Affinage

CHI3L1

Chitinase-3-like protein 1 · UniProt P36222

Length
383 aa
Mass
42.6 kDa
Annotated
2026-04-28
100 papers in source corpus 28 papers cited in narrative 27 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CHI3L1 (YKL-40) is a secreted glycoprotein lacking chitinase catalytic activity that functions as a multireceptor ligand to regulate innate immunity, tissue remodeling, and tumor progression across diverse cellular contexts. It signals through IL-13Rα2 to activate MAPK and JNK-AP-1 pathways promoting cancer metastasis (PMID:28143526, PMID:34758182), through CD44 to drive β-catenin/Akt/STAT3-dependent glioma stem cell self-renewal (PMID:37101376), and through CRTH2/RAGE to suppress β-catenin signaling and inhibit neural stem cell neurogenesis (PMID:37756391, PMID:38733586); it also directly binds the STAT3 coiled-coil domain to enhance STAT3 phosphorylation and nuclear translocation in glioblastoma (PMID:39933531). In the immune microenvironment, CHI3L1 promotes M2 macrophage polarization, neutrophil extracellular trap formation that excludes CD8+ T cells, and upregulation of immune checkpoint molecules including PD-L1 and CTLA-4 (PMID:34720089, PMID:38039967, PMID:36618349); in astrocytes, it suppresses phagocytic clearance of amyloid-β, and its transcription is controlled by STAT3, RelB/p50 NF-κB complexes, and the BMAL1/CLOCK circadian machinery (PMID:25681350, PMID:33328329, PMID:38042775).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2006 Medium

    Establishing that CHI3L1 is not merely a biomarker but an active signaling ligand: exogenous HC-gp39 induced SOX9 and collagen II in chondrocytes through ERK1/2 and AKT phosphorylation, demonstrating that the catalytically inactive lectin has direct cell-signaling capacity.

    Evidence Purified protein treatment of primary chondrocytes with pharmacological inhibitors and phospho-western blot

    PMID:16949314

    Open questions at the time
    • Receptor mediating chondrocyte signaling was not identified
    • Mechanism of downstream SOX9 transcription not resolved
  2. 2010 Medium

    Loss-of-function studies confirmed CHI3L1 as a cell-autonomous driver of glioblastoma proliferation via MAPK/AKT, linking the secreted protein to tumor cell cycle progression.

    Evidence siRNA knockdown in U87 glioblastoma cells with cell cycle analysis and phospho-ERK/AKT western blot

    PMID:20499402 PMID:21029458

    Open questions at the time
    • Receptor(s) on glioblastoma cells mediating autocrine signaling not identified
    • Downstream transcriptional targets driving G1 arrest not characterized
  3. 2015 High

    The transcriptional logic of CHI3L1 induction was resolved: IL-1/oncostatin M-driven expression in astrocytes requires cooperative STAT3 and RelB/p50 NF-κB promoter engagement, with RelB/p50 (not p65) directly binding the CHI3L1 promoter.

    Evidence Promoter-reporter mutagenesis, ChIP for RelB/p50, dominant-negative IκBα in primary human and mouse astrocytes

    PMID:25681350

    Open questions at the time
    • Whether RelB/p50 regulation operates in non-astrocyte cell types not tested
    • Epigenetic regulation of the locus not addressed
  4. 2017 High

    The first bona fide cell-surface receptor for CHI3L1 was identified: IL-13Rα2 on cancer cells, establishing a ligand-receptor axis by which M2 macrophage-derived CHI3L1 activates MAPK signaling to drive metastasis.

    Evidence GST pull-down identifying IL-13Rα2, MAPK pathway activation by western blot, in vivo metastasis models

    PMID:28143526

    Open questions at the time
    • Whether IL-13Rα2 mediates CHI3L1 signaling in non-cancer contexts not established
    • Co-receptors or adaptor mechanisms downstream of IL-13Rα2 not defined
  5. 2020 High

    CHI3L1 was established as a suppressor of glial phagocytosis relevant to Alzheimer's disease, and its expression was linked to circadian clock control via BMAL1/CLOCK, revealing a time-of-day dimension to its regulation.

    Evidence Chi3l1 KO crossed with APP/PS1 mice; in vitro phagocytosis of Aβ/zymosan; circadian gene deletion in astrocytes

    PMID:33328329

    Open questions at the time
    • Receptor through which CHI3L1 suppresses phagocytosis not identified in this study
    • Mechanism linking circadian transcription factors to CHI3L1 promoter occupancy not shown by ChIP
  6. 2021 High

    CHI3L1 was revealed as an upstream regulator of immune checkpoint molecules (PD-L1, PD-1, LAG3, TIM3), establishing it as an immunomodulatory node that could be co-targeted with checkpoint blockade for synergistic anti-tumor effects.

    Evidence Antibody blockade, T cell–tumor coculture cytotoxicity, in vivo melanoma metastasis, bispecific CHI3L1/PD-1 antibody

    PMID:34720089

    Open questions at the time
    • Signaling pathway connecting CHI3L1 to transcriptional regulation of PD-L1/LAG3/TIM3 not fully defined
    • Whether checkpoint regulation is receptor-specific or shared across CHI3L1 receptors unknown
  7. 2021 High

    A second receptor axis was defined: CHI3L1 binds BMPRIa on osteoblasts to potentiate BMP2/RUNX2 osteoblast differentiation, and Chi3l1 KO mice develop osteoporosis, demonstrating a physiological role beyond inflammation and cancer.

    Evidence Co-immunoprecipitation of Chi3l1–BMPRIa, Chi3l1 KO bone phenotyping, primary osteoblast differentiation assays

    PMID:36064078

    Open questions at the time
    • Structural basis of CHI3L1–BMPRIa interaction not resolved
    • Whether BMPRIa mediates CHI3L1 signaling in non-bone tissues not tested
  8. 2021 High

    The chitin-binding domain was validated as a druggable surface: a small molecule (K284) competitively blocks CHI3L1 binding to IL-13Rα2, suppressing JNK-AP-1 signaling and lung metastasis.

    Evidence In vitro binding and competition assays, JNK-AP-1 signaling analysis, in vivo lung metastasis models

    PMID:34758182

    Open questions at the time
    • Selectivity of K284 for CHI3L1 over other GH18 family members not shown
    • Whether K284 blocks CHI3L1 binding to other receptors (CD44, CRTH2, BMPRIa) not assessed
  9. 2023 High

    Additional receptor diversity was uncovered: CHI3L1 engages CD44 on glioma stem cells to activate β-catenin/Akt/STAT3, chromatin remodeling at MAZ sites, and mesenchymal transition; and CRTH2 on neural stem cells to suppress β-catenin-dependent neurogenesis.

    Evidence Binding assays, ATAC-seq, scRNA-seq with RNA velocity for CD44 axis; CRTH2 blocking, β-catenin analysis, NMO mouse model for CRTH2 axis

    PMID:37101376 PMID:37756391

    Open questions at the time
    • Structural determinants distinguishing CHI3L1 binding to CD44 vs. CRTH2 unknown
    • Whether CHI3L1 signals through CD44 and CRTH2 simultaneously on the same cell not tested
  10. 2023 High

    In the tumor immune microenvironment, CHI3L1 was shown to promote neutrophil recruitment and NET formation that physically excludes CD8+ T cells, establishing a STAT3-CHI3L1-NET immunosuppressive circuit in triple-negative breast cancer.

    Evidence Chi3l1 genetic ablation in PyMT breast cancer model, immune cell infiltration analysis, NET assays, Stat3 KO tumor profiling

    PMID:38039967

    Open questions at the time
    • Receptor on neutrophils that mediates CHI3L1-induced NET formation not identified
    • Whether CHI3L1-driven NETs operate in non-breast tumor types not tested
  11. 2023 High

    An intracellular role emerged: CHI3L1 resides in the ER and interacts with SOD1; its depletion triggers PERK-eIF2α-ATF4 ER stress-mediated apoptosis, suggesting functions beyond secreted signaling.

    Evidence LC-MS/MS proteomics, co-IP of CHI3L1–SOD1, ER stress marker analysis, CHI3L1-KO mouse tumors, SOD1 siRNA rescue

    PMID:37215572

    Open questions at the time
    • Whether ER-resident CHI3L1 is a distinct pool from secreted CHI3L1 not clarified
    • Structural basis of CHI3L1–SOD1 interaction unknown
    • Generalizability of ER stress phenotype to non-cancer cells not tested
  12. 2024 High

    A direct intracellular signaling mechanism was identified: CHI3L1 binds the coiled-coil domain of STAT3 to promote its phosphorylation and nuclear translocation, forming a positive feedback loop with OPN/ITGB1 and NF-κB in glioblastoma mesenchymal transition.

    Evidence scMulti-omics, domain-specific binding assays, phosphorylation/nuclear localization analysis, hygromycin B as pharmacological disruptor, mouse tumor models

    PMID:39933531

    Open questions at the time
    • Whether direct CHI3L1–STAT3 binding occurs in non-glioblastoma cells unknown
    • How CHI3L1 accesses intracellular STAT3 (internalization vs. de novo synthesis) not resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • Major unresolved questions include: (1) how CHI3L1 selects among its multiple receptors (IL-13Rα2, CD44, CRTH2, RAGE, BMPRIa) in different cellular contexts; (2) whether its intracellular ER/STAT3-binding functions are independent of its secreted extracellular receptor-mediated signaling; and (3) whether a unifying structural model explains differential ligand-receptor engagement through the chitin-binding domain.
  • No structural co-crystal with any receptor
  • No systematic comparison of receptor affinities or competition
  • Intracellular vs. extracellular functional partitioning not delineated

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 5 GO:0060089 molecular transducer activity 4 GO:0098772 molecular function regulator activity 4
Localization
GO:0005576 extracellular region 6 GO:0005783 endoplasmic reticulum 1
Pathway
R-HSA-162582 Signal Transduction 9 R-HSA-1643685 Disease 8 R-HSA-168256 Immune System 6
Partners
AGERBMPR1ACD44IL13RA2PLGPTGDR2SOD1STAT3

Evidence

Reading pass · 27 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2017 CHI3L1 (YKL-40) secreted by M2 macrophages binds to IL-13Rα2 on cancer cell plasma membranes, activating MAPK signaling and upregulating matrix metalloproteinase gene expression to promote gastric and breast cancer metastasis. GST pull-down assay identifying IL-13Rα2 as receptor; in vitro and in vivo metastasis models; western blot for MAPK pathway activation Journal of hematology & oncology High 28143526
2021 CHI3L1 regulates PD-L1, PD-L2, PD-1, LAG3, and TIM3 expression in melanoma and macrophages; IFN-γ-stimulated macrophage PD-L1 expression is dependent on CHI3L1; RIG-like helicase innate immunity suppresses CHI3L1 and PD-L1. Bispecific antibodies simultaneously targeting CHI3L1 and PD-1 show synergistic antitumor effects in T cell-tumor cell cocultures and in vivo metastasis models. Antibody blockade, T cell-tumor cell coculture cytotoxicity assay, in vivo melanoma metastasis models, gene expression analysis The Journal of clinical investigation High 34720089
2023 CHI3L1 promotes neutrophil recruitment and neutrophil extracellular trap (NET) formation in triple-negative breast cancer, which blocks CD8+ T cell tumor infiltration. Chi3l1 expression is regulated downstream of Stat3 in breast tumors. Chi3l1 ablation in PyMT breast cancer mouse model; immune cell infiltration analysis; NET formation assays; Stat3 knockout tumor profiling Immunity High 38039967
2020 Chi3l1 deletion in mice suppresses glial phagocytic activation; Chi3l1 knockdown increases phagocytosis of zymosan particles and β-amyloid peptide in astrocytes and microglia in vitro, and decreases amyloid plaque burden in APP/PS1 mice. Chi3l1 expression is regulated by the circadian clock via BMAL1/CLOCK/NPAS2 and PER1/PER2. Chi3l1 knockout mice crossed with APP/PS1 AD model; in vitro phagocytosis assay; circadian clock gene deletion; inflammatory induction experiments in astrocytes Science translational medicine High 33328329
2015 Cytokine-driven YKL-40 expression in astrocytes requires both STAT3 and NF-κB binding elements of the YKL-40 promoter; specifically IL-1 and oncostatin M promote RelB/p50 complex formation which directly binds the YKL-40 promoter. Expression is independent of p65 NF-κB subunit. Promoter reporter assays, dominant-negative IκBα, constitutively active STAT3, chromatin immunoprecipitation for RelB/p50 binding to YKL-40 promoter, primary human and mouse astrocytes Journal of immunology High 25681350
2023 Chi3l1 binds CD44 on glioma stem cells (GSCs) and induces phosphorylation and nuclear translocation of β-catenin, Akt, and STAT3, driving GSCs toward a mesenchymal state. Chi3l1 increases promoter accessibility at MAZ transcription factor sites; MAZ deficiency rescues Chi3L1-induced increase of GSC self-renewal. Binding assay (Chi3l1 to CD44), phosphorylation western blots, scRNA-seq with RNA velocity, ATAC-seq, MAZ inhibition, in vivo tumor growth with blocking antibody Cancer research High 37101376
2023 CHI3L1 secreted by activated astrocytes engages the CRTH2 receptor on neural stem cells and dampens β-catenin signaling, inhibiting proliferation and neuronal differentiation of neural stem cells in the context of neuromyelitis optica (NMO). Blocking CHI3L1/CRTH2/β-catenin restores neurogenesis and improves cognitive deficits. CHI3L1 knockdown in astrocytes (in vitro and in vivo NMO mouse model), neural stem cell proliferation/differentiation assays, β-catenin signaling analysis, CRTH2 blocking experiments Science advances High 37756391
2024 Astrocyte-derived CHI3L1 interacts with CRTH2/RAGE receptors and attenuates β-catenin signaling in the demyelinated hippocampus, impairing neural stem cell proliferation, neuronal differentiation, dendritic growth, and spine formation. Astrocytic deletion of CHI3L1 mitigates neurogenic deficits and cognitive dysfunction. Astrocyte-specific CHI3L1 deletion in demyelination mouse model, receptor co-immunoprecipitation (CRTH2/RAGE), β-catenin signaling assays, neural stem cell assays, cognitive behavioral tests Cell reports High 38733586
2021 CHI3L1 interacts with BMPRIa on osteoblasts, increasing surface expression of BMPRIa and promoting BMP2 signaling and RUNX2 expression to induce osteoblast differentiation. Chi3l1 KO mice show impaired osteoblast differentiation and aging-related osteoporosis with decreased OPG and increased osteoclast numbers. Co-immunoprecipitation of Chi3l1 with BMPRIa, Chi3l1 KO mouse bone phenotype, primary osteoblast differentiation assays, western blot for BMP2 signaling Pharmacological research High 36064078
2020 CHI3L1 activates AKT3 signaling in nucleus pulposus (NP) cells to protect against intervertebral disc degeneration. CHI3L1 expression is NP tissue-specific and increases during degeneration; overexpression decreases catabolism and increases anabolism of extracellular matrix via AKT3. High-throughput label-free proteomics, RNA sequencing, CHI3L1 overexpression and siRNA knockdown in NP cells, AKT3 phosphorylation analysis, validation in human and mouse degenerated NP tissues FASEB journal High 31997395
2021 A small molecule (K284) that binds to the chitin-binding domain (CBD) of CHI3L1 prevents CHI3L1 binding to IL-13Rα2, thereby suppressing JNK-AP-1 signaling and inhibiting lung metastasis and cancer cell growth. In vitro binding assay of K284 to CHI3L1 CBD, CHI3L1-IL-13Rα2 binding competition assay, JNK-AP-1 signaling analysis, in vitro and in vivo lung metastasis models Molecular oncology High 34758182
2020 YKL-40 promotes airway remodeling in asthma by increasing airway smooth muscle mass, inducing EMT and sub-epithelial fibrosis through activation of FAK and MAPK signaling pathways. Inhibiting FAK or MAPK significantly ameliorates YKL-40-induced airway remodeling in vitro and in vivo. YKL-40 treatment of airway smooth muscle cells, FAK/MAPK inhibitor experiments, asthma mouse model, EMT marker analysis Cell cycle Medium 32286145
2018 CHI3L1 promotes hepatocellular carcinoma cell growth, migration, and invasion by activating TGF-β signaling pathways, including phosphorylation of SMAD2 and SMAD3. CHI3L1 overexpression affects genes involved in cell-cell adhesion, extracellular exosome, and adherens junction. CHI3L1 overexpression in HCC cell lines, RNA-seq gene expression profiling, western blot for SMAD2/3 phosphorylation, in vivo tumor models Scientific reports Medium 30301907
2006 HC-gp39 (CHI3L1) induces SOX9 and type II collagen expression in chondrocytes via MAP kinase (ERK1/2 phosphorylation) and PI3 kinase (AKT phosphorylation) signaling pathways, promoting chondrocyte differentiation. Purified HC-gp39 treatment of primary neonatal mouse rib chondrocytes, phosphorylation-specific western blot, selective signaling inhibitors Osteoarthritis and cartilage Medium 16949314
2023 YKL-40-expressing M2-like macrophages in gallbladder cancer induce tumor cell secretion of GDF15, which cooperates with YKL-40 to promote PD-L1 expression via PI3K, AKT, and/or Erk activation, leading to T cell cytotoxicity inhibition and tumor immune evasion. YKL-40 shRNA reprogrammed M2-like THP-1 cells to M1-like macrophages. Single-cell transcriptome analysis, YKL-40 shRNA knockdown, PI3K/AKT/Erk signaling analysis by western blot, co-culture assays for T cell function Cancer letters Medium 37088328
2024 CHI3L1 directly binds the coiled-coil domain (CCD) of STAT3 to enhance its phosphorylation, nuclear localization, and transcriptional activity. CHI3L1 and OPN/ITGB1 form a positive feedback loop maintaining NF-κB and STAT3 pathway activation in glioblastoma mesenchymal transition. Hygromycin B disrupts the CHI3L1-STAT3 interaction. scMulti-omics, direct binding assay of CHI3L1 to STAT3 CCD, phosphorylation and nuclear localization analysis, C57BL/6 and NSG mouse tumor models, pharmacological inhibition with hygromycin B Developmental cell High 39933531
2010 YKL-40 knockdown (siRNA) in glioblastoma U87 cells arrests the cell cycle in G1 phase and decreases phosphorylated ERK1/2 and AKT levels. YKL-40 promotes glioma cell proliferation through activation of MAPK and AKT pathways; resveratrol represses YKL-40 via the ERK1/2 pathway. siRNA knockdown, flow cytometry cell cycle analysis, western blot for phospho-ERK1/2, phospho-AKT, p38 MAPK inhibitor (SB203580) rescue experiments Cancer; BMC cancer Medium 20499402 21029458
2023 CHI3L1 depletion in cancer cells induces ER stress through PERK-eIF2α-ATF4 signaling activation, leading to ER stress-mediated apoptosis. CHI3L1 is localized in the ER. Superoxide dismutase-1 (SOD1) was identified as a novel interacting protein of CHI3L1; CHI3L1 depletion increases SOD1 expression resulting in ER stress and apoptosis in cancer cells. LC-MS/MS proteomics in CHI3L1-overexpressing cells, co-immunoprecipitation of CHI3L1 and SOD1, ER stress marker analysis, CHI3L1-KO mouse tumor models, SOD1 siRNA rescue experiments Theranostics High 37215572
2021 Anti-CHI3L1 antibody inhibits lung tumor growth and metastasis by blocking STAT6-dependent M2 macrophage polarization. Proteomics analysis revealed that plasminogen (PLG) interacts with CHI3L1 and affects M2 polarization. Anti-CHI3L1 humanized antibody in lung cancer mouse model, STAT6 pathway analysis, proteomics identification of PLG-CHI3L1 interaction Molecular oncology Medium 34861103
2022 CHI3L1 inhibits ICOS, ICOSL, and CD28 expression while stimulating CTLA-4 and B7 ligands in melanoma lung metastasis. Bispecific antibodies targeting both CHI3L1 and CTLA-4 synergistically induce cytotoxic T cell-mediated tumor cell death and heighten PTEN expression. CHI3L1 antibody blockade, T cell-tumor cell cocultures, melanoma lung metastasis mouse model, bispecific antibody treatment, flow cytometry for checkpoint markers Frontiers in immunology Medium 36618349
2023 pSTAT3+ reactive astrocytes secrete CHI3L1 (a STAT3 transcriptional target) at the brain-tumor interface; this CHI3L1 promotes highly invasive brain metastasis invasion into the brain parenchyma. Recombinant CHI3L1 alone or STAT3 activation induced cancer cell invasion into brain parenchyma in a brain slice-tumor co-culture assay. Single-cell RNA sequencing, immunohistochemistry, STAT3 inhibition and genetic ablation, brain slice-tumor plug co-culture invasion assay, PDX and syngeneic mouse models Neuro-oncology High 38271182
2024 CHI3L1 gene expression functionally influences tumor microtube (TM) network connectivity in glioblastoma; Chi3l1 serves as a robust molecular marker of TM connectivity associated with the mesenchymal subtype. scRNA-seq from xenografted primary GB cells with dye uptake connectivity assay, calcium imaging, clinical correlation in large GB cohorts Nature communications Medium 38320988
2023 Astrocyte-derived CHI3L1 expression promotes Aβ accumulation by suppressing glial phagocytosis of amyloid. Astrocyte-specific YKL-40 knockout in 5xFAD mice reduces amyloid plaque deposition through enhanced Aβ uptake, increased Aβ degradation rate, and lysosomal acidification in YKL-40 KO astrocytes. In primary neurons, YKL-40 combined with Aβ induces synaptic degeneration and impairs electrical parameters. Astrocyte-specific Chi3l1 KO in 5xFAD mice, primary astrocyte phagocytosis assay, Aβ uptake/degradation assay, lysosomal acidification assay, primary neuron treatment with recombinant YKL-40 Journal of neuroinflammation High 38042775
2017 Molecular dynamics simulations predict that hyaluronan is the preferred physiological ligand for YKL-40 over chito-oligosaccharides and collagen-like peptides, based on calculated free energies of binding. Heparin binds non-specifically at the YKL-40 surface. Molecular dynamics simulations with free energy calculations for multiple ligands The Journal of biological chemistry Low 28053085
2023 P. gingivalis increases CHI3L1 expression in iNKT cells, impairing their cytotoxic (lytic) functions and promoting colorectal cancer immune evasion. Neutralization of CHI3L1 restored iNKT cell cytotoxic functions. In vivo P. gingivalis CRC mouse model, in vitro iNKT cell stimulation assays, CHI3L1 neutralizing antibody, cytotoxicity assays Gut microbes Medium 39132842
2021 Nrf2 overexpression suppresses CHI3L1 expression in synoviocytes stimulated with LPS; LPS-induced CHI3L1 increase correlates with ROS and inflammatory cytokine (TNF-α, IL-1β, IL-6) production. Nrf2 acts as a negative regulator of CHI3L1 in post-traumatic osteoarthritis. Nrf2 overexpression lentiviral vector in PTOA mouse model (intra-articular injection), LPS-stimulated murine synoviocyte in vitro model, ELISA/western blot for CHI3L1 and inflammatory markers Journal of inflammation research Medium 34466014
2023 M2 macrophage-secreted CHI3L1 promotes hepatocyte recovery from ischemia-reperfusion injury by improving hepatocellular lipid metabolism. Downstream of CX3CR1 deficiency and RelA suppression, M2 macrophages upregulate CHIL3/CHI3L1 which improves mitochondrial function and reduces injury in cultured hepatocytes. CX3CR1 KO mice, 5-ALA treatment, M2 macrophage polarization assay, hepatocyte co-culture with recombinant CHIL3/CHI3L1, metabolic and mitochondrial function assays Theranostics Medium 37771779

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1993 The CD40 ligand, gp39, is defective in activated T cells from patients with X-linked hyper-IgM syndrome. Cell 748 7678782
1996 Immune regulation by CD40 and its ligand GP39. Annual review of immunology 504 8717526
2017 Tumor-recruited M2 macrophages promote gastric and breast cancer metastasis via M2 macrophage-secreted CHI3L1 protein. Journal of hematology & oncology 385 28143526
1994 gp39-CD40 interactions are essential for germinal center formation and the development of B cell memory. The Journal of experimental medicine 367 7516405
1993 The regulation of the expression of gp39, the CD40 ligand, on normal and cloned CD4+ T cells. Journal of immunology (Baltimore, Md. : 1950) 333 8103067
1993 In vivo CD40-gp39 interactions are essential for thymus-dependent humoral immunity. II. Prolonged suppression of the humoral immune response by an antibody to the ligand for CD40, gp39. The Journal of experimental medicine 312 7693850
1995 Interaction between CD40 and its ligand gp39 in the development of murine lupus nephritis. Journal of immunology (Baltimore, Md. : 1950) 296 7529804
1996 CD40-gp39 interactions play a critical role during allograft rejection. Suppression of allograft rejection by blockade of the CD40-gp39 pathway. Transplantation 266 8560571
1999 Serum YKL-40 and colorectal cancer. British journal of cancer 167 10188896
2020 Chi3l1/YKL-40 is controlled by the astrocyte circadian clock and regulates neuroinflammation and Alzheimer's disease pathogenesis. Science translational medicine 159 33328329
1996 Functions of CD40 and its ligand, gp39 (CD40L). Critical reviews in immunology 139 8809473
2009 Plasma YKL-40: a potential new cancer biomarker? Future oncology (London, England) 133 19792974
1995 An essential role for gp39, the ligand for CD40, in thymic selection. The Journal of experimental medicine 132 7595208
2005 Regulation of YKL-40 expression during genotoxic or microenvironmental stress in human glioblastoma cells. Cancer science 110 15771622
2005 Expression of YKL-40 by peritumoral macrophages in human small cell lung cancer. Lung cancer (Amsterdam, Netherlands) 108 15829322
2017 CSF sAPPβ, YKL-40, and neurofilament light in frontotemporal lobar degeneration. Neurology 107 28592456
2023 The tumor-derived cytokine Chi3l1 induces neutrophil extracellular traps that promote T cell exclusion in triple-negative breast cancer. Immunity 101 38039967
2017 Functions of CD40 and Its Ligand, gp39 (CD40L). Critical reviews in immunology 90 29773027
2013 Evaluation of CHI3L-1 and CHIT-1 expression in differentiated and polarized macrophages. Inflammation 84 23149946
2023 Astrocyte biomarkers GFAP and YKL-40 mediate early Alzheimer's disease progression. Alzheimer's & dementia : the journal of the Alzheimer's Association 83 37690071
1996 The relative contribution of the CD28 and gp39 costimulatory pathways in the clonal expansion and pathogenic acquisition of self-reactive T cells. The Journal of experimental medicine 83 8642284
2015 YKL-40/CHI3L1 drives inflammation on the road of tumor progression. Journal of leukocyte biology 82 26310833
2010 Increased YKL-40 expression in patients with carotid atherosclerosis. Atherosclerosis 77 20347092
2018 CSF sAPPβ, YKL-40, and NfL along the ALS-FTD spectrum. Neurology 75 30291183
1997 Thymus dysfunction and chronic inflammatory disease in gp39 transgenic mice. International immunology 68 9263008
2018 CHI3L1 promotes tumor progression by activating TGF-β signaling pathway in hepatocellular carcinoma. Scientific reports 67 30301907
2017 CHI3L1 and CHI3L2 overexpression in motor cortex and spinal cord of sALS patients. Molecular and cellular neurosciences 66 28989002
2014 Expression of CHI3L1 and CHIT1 in osteoarthritic rat cartilage model. A morphological study. European journal of histochemistry : EJH 62 25308850
2009 YKL-40 tissue expression and plasma levels in patients with ovarian cancer. BMC cancer 62 19134206
2021 CHI3L1 regulates PD-L1 and anti-CHI3L1-PD-1 antibody elicits synergistic antitumor responses. The Journal of clinical investigation 57 34720089
2019 Astrogliogenesis in human fetal brain: complex spatiotemporal immunoreactivity patterns of GFAP, S100, AQP4 and YKL-40. Journal of anatomy 55 30901080
2015 RelB/p50 complexes regulate cytokine-induced YKL-40 expression. Journal of immunology (Baltimore, Md. : 1950) 55 25681350
1995 Analysis of gp39/CD40 interactions using molecular models and site-directed mutagenesis. Biochemistry 55 7543281
2018 Combined Assessment of Serum Periostin and YKL-40 May Identify Asthma-COPD Overlap. The journal of allergy and clinical immunology. In practice 52 29981861
2006 The phylogenetically conserved molluscan chitinase-like protein 1 (Cg-Clp1), homologue of human HC-gp39, stimulates proliferation and regulates synthesis of extracellular matrix components of mammalian chondrocytes. The Journal of biological chemistry 50 16882657
2007 Is YKL-40 a new therapeutic target in cancer? Expert opinion on therapeutic targets 48 17227236
2016 High CHI3L1 expression is associated with glioma patient survival. Diagnostic pathology 47 27121858
2023 YKL-40 derived from infiltrating macrophages cooperates with GDF15 to establish an immune suppressive microenvironment in gallbladder cancer. Cancer letters 46 37088328
2022 The role of YKL-40 in the pathogenesis of autoimmune diseases: a comprehensive review. International journal of biological sciences 46 35813465
2021 Potential Role of CHI3L1+ Astrocytes in Progression in MS. Neurology(R) neuroimmunology & neuroinflammation 46 33658322
2023 Chi3l1 Is a Modulator of Glioma Stem Cell States and a Therapeutic Target in Glioblastoma. Cancer research 45 37101376
2021 Anti-Chi3L1 antibody suppresses lung tumor growth and metastasis through inhibition of M2 polarization. Molecular oncology 44 34861103
2023 CHI3L1 signaling impairs hippocampal neurogenesis and cognitive function in autoimmune-mediated neuroinflammation. Science advances 43 37756391
2020 CHI3L1 in the pathophysiology and diagnosis of liver diseases. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 41 32861071
2014 Analysis of YKL-40 acute-phase protein and interleukin-6 levels in periodontal disease. Journal of periodontology 40 24635545
2016 Mycobacteriophage SWU1 gp39 can potentiate multiple antibiotics against Mycobacterium via altering the cell wall permeability. Scientific reports 38 27350398
2024 A clinically applicable connectivity signature for glioblastoma includes the tumor network driver CHI3L1. Nature communications 36 38320988
2021 A small molecule targeting CHI3L1 inhibits lung metastasis by blocking IL-13Rα2-mediated JNK-AP-1 signals. Molecular oncology 36 34758182
1996 Antibody to the ligand for CD40 (gp39) inhibits murine AIDS-associated splenomegaly, hypergammaglobulinemia, and immunodeficiency in disease-susceptible C57BL/6 mice. Journal of virology 36 8642687
2020 Cerebrospinal Fluid YKL-40 and Chitotriosidase Levels in Frontotemporal Dementia Vary by Clinical, Genetic and Pathological Subtype. Dementia and geriatric cognitive disorders 35 32344399
2021 LncRNA KCNQ1OT1 Promotes Proliferation, Invasion and Metastasis of Prostate Cancer by Regulating miR-211-5p/CHI3L1 Pathway. OncoTargets and therapy 34 33688211
2018 Single Nucleotide Polymorphism in SMAD7 and CHI3L1 and Colorectal Cancer Risk. Mediators of inflammation 34 30498395
2024 Porphyromonas gingivalis fuels colorectal cancer through CHI3L1-mediated iNKT cell-driven immune evasion. Gut microbes 32 39132842
2014 The significance of YKL-40 protein in liver fibrosis. Inflammation research : official journal of the European Histamine Research Society ... [et al.] 32 24442412
2023 5-aminolevulinate and CHIL3/CHI3L1 treatment amid ischemia aids liver metabolism and reduces ischemia-reperfusion injury. Theranostics 31 37771779
2006 HC-gp39 contributes to chondrocyte differentiation by inducing SOX9 and type II collagen expressions. Osteoarthritis and cartilage 30 16949314
2017 Inhibition of Mammalian Glycoprotein YKL-40: IDENTIFICATION OF THE PHYSIOLOGICAL LIGAND. The Journal of biological chemistry 29 28053085
2024 The Role of Chitinase-3-like Protein-1 (YKL40) in the Therapy of Cancer and Other Chronic-Inflammation-Related Diseases. Pharmaceuticals (Basel, Switzerland) 28 38543093
2010 Resveratrol represses YKL-40 expression in human glioma U87 cells. BMC cancer 28 21029458
2018 Angiogenic potential of YKL-40 in the dynamics of tumor niche. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 27 29477911
1994 The expansive role of CD40 and its ligand, gp39, in immunity. Seminars in immunology 27 7532456
2019 CHI3L1 promotes proliferation and improves sensitivity to cetuximab in colon cancer cells by down-regulating p53. Journal of clinical laboratory analysis 26 31536166
2022 CHI3L1 enhances melanoma lung metastasis via regulation of T cell co-stimulators and CTLA-4/B7 axis. Frontiers in immunology 25 36618349
2021 Circular RNA circ-CHI3L1.2 modulates cisplatin resistance of osteosarcoma cells via the miR-340-5p/LPAATβ axis. Human cell 25 34164774
2022 Chi3L1 is a therapeutic target in bone metabolism and a potential clinical marker in patients with osteoporosis. Pharmacological research 24 36064078
2021 Nrf2 Regulates CHI3L1 to Suppress Inflammation and Improve Post-Traumatic Osteoarthritis. Journal of inflammation research 24 34466014
2020 YKL-40 and neuron-specific enolase in neurodegeneration and neuroinflammation. Reviews in the neurosciences 24 32045356
1994 The role of CD40L (gp39)/CD40 in T/B cell interaction and primary immunodeficiency. Seminars in immunology 24 7532462
2024 Astrocyte-derived CHI3L1 signaling impairs neurogenesis and cognition in the demyelinated hippocampus. Cell reports 23 38733586
2020 YKL-40 mediates airway remodeling in asthma via activating FAK and MAPK signaling pathway. Cell cycle (Georgetown, Tex.) 23 32286145
2010 Association between YKL-40 and adult primary astrocytoma. Cancer 23 20499402
1998 Purification of guinea pig YKL40 and modulation of its secretion by cultured articular chondrocytes. Journal of cellular biochemistry 23 9620168
2024 Invasive growth of brain metastases is linked to CHI3L1 release from pSTAT3-positive astrocytes. Neuro-oncology 22 38271182
2017 Genetic and epigenetic regulation of YKL-40 in childhood. The Journal of allergy and clinical immunology 22 28739286
2014 Elevated YKL40 is associated with advanced prostate cancer (PCa) and positively regulates invasion and migration of PCa cells. Endocrine-related cancer 22 24981110
2011 YKL-40 expression in CD14⁺ liver cells in acute and chronic injury. World journal of gastroenterology 22 21987626
2024 Association of Plasma YKL-40 With MRI, CSF, and Cognitive Markers of Brain Health and Dementia. Neurology 21 38290090
2014 Unveiling YKL-40, from Serum Marker to Target Therapy in Glioblastoma. Frontiers in oncology 21 24809021
2023 Induction of ER stress-mediated apoptosis through SOD1 upregulation by deficiency of CHI3L1 inhibits lung metastasis. Theranostics 20 37215572
2023 Cancer stem cell-derived CHI3L1 activates the MAF/CTLA4 signaling pathway to promote immune escape in triple-negative breast cancer. Journal of translational medicine 20 37838657
2018 The Role of CHI3L1 Expression in Angiogenesis in Invasive Ductal Breast Carcinoma. Anticancer research 20 29848684
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2022 Further evidence for association of YKL-40 with severe asthma airway remodeling. Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology 19 35342020
2021 Serum YKL-40 levels in patients with multiple sclerosis. Arquivos de neuro-psiquiatria 19 34669813
2025 STAT3-controlled CHI3L1/SPP1 positive feedback loop demonstrates the spatial heterogeneity and immune characteristics of glioblastoma. Developmental cell 18 39933531
2021 YKL-40 promotes invasion and metastasis of bladder cancer by regulating epithelial mesenchymal transition. Annals of medicine 18 34259106
2015 Bortezomib modulates CHIT1 and YKL40 in monocyte-derived osteoclast and in myeloma cells. Frontiers in pharmacology 18 26528182
2007 YKL-40 expression in benign and malignant lesions of the breast: a methodologic study. Applied immunohistochemistry & molecular morphology : AIMM 18 18091378
2023 Astrocyte-specific knockout of YKL-40/Chi3l1 reduces Aβ burden and restores memory functions in 5xFAD mice. Journal of neuroinflammation 17 38042775
2020 Inflammatory-sensitive CHI3L1 protects nucleus pulposus via AKT3 signaling during intervertebral disc degeneration. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 17 31997395
2018 Correlation between protein YKL-40 and ultrasonographic findings in active knee osteoarthritis. Medical ultrasonography 17 29400369
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2017 Serum YKL-40 as a potential biomarker of inflammation in psoriasis. The Journal of dermatological treatment 17 28498006
2016 The role of YKL-40 in a cancerous process. Postepy higieny i medycyny doswiadczalnej (Online) 17 28026831
2010 YKL-40 protein levels and clinical outcome of human endometrial cancer. The Journal of international medical research 17 20926018
2022 Longitudinal and Comparative Measures of Serum Chitotriosidase and YKL-40 in Patients With Idiopathic Pulmonary Fibrosis. Frontiers in immunology 16 35222369
2020 Astrocytic IGFBP2 and CHI3L1 in cerebrospinal fluid drive cortical metastasis of HER2+breast cancer. Clinical & experimental metastasis 16 32279122
2020 Clinical Potentials of miR-576-3p, miR-613, NDRG2 and YKL40 in Colorectal Cancer Patients. Asian Pacific journal of cancer prevention : APJCP 16 32592365
2020 The different role of YKL-40 in glioblastoma is a function of MGMT promoter methylation status. Cell death & disease 16 32820151
2019 Aberrant progranulin, YKL-40, cathepsin D and cathepsin S in Gaucher disease. Molecular genetics and metabolism 16 31358474