz.12612"},{"key":"e_1_2_16_102_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1162340"},{"key":"e_1_2_16_103_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aax3519"},{"key":"e_1_2_16_104_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2020.07.009"},{"key":"e_1_2_16_105_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnagi.2025.1630022"},{"key":"e_1_2_16_106_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41380-022-01716-2"},{"key":"e_1_2_16_107_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12974-017-0893-7"},{"key":"e_1_2_16_108_1","doi-asserted-by":"publisher","DOI":"10.1002\/brb3.70619"},{"key":"e_1_2_16_109_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells13242086"},{"key":"e_1_2_16_110_1","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-12-823347-4.00009-9"},{"key":"e_1_2_16_111_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12974-023-02970-z"},{"key":"e_1_2_16_112_1","doi-asserted-by":"publisher","DOI":"10.1017\/s1461145711000149"},{"key":"e_1_2_16_113_1","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.127623"},{"key":"e_1_2_16_114_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.imbio.2013.04.010"},{"key":"e_1_2_16_115_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-022-11532-x"},{"key":"e_1_2_16_116_1","doi-asserted-by":"publisher","DOI":"10.4110\/in.2025.25.e5"},{"key":"e_1_2_16_117_1","doi-asserted-by":"publisher","DOI":"10.3389\/fmed.2020.00123"},{"key":"e_1_2_16_118_1","doi-asserted-by":"publisher","DOI":"10.1002\/1878-0261.13138"},{"key":"e_1_2_16_119_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2025.117924"},{"key":"e_1_2_16_120_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsmedchemlett.5c00550"},{"key":"e_1_2_16_121_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmcl.2025.130460"},{"key":"e_1_2_16_122_1","doi-asserted-by":"publisher","DOI":"10.64898\/2026.01.28.702243"},{"key":"e_1_2_16_123_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2025.117960"},{"key":"e_1_2_16_124_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.allmed.2024.100001"},{"key":"e_1_2_16_125_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00408-014-9651-0"},{"key":"e_1_2_16_126_1","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2017-0079ED"},{"key":"e_1_2_16_127_1","doi-asserted-by":"publisher","DOI":"10.1038\/s12276-020-00500-y"},{"key":"e_1_2_16_128_1","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.2001.5253"},{"key":"e_1_2_16_129_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsmedchemlett.5c00550"},{"key":"e_1_2_16_130_1","doi-asserted-by":"publisher","DOI":"10.3390\/molecules22010139"},{"key":"e_1_2_16_131_1","doi-asserted-by":"publisher","DOI":"10.7150\/thno.75069"},{"key":"e_1_2_16_132_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2022.05.009"},{"key":"e_1_2_16_133_1","doi-asserted-by":"publisher","DOI":"10.7150\/ijbs.8.39"},{"key":"e_1_2_16_134_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2021.611038"},{"key":"e_1_2_16_135_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmcl.2025.130310"}],"container-title":["Medicinal Research Reviews"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/med.70076","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/med.70076","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/med.70076","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T11:53:52Z","timestamp":1791201232000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/med.70076"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,16]]},"references-count":134,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2026,11]]}},"alternative-id":["10.1002\/med.70076"],"URL":"https:\/\/doi.org\/10.1002\/med.70076","archive":["Portico"],"relation":{},"ISSN":["0198-6325","1098-1128"],"issn-type":[{"value":"0198-6325","type":"print"},{"value":"1098-1128","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,16]]},"assertion":[{"value":"2025-11-17","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-07-07","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-07-16","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}