{"gene":"ITLN1","run_date":"2026-06-10T01:55:23","timeline":{"discoveries":[{"year":2021,"finding":"ITLN1 suppresses lactotransferrin-driven ovarian cancer cell invasion and proliferation by decreasing MMP1 expression, and induces a metabolic shift in metastatic ovarian cancer cells. In vivo, ITLN1-treated tumor-bearing mice showed marked decreases in tumor growth rates.","method":"Cell invasion assays, MMP1 expression analysis (Western blot/qPCR), metabolic flux assays, and xenograft mouse models with ITLN1 treatment","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro functional assays combined with in vivo xenograft model, single lab, multiple orthogonal readouts but mechanistic pathway only partially defined","pmids":["32669559"],"is_preprint":false},{"year":2021,"finding":"ITLN1 inhibits tumor neovascularization and myeloid-derived suppressor cell (MDSC) accumulation in colorectal carcinoma by suppressing tumor-derived IL-17D and CXCL2 through the KEAP1/Nrf2/ROS/IL-17D and p65 NF-κB/CXCL2 signaling cascades, both dependent on PI3K/AKT/GSK3β; this was reversed by the PI3K inhibitor LY294002.","method":"Orthotopic and subcutaneous xenograft tumor models, bone marrow transplantation chimera experiments, Western blot, ELISA, flow cytometry, PI3K inhibitor rescue experiments","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple in vivo models and orthogonal mechanistic approaches in a single lab; PI3K pathway placement supported by pharmacological rescue","pmids":["34363021"],"is_preprint":false},{"year":2021,"finding":"The ITLN1 missense variant V109D does not influence ITLN1 glycan binding to β-D-galactofuranose or protein oligomerization, and neither ITLN1 mRNA nor protein abundance in intestinal tissue (goblet-cell derived) is altered by Crohn's disease-associated SNPs at the ITLN1 locus.","method":"Glycan-binding assay (β-D-galactofuranose), protein oligomerization analysis, intestinal tissue expression profiling by genotype","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — direct in vitro glycan-binding and oligomerization assays with the V109D variant; negative result for carbohydrate recognition alteration is experimentally established","pmids":["34145348"],"is_preprint":false},{"year":2022,"finding":"In C57BL/6 mice, Itln1 is expressed in Paneth cells of the small intestine (in contrast to human ITLN1 which localizes to goblet cells). Mice with ~10,000-fold reduced Itln1 expression showed increased susceptibility in an acute DSS-induced colitis model, indicating Itln1 contributes to intestinal mucosal defense.","method":"Knockout mouse model (hypomorphic trapping allele), mRNA and protein expression analysis, DSS-induced colitis model with disease activity scoring","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function in vivo with defined phenotypic readout; single lab, but Itln1 KO model with multiple outcome measures","pmids":["36072603"],"is_preprint":false},{"year":2019,"finding":"Fish ortholog WR-ITLN (teleost intelectin) binds directly to Aeromonas hydrophila and Streptococcus agalactiae in a Ca2+-dependent manner, reduces relative bacterial activity, limits bacterial growth in vitro, restricts bacterial dissemination in vivo, and attenuates pro-inflammatory cytokine production via MyD88-dependent pathways.","method":"Recombinant protein purification, direct bacterial binding assay, in vitro bacteriostatic assay with Ca2+ dependency, in vivo bacterial challenge model, cytokine measurement","journal":"Developmental and comparative immunology","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — reconstituted direct binding with purified protein and Ca2+ dependency established in vitro, confirmed in vivo; ortholog study in teleost fish","pmids":["31626818"],"is_preprint":false},{"year":2025,"finding":"ITLN1 binds to calpain-2 (CAPN2) and enhances its protein stability by antagonizing TRIM8-mediated ubiquitination degradation of CAPN2. Through this ITLN1-TRIM8-CAPN2 axis, ITLN1 drives ZBP1-dependent PANoptosis (combined pyroptosis/apoptosis/necroptosis) in intestinal epithelial cells, promotes inflammation, and impairs tight junctions. ITLN1 also binds TRIM8 directly, competing with CAPN2-TRIM8 interaction.","method":"Co-immunoprecipitation combined with mass spectrometry, RNA-seq, in vitro knockdown/overexpression rescue experiments, IL-10 KO colitis mouse model with shRNA-ITLN1 knockdown","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP/MS identifies ITLN1-CAPN2 and ITLN1-TRIM8 interactions; ubiquitination mechanism supported by rescue experiments and in vivo validation; single lab","pmids":["40520022"],"is_preprint":false}],"current_model":"ITLN1 (intelectin-1) is a secreted, Ca2+-dependent carbohydrate-binding protein (lectin) that recognizes microbial but not host glycans; it functions in innate mucosal immunity (with intestinal expression localized to goblet cells in humans and Paneth cells in mice), suppresses tumor progression by inhibiting MMP1-driven invasion, blocking IL-17D/CXCL2-mediated neovascularization and MDSC recruitment via PI3K/AKT/GSK3β/NF-κB signaling, and in the context of Crohn's disease promotes PANoptosis of intestinal epithelial cells by binding CAPN2 and antagonizing TRIM8-mediated ubiquitin degradation of CAPN2 to activate ZBP1-dependent cell death."},"narrative":{"mechanistic_narrative":"ITLN1 (intelectin-1) is a secreted, Ca2+-dependent carbohydrate-binding lectin that functions in mucosal innate immune defense, with intestinal expression localized to human goblet cells and mouse Paneth cells [PMID:34145348, PMID:36072603]. Its lectin activity is direct and microbe-directed: the teleost ortholog binds bacterial pathogens in a Ca2+-dependent manner, restricts their growth and dissemination in vivo, and dampens pro-inflammatory cytokine output through MyD88-dependent signaling [PMID:31626818]. Genetic reduction of Itln1 in mice increases susceptibility to DSS-induced colitis, establishing a protective role in intestinal mucosal defense [PMID:36072603]. In cancer, ITLN1 acts as a tumor suppressor: it limits ovarian cancer cell invasion and proliferation by downregulating MMP1 and shifting tumor cell metabolism [PMID:32669559], and in colorectal carcinoma it suppresses IL-17D and CXCL2 production via KEAP1/Nrf2/ROS and p65 NF-κB cascades downstream of PI3K/AKT/GSK3β, thereby inhibiting tumor neovascularization and MDSC accumulation [PMID:34363021]. In the context of intestinal inflammation, ITLN1 binds and stabilizes calpain-2 (CAPN2) by competing with and antagonizing TRIM8-mediated ubiquitin-dependent degradation, and through this ITLN1–TRIM8–CAPN2 axis drives ZBP1-dependent PANoptosis of intestinal epithelial cells, promoting inflammation and impairing tight junctions [PMID:40520022]. A Crohn's-associated V109D missense variant does not alter glycan binding or oligomerization, and disease-linked SNPs do not change ITLN1 abundance [PMID:34145348].","teleology":[{"year":2019,"claim":"Establishing that intelectin acts as a direct, Ca2+-dependent antibacterial lectin defined its core molecular activity in innate immunity rather than leaving it as a presumed pattern-recognition role.","evidence":"Recombinant teleost ortholog binding and bacteriostatic assays with Ca2+ dependency, plus in vivo bacterial challenge and cytokine measurement","pmids":["31626818"],"confidence":"Medium","gaps":["Demonstrated in a fish ortholog, not human ITLN1","Glycan target specificity for these bacteria not resolved","Mechanism linking lectin binding to MyD88 attenuation unclear"]},{"year":2021,"claim":"Linking ITLN1 to MMP1 suppression and metabolic reprogramming showed it is a functional tumor suppressor in ovarian cancer, not merely a biomarker.","evidence":"Cell invasion assays, MMP1 expression analysis, metabolic flux assays, and ITLN1-treated xenograft mouse models","pmids":["32669559"],"confidence":"Medium","gaps":["Direct molecular link between ITLN1 and MMP1 regulation undefined","Receptor or binding partner mediating the anti-invasive effect unknown","Single lab"]},{"year":2021,"claim":"Placing ITLN1 upstream of IL-17D/CXCL2 via PI3K/AKT/GSK3β signaling defined the pathway through which it limits tumor angiogenesis and immunosuppressive cell recruitment.","evidence":"Orthotopic/subcutaneous xenografts, bone marrow chimeras, flow cytometry, and PI3K inhibitor (LY294002) rescue","pmids":["34363021"],"confidence":"Medium","gaps":["How secreted ITLN1 engages the PI3K cascade not identified","No direct ITLN1 receptor characterized","Confined to colorectal models"]},{"year":2021,"claim":"Testing the Crohn's-associated V109D variant and locus SNPs ruled out altered glycan recognition or expression as the disease mechanism, redirecting attention away from binding/abundance defects.","evidence":"β-D-galactofuranose glycan-binding assay, oligomerization analysis, and genotype-stratified intestinal expression profiling","pmids":["34145348"],"confidence":"Medium","gaps":["Functional consequence of V109D, if any, remains unidentified","Negative results do not establish the actual disease-relevant mechanism"]},{"year":2022,"claim":"Genetic loss-of-function in mice established that Itln1 contributes causally to intestinal mucosal defense and revealed a species difference in cellular source (Paneth vs goblet cells).","evidence":"Hypomorphic Itln1 knockout mouse with DSS-induced colitis and disease activity scoring","pmids":["36072603"],"confidence":"Medium","gaps":["Molecular effectors downstream of Itln1 in colitis protection not defined","Relevance of Paneth-cell localization to human goblet-cell biology unclear"]},{"year":2025,"claim":"Identifying ITLN1 as a CAPN2-binding protein that antagonizes TRIM8-mediated degradation revealed an intracellular, ubiquitin-regulated mechanism by which ITLN1 drives epithelial PANoptosis, contrasting with its protective extracellular lectin role.","evidence":"Co-IP/MS, RNA-seq, knockdown/overexpression rescue, and IL-10 KO colitis model with shRNA-ITLN1","pmids":["40520022"],"confidence":"Medium","gaps":["Reconciliation of pro-death intracellular role with protective extracellular role unresolved","Reciprocal validation and structural basis of ITLN1-CAPN2/TRIM8 binding not established","Single lab"]},{"year":null,"claim":"The receptor or surface interaction through which secreted ITLN1 transmits its tumor-suppressive and immunomodulatory signaling remains unidentified.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No ITLN1 cell-surface receptor characterized","How an extracellular lectin engages intracellular CAPN2/TRIM8 is unexplained","Glycan ligand repertoire for human ITLN1 not fully defined"]}],"mechanism_profile":{"molecular_activity":[],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[2,3,4]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[3,4]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[5]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1]}],"complexes":[],"partners":["CAPN2","TRIM8"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8WWA0","full_name":"Intelectin-1","aliases":["Endothelial lectin HL-1","Galactofuranose-binding lectin","Intestinal lactoferrin receptor","Omentin"],"length_aa":313,"mass_kda":35.0,"function":"Lectin that specifically recognizes microbial carbohydrate chains in a calcium-dependent manner (PubMed:11313366, PubMed:26148048). Binds to microbial glycans that contain a terminal acyclic 1,2-diol moiety, including beta-linked D-galactofuranose (beta-Galf), D-phosphoglycerol-modified glycans, D-glycero-D-talo-oct-2-ulosonic acid (KO) and 3-deoxy-D-manno-oct-2-ulosonic acid (KDO) (PubMed:26148048). Binds to glycans from Gram-positive and Gram-negative bacteria, including K.pneumoniae, S.pneumoniae, Y.pestis, P.mirabilis and P.vulgaris (PubMed:26148048). Does not bind human glycans (PubMed:26148048). Probably plays a role in the defense system against microorganisms (Probable). May function as adipokine that has no effect on basal glucose uptake but enhances insulin-stimulated glucose uptake in adipocytes (PubMed:16531507). Increases AKT phosphorylation in the absence and presence of insulin (PubMed:16531507). May interact with lactoferrin/LTF and increase its uptake, and may thereby play a role in iron absorption (PubMed:11747454, PubMed:23921499)","subcellular_location":"Cell membrane; Secreted","url":"https://www.uniprot.org/uniprotkb/Q8WWA0/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ITLN1","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ITLN1","total_profiled":1310},"omim":[{"mim_id":"609874","title":"INTELECTIN 2; ITLN2","url":"https://www.omim.org/entry/609874"},{"mim_id":"609873","title":"INTELECTIN 1; ITLN1","url":"https://www.omim.org/entry/609873"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"},{"location":"Equatorial segment","reliability":"Approved"},{"location":"Acrosome","reliability":"Additional"},{"location":"Mid piece","reliability":"Additional"},{"location":"Principal piece","reliability":"Additional"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"adipose tissue","ntpm":714.6},{"tissue":"intestine","ntpm":1172.6}],"url":"https://www.proteinatlas.org/search/ITLN1"},"hgnc":{"alias_symbol":["ITLN","FLJ20022","LFR","HL-1","hIntL"],"prev_symbol":[]},"alphafold":{"accession":"Q8WWA0","domains":[{"cath_id":"3.90.215","chopping":"42-313","consensus_level":"medium","plddt":98.5657,"start":42,"end":313}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8WWA0","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8WWA0-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8WWA0-F1-predicted_aligned_error_v6.png","plddt_mean":92.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ITLN1","jax_strain_url":"https://www.jax.org/strain/search?query=ITLN1"},"sequence":{"accession":"Q8WWA0","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8WWA0.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8WWA0/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8WWA0"}},"corpus_meta":[{"pmid":"9501201","id":"PMC_9501201","title":"HL-1 cells: a cardiac muscle cell line that contracts and retains phenotypic characteristics of the adult cardiomyocyte.","date":"1998","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/9501201","citation_count":1311,"is_preprint":false},{"pmid":"14766671","id":"PMC_14766671","title":"Cardiac physiology at the cellular level: use of cultured HL-1 cardiomyocytes for studies of cardiac muscle cell structure and function.","date":"2004","source":"American journal of physiology. 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Cell physiology","url":"https://pubmed.ncbi.nlm.nih.gov/19261908","citation_count":21,"is_preprint":false},{"pmid":"14559445","id":"PMC_14559445","title":"HL-1 myocytes exhibit PKC and K(ATP) channel-dependent delta opioid preconditioning.","date":"2003","source":"The Journal of surgical research","url":"https://pubmed.ncbi.nlm.nih.gov/14559445","citation_count":20,"is_preprint":false},{"pmid":"23268359","id":"PMC_23268359","title":"Murine atrial HL-1 cell line is a reliable model to study drug metabolizing enzymes in the heart.","date":"2012","source":"Vascular pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/23268359","citation_count":20,"is_preprint":false},{"pmid":"31419437","id":"PMC_31419437","title":"A small-molecule LF3 abrogates β-catenin/TCF4-mediated suppression of NaV1.5 expression in HL-1 cardiomyocytes.","date":"2019","source":"Journal of molecular and cellular 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approaches.","date":"2017","source":"Cardiovascular research","url":"https://pubmed.ncbi.nlm.nih.gov/28898995","citation_count":18,"is_preprint":false},{"pmid":"22277902","id":"PMC_22277902","title":"Common variants of SLAMF1 and ITLN1 on 1q21 are associated with type 2 diabetes in Indian population.","date":"2012","source":"Journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/22277902","citation_count":17,"is_preprint":false},{"pmid":"11841924","id":"PMC_11841924","title":"Roles of protein kinase C and alpha-tocopherol in regulation of signal transduction for GATA-4 phosphorylation in HL-1 cardiac muscle cells.","date":"2002","source":"Free radical biology & medicine","url":"https://pubmed.ncbi.nlm.nih.gov/11841924","citation_count":17,"is_preprint":false},{"pmid":"17982475","id":"PMC_17982475","title":"Functional coupling of angiotensin II type 1 receptor with insulin resistance of energy substrate uptakes in immortalized cardiomyocytes (HL-1 cells).","date":"2007","source":"British journal of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/17982475","citation_count":17,"is_preprint":false},{"pmid":"22979989","id":"PMC_22979989","title":"The promotion of HL-1 cardiomyocyte beating using anisotropic collagen-GAG scaffolds.","date":"2012","source":"Biomaterials","url":"https://pubmed.ncbi.nlm.nih.gov/22979989","citation_count":17,"is_preprint":false},{"pmid":"20186548","id":"PMC_20186548","title":"HL-1 cells express an inwardly rectifying K+ current activated via muscarinic receptors comparable to that in mouse atrial myocytes.","date":"2010","source":"Pflugers Archiv : European journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/20186548","citation_count":17,"is_preprint":false},{"pmid":"22527949","id":"PMC_22527949","title":"Delineation of the effects of angiotensin type 1 and 2 receptors on HL-1 cardiomyocyte apoptosis.","date":"2012","source":"Apoptosis : an international journal on programmed cell death","url":"https://pubmed.ncbi.nlm.nih.gov/22527949","citation_count":16,"is_preprint":false},{"pmid":"19318426","id":"PMC_19318426","title":"Regulation of urocortin I and its related peptide urocortin II by inflammatory and oxidative stresses in HL-1 cardiomyocytes.","date":"2009","source":"Journal of molecular endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/19318426","citation_count":16,"is_preprint":false},{"pmid":"36072603","id":"PMC_36072603","title":"Characterization of an intelectin-1 (Itln1) knockout mouse model.","date":"2022","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/36072603","citation_count":15,"is_preprint":false},{"pmid":"31626818","id":"PMC_31626818","title":"ITLN in diploid hybrid fish (Carassius auratus cuvieri ♀ × Carassius auratus red var ♂) is involved in host defense against bacterial infection.","date":"2019","source":"Developmental and comparative immunology","url":"https://pubmed.ncbi.nlm.nih.gov/31626818","citation_count":15,"is_preprint":false},{"pmid":"34439528","id":"PMC_34439528","title":"Pterostilbene Increases LDL Metabolism in HL-1 Cardiomyocytes by Modulating the PCSK9/HNF1α/SREBP2/LDLR Signaling Cascade, Upregulating Epigenetic hsa-miR-335 and hsa-miR-6825, and LDL Receptor Expression.","date":"2021","source":"Antioxidants (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/34439528","citation_count":15,"is_preprint":false},{"pmid":"14551048","id":"PMC_14551048","title":"Inhibition of glucose uptake in murine cardiomyocyte cell line HL-1 by cardioprotective drugs dilazep and dipyridamole.","date":"2003","source":"American journal of physiology. Heart and circulatory physiology","url":"https://pubmed.ncbi.nlm.nih.gov/14551048","citation_count":15,"is_preprint":false},{"pmid":"18424636","id":"PMC_18424636","title":"Inosine and equilibrative nucleoside transporter 2 contribute to hypoxic preconditioning in the murine cardiomyocyte HL-1 cell line.","date":"2008","source":"American journal of physiology. Heart and circulatory physiology","url":"https://pubmed.ncbi.nlm.nih.gov/18424636","citation_count":15,"is_preprint":false},{"pmid":"25939765","id":"PMC_25939765","title":"Nanostructured cavity devices for extracellular stimulation of HL-1 cells.","date":"2015","source":"Nanoscale","url":"https://pubmed.ncbi.nlm.nih.gov/25939765","citation_count":15,"is_preprint":false},{"pmid":"32351020","id":"PMC_32351020","title":"Hypoxia-induced alterations of transcriptome and chromatin accessibility in HL-1 cells.","date":"2020","source":"IUBMB life","url":"https://pubmed.ncbi.nlm.nih.gov/32351020","citation_count":14,"is_preprint":false},{"pmid":"25657056","id":"PMC_25657056","title":"Maintenance of HL-1 cardiomyocyte functional activity in PEGylated fibrin gels.","date":"2015","source":"Biotechnology and bioengineering","url":"https://pubmed.ncbi.nlm.nih.gov/25657056","citation_count":14,"is_preprint":false},{"pmid":"32894303","id":"PMC_32894303","title":"Mitoxantrone impairs proteasome activity and prompts early energetic and proteomic changes in HL-1 cardiomyocytes at clinically relevant concentrations.","date":"2020","source":"Archives of toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/32894303","citation_count":14,"is_preprint":false},{"pmid":"24281896","id":"PMC_24281896","title":"Monounsaturated 14:1n-9 and 16:1n-9 fatty acids but not 18:1n-9 induce apoptosis and necrosis in murine HL-1 cardiomyocytes.","date":"2013","source":"Lipids","url":"https://pubmed.ncbi.nlm.nih.gov/24281896","citation_count":14,"is_preprint":false},{"pmid":"20393597","id":"PMC_20393597","title":"Integrin β3 prevents apoptosis of HL-1 cardiomyocytes under conditions of oxidative stress.","date":"2010","source":"Canadian journal of physiology and pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/20393597","citation_count":14,"is_preprint":false},{"pmid":"16236026","id":"PMC_16236026","title":"Effects of hypoxia, glucose deprivation and acidosis on phosphatidylcholine synthesis in HL-1 cardiomyocytes. CTP:phosphocholine cytidylyltransferase activity correlates with sarcolemmal disruption.","date":"2006","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/16236026","citation_count":14,"is_preprint":false},{"pmid":"40520022","id":"PMC_40520022","title":"ITLN1 exacerbates Crohn's colitis by driving ZBP1-dependent PANoptosis in intestinal epithelial cells through antagonizing TRIM8-mediated CAPN2 ubiquitination.","date":"2025","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/40520022","citation_count":13,"is_preprint":false},{"pmid":"31936892","id":"PMC_31936892","title":"LRP1-Mediated AggLDL Endocytosis Promotes Cholesteryl Ester Accumulation and Impairs Insulin Response in HL-1 Cells.","date":"2020","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/31936892","citation_count":12,"is_preprint":false},{"pmid":"35563066","id":"PMC_35563066","title":"Rotenone-Induced 4-HNE Aggresome Formation and Degradation in HL-1 Cardiomyocytes: Role of Autophagy Flux.","date":"2022","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/35563066","citation_count":12,"is_preprint":false},{"pmid":"31496037","id":"PMC_31496037","title":"Sodium hydrosulphide restores tumour necrosis factor-α-induced mitochondrial dysfunction and metabolic dysregulation in HL-1 cells.","date":"2019","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/31496037","citation_count":12,"is_preprint":false},{"pmid":"11112994","id":"PMC_11112994","title":"An immortalized myocyte cell line, HL-1, expresses a functional delta -opioid receptor.","date":"2000","source":"Journal of molecular and cellular cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/11112994","citation_count":12,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":58528,"output_tokens":2173,"usd":0.10409,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8709,"output_tokens":2627,"usd":0.05461,"stage2_stop_reason":"end_turn"},"total_usd":0.1587,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking at the corpus, I need to identify papers about the canonical ITLN1 protein (intelectin-1, also known as omentin, hIntL, HL-1 the protein — NOT the HL-1 cardiomyocyte cell line).\n\nThe vast majority of papers (1–13, etc.) are about the **HL-1 cardiomyocyte cell line** — \"HL-1\" here is an alias collision (a cell line, not the ITLN1 protein). I must exclude all of these.\n\nThe relevant papers about ITLN1 protein are:\n- PMID 32669559 (paper 15): ITLN1 in ovarian cancer\n- PMID 34145348 (paper 51): ITLN1 genetic variation and intestinal expression\n- PMID 36072603 (paper 84): Itln1 knockout mouse\n- PMID 31626818 (paper 85): Fish ITLN (ortholog — fish immune defense)\n- PMID 34363021 (paper 50): ITLN1 in colorectal carcinoma\n- PMID 40520022 (paper 96): ITLN1 in Crohn's colitis/PANoptosis\n- PMID 22277902 (paper 77): GWAS association — exclude (no mechanism)\n\nPaper 85 is about a fish ortholog (teleost ITLN) — the function described (Ca2+-dependent lectin binding bacteria) is consistent with the mammalian carbohydrate-binding intelectin family, so I'll include it as an ortholog study.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2021,\n      \"finding\": \"ITLN1 suppresses lactotransferrin-driven ovarian cancer cell invasion and proliferation by decreasing MMP1 expression, and induces a metabolic shift in metastatic ovarian cancer cells. In vivo, ITLN1-treated tumor-bearing mice showed marked decreases in tumor growth rates.\",\n      \"method\": \"Cell invasion assays, MMP1 expression analysis (Western blot/qPCR), metabolic flux assays, and xenograft mouse models with ITLN1 treatment\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro functional assays combined with in vivo xenograft model, single lab, multiple orthogonal readouts but mechanistic pathway only partially defined\",\n      \"pmids\": [\"32669559\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ITLN1 inhibits tumor neovascularization and myeloid-derived suppressor cell (MDSC) accumulation in colorectal carcinoma by suppressing tumor-derived IL-17D and CXCL2 through the KEAP1/Nrf2/ROS/IL-17D and p65 NF-κB/CXCL2 signaling cascades, both dependent on PI3K/AKT/GSK3β; this was reversed by the PI3K inhibitor LY294002.\",\n      \"method\": \"Orthotopic and subcutaneous xenograft tumor models, bone marrow transplantation chimera experiments, Western blot, ELISA, flow cytometry, PI3K inhibitor rescue experiments\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple in vivo models and orthogonal mechanistic approaches in a single lab; PI3K pathway placement supported by pharmacological rescue\",\n      \"pmids\": [\"34363021\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The ITLN1 missense variant V109D does not influence ITLN1 glycan binding to β-D-galactofuranose or protein oligomerization, and neither ITLN1 mRNA nor protein abundance in intestinal tissue (goblet-cell derived) is altered by Crohn's disease-associated SNPs at the ITLN1 locus.\",\n      \"method\": \"Glycan-binding assay (β-D-galactofuranose), protein oligomerization analysis, intestinal tissue expression profiling by genotype\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — direct in vitro glycan-binding and oligomerization assays with the V109D variant; negative result for carbohydrate recognition alteration is experimentally established\",\n      \"pmids\": [\"34145348\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In C57BL/6 mice, Itln1 is expressed in Paneth cells of the small intestine (in contrast to human ITLN1 which localizes to goblet cells). Mice with ~10,000-fold reduced Itln1 expression showed increased susceptibility in an acute DSS-induced colitis model, indicating Itln1 contributes to intestinal mucosal defense.\",\n      \"method\": \"Knockout mouse model (hypomorphic trapping allele), mRNA and protein expression analysis, DSS-induced colitis model with disease activity scoring\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function in vivo with defined phenotypic readout; single lab, but Itln1 KO model with multiple outcome measures\",\n      \"pmids\": [\"36072603\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Fish ortholog WR-ITLN (teleost intelectin) binds directly to Aeromonas hydrophila and Streptococcus agalactiae in a Ca2+-dependent manner, reduces relative bacterial activity, limits bacterial growth in vitro, restricts bacterial dissemination in vivo, and attenuates pro-inflammatory cytokine production via MyD88-dependent pathways.\",\n      \"method\": \"Recombinant protein purification, direct bacterial binding assay, in vitro bacteriostatic assay with Ca2+ dependency, in vivo bacterial challenge model, cytokine measurement\",\n      \"journal\": \"Developmental and comparative immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — reconstituted direct binding with purified protein and Ca2+ dependency established in vitro, confirmed in vivo; ortholog study in teleost fish\",\n      \"pmids\": [\"31626818\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ITLN1 binds to calpain-2 (CAPN2) and enhances its protein stability by antagonizing TRIM8-mediated ubiquitination degradation of CAPN2. Through this ITLN1-TRIM8-CAPN2 axis, ITLN1 drives ZBP1-dependent PANoptosis (combined pyroptosis/apoptosis/necroptosis) in intestinal epithelial cells, promotes inflammation, and impairs tight junctions. ITLN1 also binds TRIM8 directly, competing with CAPN2-TRIM8 interaction.\",\n      \"method\": \"Co-immunoprecipitation combined with mass spectrometry, RNA-seq, in vitro knockdown/overexpression rescue experiments, IL-10 KO colitis mouse model with shRNA-ITLN1 knockdown\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP/MS identifies ITLN1-CAPN2 and ITLN1-TRIM8 interactions; ubiquitination mechanism supported by rescue experiments and in vivo validation; single lab\",\n      \"pmids\": [\"40520022\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ITLN1 (intelectin-1) is a secreted, Ca2+-dependent carbohydrate-binding protein (lectin) that recognizes microbial but not host glycans; it functions in innate mucosal immunity (with intestinal expression localized to goblet cells in humans and Paneth cells in mice), suppresses tumor progression by inhibiting MMP1-driven invasion, blocking IL-17D/CXCL2-mediated neovascularization and MDSC recruitment via PI3K/AKT/GSK3β/NF-κB signaling, and in the context of Crohn's disease promotes PANoptosis of intestinal epithelial cells by binding CAPN2 and antagonizing TRIM8-mediated ubiquitin degradation of CAPN2 to activate ZBP1-dependent cell death.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ITLN1 (intelectin-1) is a secreted, Ca2+-dependent carbohydrate-binding lectin that functions in mucosal innate immune defense, with intestinal expression localized to human goblet cells and mouse Paneth cells [#2, #3]. Its lectin activity is direct and microbe-directed: the teleost ortholog binds bacterial pathogens in a Ca2+-dependent manner, restricts their growth and dissemination in vivo, and dampens pro-inflammatory cytokine output through MyD88-dependent signaling [#4]. Genetic reduction of Itln1 in mice increases susceptibility to DSS-induced colitis, establishing a protective role in intestinal mucosal defense [#3]. In cancer, ITLN1 acts as a tumor suppressor: it limits ovarian cancer cell invasion and proliferation by downregulating MMP1 and shifting tumor cell metabolism [#0], and in colorectal carcinoma it suppresses IL-17D and CXCL2 production via KEAP1/Nrf2/ROS and p65 NF-\\u03baB cascades downstream of PI3K/AKT/GSK3\\u03b2, thereby inhibiting tumor neovascularization and MDSC accumulation [#1]. In the context of intestinal inflammation, ITLN1 binds and stabilizes calpain-2 (CAPN2) by competing with and antagonizing TRIM8-mediated ubiquitin-dependent degradation, and through this ITLN1\\u2013TRIM8\\u2013CAPN2 axis drives ZBP1-dependent PANoptosis of intestinal epithelial cells, promoting inflammation and impairing tight junctions [#5]. A Crohn's-associated V109D missense variant does not alter glycan binding or oligomerization, and disease-linked SNPs do not change ITLN1 abundance [#2].\",\n  \"teleology\": [\n    {\n      \"year\": 2019,\n      \"claim\": \"Establishing that intelectin acts as a direct, Ca2+-dependent antibacterial lectin defined its core molecular activity in innate immunity rather than leaving it as a presumed pattern-recognition role.\",\n      \"evidence\": \"Recombinant teleost ortholog binding and bacteriostatic assays with Ca2+ dependency, plus in vivo bacterial challenge and cytokine measurement\",\n      \"pmids\": [\"31626818\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Demonstrated in a fish ortholog, not human ITLN1\", \"Glycan target specificity for these bacteria not resolved\", \"Mechanism linking lectin binding to MyD88 attenuation unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Linking ITLN1 to MMP1 suppression and metabolic reprogramming showed it is a functional tumor suppressor in ovarian cancer, not merely a biomarker.\",\n      \"evidence\": \"Cell invasion assays, MMP1 expression analysis, metabolic flux assays, and ITLN1-treated xenograft mouse models\",\n      \"pmids\": [\"32669559\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular link between ITLN1 and MMP1 regulation undefined\", \"Receptor or binding partner mediating the anti-invasive effect unknown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Placing ITLN1 upstream of IL-17D/CXCL2 via PI3K/AKT/GSK3\\u03b2 signaling defined the pathway through which it limits tumor angiogenesis and immunosuppressive cell recruitment.\",\n      \"evidence\": \"Orthotopic/subcutaneous xenografts, bone marrow chimeras, flow cytometry, and PI3K inhibitor (LY294002) rescue\",\n      \"pmids\": [\"34363021\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How secreted ITLN1 engages the PI3K cascade not identified\", \"No direct ITLN1 receptor characterized\", \"Confined to colorectal models\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Testing the Crohn's-associated V109D variant and locus SNPs ruled out altered glycan recognition or expression as the disease mechanism, redirecting attention away from binding/abundance defects.\",\n      \"evidence\": \"\\u03b2-D-galactofuranose glycan-binding assay, oligomerization analysis, and genotype-stratified intestinal expression profiling\",\n      \"pmids\": [\"34145348\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of V109D, if any, remains unidentified\", \"Negative results do not establish the actual disease-relevant mechanism\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Genetic loss-of-function in mice established that Itln1 contributes causally to intestinal mucosal defense and revealed a species difference in cellular source (Paneth vs goblet cells).\",\n      \"evidence\": \"Hypomorphic Itln1 knockout mouse with DSS-induced colitis and disease activity scoring\",\n      \"pmids\": [\"36072603\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular effectors downstream of Itln1 in colitis protection not defined\", \"Relevance of Paneth-cell localization to human goblet-cell biology unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identifying ITLN1 as a CAPN2-binding protein that antagonizes TRIM8-mediated degradation revealed an intracellular, ubiquitin-regulated mechanism by which ITLN1 drives epithelial PANoptosis, contrasting with its protective extracellular lectin role.\",\n      \"evidence\": \"Co-IP/MS, RNA-seq, knockdown/overexpression rescue, and IL-10 KO colitis model with shRNA-ITLN1\",\n      \"pmids\": [\"40520022\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Reconciliation of pro-death intracellular role with protective extracellular role unresolved\", \"Reciprocal validation and structural basis of ITLN1-CAPN2/TRIM8 binding not established\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The receptor or surface interaction through which secreted ITLN1 transmits its tumor-suppressive and immunomodulatory signaling remains unidentified.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No ITLN1 cell-surface receptor characterized\", \"How an extracellular lectin engages intracellular CAPN2/TRIM8 is unexplained\", \"Glycan ligand repertoire for human ITLN1 not fully defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0030246\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [2, 3, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [3, 4]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CAPN2\", \"TRIM8\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}