{"gene":"ITGA8","run_date":"2026-06-10T01:55:23","timeline":{"discoveries":[{"year":2016,"finding":"In zebrafish, Itga8 (expressed in facial mesenchyme) and Fras1 (expressed in epithelia) function together in epithelial-mesenchymal interactions during pharyngeal pouch morphogenesis; itga8 mutants display defective outpocketing of the first pharyngeal pouch and skeletal defects phenotypically similar to fras1 mutants, consistent with both proteins acting within the same Fraser protein complex.","method":"Forward mutagenesis screen, CRISPR allele generation, double-mutant analysis, in situ hybridization for expression domains, phenotypic comparison","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis via double mutants, CRISPR validation, complementary expression domains established in a single rigorous study with multiple orthogonal methods","pmids":["27265864"],"is_preprint":false},{"year":2016,"finding":"In the unilateral ureteral obstruction model, Itga8 deficiency leads to increased phospho-SMAD2/3-positive cells and more α-smooth muscle actin-positive fibroblasts in the tubulointerstitium, as well as enhanced macrophage and T-cell infiltration, indicating that Itga8 attenuates renal interstitial fibrosis by suppressing TGF-β/SMAD signaling and fibroblast activation rather than by regulating cell turnover or apoptosis.","method":"Knockout mouse model (Itga8-/-) with UUO, immunohistochemistry for phospho-SMAD2/3, α-SMA, macrophage and T-cell markers; proliferation and apoptosis assays","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO with defined cellular phenotype and multiple markers, single lab","pmids":["26938996"],"is_preprint":false},{"year":2022,"finding":"Itga8-CreER knock-in mice drive tamoxifen-dependent recombination preferentially in vascular smooth muscle cells (but not visceral SMCs), and Srf knockout using this driver causes vascular contractile incompetence and failure to mount angiotensin II-induced blood pressure elevation, placing Itga8 expression in vascular SMCs upstream of SRF-dependent contractile gene regulation.","method":"Knock-in Cre mouse generation, tamoxifen induction, comparison with Myh11-CreER, conditional Srf knockout, blood pressure measurement, contractility assays","journal":"Nature cardiovascular research","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic tool validated by comparison with existing Cre line, conditional KO with clear functional phenotype, multiple orthogonal readouts in a single rigorous study","pmids":["36424917"],"is_preprint":false},{"year":2023,"finding":"Using the Itga8-CreER model to delete YAP and TAZ in smooth muscle cells, YAP/TAZ were found to regulate myocardin (Myocd) expression and SRF levels in bladder detrusor, which in turn drives contractile gene expression, smooth muscle-specific splicing, and bladder contractility; loss of YAP/TAZ reduced cholinergic receptor expression and impaired carbachol- and myosin phosphatase inhibitor-induced contraction.","method":"Itga8-CreER-mediated conditional deletion of YAP/TAZ in adult mice, RT-qPCR, Western blot, gel contraction assay, constitutively active YAP overexpression in HEK293 cells","journal":"American journal of physiology. Cell physiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — inducible conditional KO with multiple orthogonal readouts (transcriptomics, protein, functional contractility), gain-of-function validation in cell line","pmids":["37927241"],"is_preprint":false},{"year":2025,"finding":"In neurogenic bladder fibrosis, Itga8+ fibroblasts coordinate cytoskeletal remodeling via the FAK/RhoA/ROCK signaling axis; Trem2+ macrophage-secreted Fn1 engages Itga8 on fibroblasts to activate them, and conditional deletion (Col1a2-CreERT; Itga8fl/fl) or local Itga8 knockdown attenuates collagen deposition and restores voiding efficiency.","method":"Single-cell RNA sequencing, conditional knockout (Col1a2-CreERT; Itga8fl/fl), AAV-mediated knockdown in vivo, macrophage depletion experiments, pathway analysis","journal":"Advanced science","confidence":"High","confidence_rationale":"Tier 2 / Strong — ligand-receptor interaction identified by scRNAseq, conditional KO with defined phenotype, macrophage depletion epistasis, multiple orthogonal in vivo methods","pmids":["41355531"],"is_preprint":false},{"year":2025,"finding":"In hepatic stellate cells (HSCs), ITGA8 expression is upregulated during liver fibrosis and promotes ECM accumulation; AAV2/6-mediated silencing of Itga8 in HSCs reduces fibrosis markers (α-SMA, collagen I), decreases inflammatory cytokines, and suppresses COL11A1 expression as identified by proteomics, implicating ITGA8 in ECM cross-linking via COL11A1 regulation and reducing HSC-mediated collagen contraction.","method":"CCl4 mouse fibrosis model, AAV2/6-shItga8 selective silencing, in vitro ITGA8 knockdown with proteomic analysis, Sirius Red staining, collagen contraction assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo AAV knockdown with proteomic downstream target identification and functional contraction assay, single lab","pmids":["40056500"],"is_preprint":false},{"year":2025,"finding":"ITGA8 sensitizes lung adenocarcinoma cells to EGFR-TKIs (abivertinib) by attenuating the downstream FAK/SRC/AKT/MAPK signaling pathway; ITGA8 knockdown enhanced proliferation, migration, and invasion of H1975 cells and increased tumor growth in xenografts, while overexpression in resistant cells (H1975/ABIR) reduced malignant phenotypes and enhanced drug sensitivity.","method":"Genome-wide CRISPR-Cas9 screen, ITGA8 knockdown and overexpression, western blot for FAK/SRC/AKT/MAPK pathway, H1975 xenograft mouse model","journal":"Acta pharmacologica Sinica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR screen plus orthogonal KD/OE with in vivo validation, pathway identified by western blot, single lab","pmids":["39809840"],"is_preprint":false},{"year":2026,"finding":"ITGA8 overexpression in lung adenocarcinoma suppresses aerobic glycolysis (reducing ECAR, glucose uptake, lactate production) by activating the AMPK signaling pathway and inhibiting the mTOR/S6K/4EBP1 axis; AMPK inhibition reversed ITGA8-mediated glycolysis suppression and restoration of malignant phenotypes, establishing ITGA8 as a metabolic gatekeeper.","method":"ITGA8 overexpression in LUAD cells, Seahorse metabolic assays (ECAR), glucose/lactate measurements, AMPK inhibitor rescue experiments, in vivo xenograft models, western blot for mTOR/S6K/4EBP1","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — OE with functional metabolic assays, pharmacological rescue, and in vivo validation; single lab","pmids":["41731056"],"is_preprint":false},{"year":2021,"finding":"ITGA8-positive cells isolated from human trabecular meshwork display properties of Schlemm's canal (SC) endothelial cells: enhanced expression of SC biomarkers, reduced dexamethasone-inducible myocilin secretion, and stronger endothelin 1-induced contractility compared to ITGA8-negative cells, indicating ITGA8 marks a functionally distinct SC-like population involved in aqueous humor outflow resistance.","method":"Fluorescence in situ hybridization, immunofluorescence, magnetic bead-based cell sorting, flow cytometry, RT-PCR, Western blot, gel contraction assay","journal":"Life sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct isolation and functional characterization of ITGA8+ cells using multiple orthogonal methods; single lab","pmids":["33961857"],"is_preprint":false},{"year":2025,"finding":"RAGE regulates cell adhesion through upregulation of ITGA8; the intracellular (cytoplasmic) domain of RAGE is required for modulating cell spreading and for ITGA8 regulation, indicating a signaling link from RAGE's cytoplasmic domain to ITGA8-mediated adhesion to extracellular matrix proteins.","method":"RAGE domain deletion constructs, cell adhesion assays, cell spreading assays, protein expression analysis","journal":"Cells","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, domain-deletion approach with adhesion assay; abstract provides limited methodological detail","pmids":["41294858"],"is_preprint":false},{"year":2020,"finding":"In ER-positive breast cancer cells, ITGA8 is silenced by promoter hypermethylation; treatment with 5-aza-2'-deoxycytidine restores ITGA8 protein expression, but this restoration is abolished by 17-beta-estradiol (ERα agonist), indicating that ERα-dependent signaling promotes ITGA8 methylation and silencing in ER-positive breast cancer.","method":"Methylation-specific PCR, Western blot, 5-aza-dC demethylation treatment, 17-beta-estradiol treatment, clinical tissue methylation analysis","journal":"Annals of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological interventions with multiple molecular readouts in cell lines and clinical specimens; single lab","pmids":["32953793"],"is_preprint":false},{"year":2024,"finding":"In ovarian cancer, M2 macrophage-derived exosomes deliver circTMCO3, which acts as a competing endogenous RNA for miR-515-5p, thereby reducing miR-515-5p abundance and upregulating ITGA8; miR-515-5p directly downregulates ITGA8, and ITGA8 overexpression reverses the reduced oncogenic activity caused by circTMCO3 silencing, placing ITGA8 downstream of the circTMCO3/miR-515-5p axis in promoting ovarian cancer malignancy.","method":"Exosome isolation, circRNA knockdown, miRNA mimic/inhibitor experiments, luciferase reporter assay (implied by competing endogenous RNA mechanism), in vivo nude mouse xenograft","journal":"Communications biology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — functional rescue experiments support pathway placement but abstract lacks explicit binding validation details; single lab","pmids":["38755265"],"is_preprint":false}],"current_model":"ITGA8 encodes the α8 integrin subunit that forms the heterodimeric integrin α8β1, functioning as a cell adhesion and signaling receptor expressed in mesenchymal cells (smooth muscle cells, fibroblasts, renal mesangium); it participates in epithelial-mesenchymal interactions via the Fraser protein complex (with Fras1/FRAS1), suppresses fibrosis by attenuating TGF-β/SMAD signaling and fibroblast activation, signals through FAK/RhoA/ROCK and FAK/SRC/AKT/MAPK axes downstream of extracellular matrix ligands (including Fn1 from macrophages), acts as a metabolic gatekeeper suppressing aerobic glycolysis via AMPK/mTOR in cancer cells, and its expression is regulated by promoter methylation controlled in part by ERα-dependent mechanisms."},"narrative":{"mechanistic_narrative":"ITGA8 encodes the α8 integrin subunit, an extracellular matrix adhesion and signaling receptor expressed in mesenchymal and smooth-muscle lineages that links matrix engagement to cytoskeletal remodeling, contractile gene programs, and fibrotic responses [PMID:36424917, PMID:41355531]. During development it cooperates with the epithelial Fraser-complex protein Fras1 to drive epithelial–mesenchymal interactions, with Itga8 expressed in facial mesenchyme and loss producing pharyngeal pouch and skeletal defects [PMID:27265864]. In smooth muscle, Itga8-expressing cells mark vascular and detrusor SMC populations in which YAP/TAZ and SRF/myocardin govern contractile gene expression and tissue contractility [PMID:36424917, PMID:37927241]. In fibrotic disease ITGA8 has context-dependent roles: in renal interstitial fibrosis it attenuates TGF-β/SMAD signaling and fibroblast activation [PMID:26938996], whereas in neurogenic bladder it transduces Trem2+ macrophage-derived Fn1 signals through a FAK/RhoA/ROCK axis to activate fibroblasts and drive collagen deposition [PMID:41355531], and in hepatic stellate cells it promotes ECM accumulation through COL11A1 [PMID:40056500]. In lung adenocarcinoma ITGA8 acts as a tumor suppressor, dampening FAK/SRC/AKT/MAPK signaling to sensitize cells to EGFR-TKIs [PMID:39809840] and restraining aerobic glycolysis via AMPK activation and mTOR/S6K/4EBP1 inhibition [PMID:41731056]. ITGA8 expression is itself regulated epigenetically, being silenced by ERα-dependent promoter hypermethylation in ER-positive breast cancer [PMID:32953793].","teleology":[{"year":2016,"claim":"Established that Itga8 functions in epithelial-mesenchymal interactions during craniofacial development as a partner of the Fraser complex, defining a developmental adhesion role.","evidence":"Forward mutagenesis screen, CRISPR alleles, and double-mutant epistasis with fras1 in zebrafish, with complementary expression domains by in situ hybridization","pmids":["27265864"],"confidence":"High","gaps":["Direct biochemical interaction of Itga8 with Fras1 not demonstrated","Mammalian relevance of this developmental role not shown","Downstream signaling not defined"]},{"year":2016,"claim":"Showed that Itga8 restrains rather than promotes fibrosis in the kidney by suppressing TGF-β/SMAD signaling and fibroblast activation, defining an anti-fibrotic function.","evidence":"Itga8-/- mice in the unilateral ureteral obstruction model with IHC for phospho-SMAD2/3, α-SMA, and immune-cell markers","pmids":["26938996"],"confidence":"Medium","gaps":["Ligand engaging Itga8 in this context not identified","Mechanism linking Itga8 to SMAD attenuation unresolved","Single lab"]},{"year":2021,"claim":"Identified ITGA8 as a marker of a functionally distinct Schlemm's-canal-like contractile cell population in the trabecular meshwork, linking expression to aqueous outflow physiology.","evidence":"Magnetic-bead sorting of ITGA8+/- cells from human trabecular meshwork with FISH, flow cytometry, and gel contraction assays","pmids":["33961857"],"confidence":"Medium","gaps":["Causal role of ITGA8 in the SC phenotype not tested by perturbation","Signaling downstream of ITGA8 in these cells unknown"]},{"year":2022,"claim":"Validated Itga8 as a vascular smooth-muscle-restricted marker and genetic tool, placing its expression upstream of SRF-dependent contractile gene regulation.","evidence":"Itga8-CreER knock-in mice compared to Myh11-CreER, conditional Srf deletion, blood pressure and contractility assays","pmids":["36424917"],"confidence":"High","gaps":["Whether Itga8 protein itself drives the contractile program not directly tested","Defines expression domain, not Itga8 cell-autonomous function"]},{"year":2023,"claim":"Used the Itga8-CreER driver to define a YAP/TAZ–myocardin–SRF axis controlling detrusor smooth-muscle contractile identity and bladder function.","evidence":"Itga8-CreER-mediated conditional YAP/TAZ deletion in adult mice with RT-qPCR, Western blot, contraction assays, and YAP gain-of-function in HEK293","pmids":["37927241"],"confidence":"High","gaps":["Result concerns YAP/TAZ biology using Itga8 as a tool, not ITGA8 function per se","ITGA8 receptor role in this circuit not addressed"]},{"year":2024,"claim":"Placed ITGA8 downstream of a macrophage exosome-delivered circTMCO3/miR-515-5p axis promoting ovarian cancer malignancy.","evidence":"Exosome isolation, circRNA knockdown, miRNA mimic/inhibitor and rescue experiments with xenografts","pmids":["38755265"],"confidence":"Low","gaps":["Abstract lacks explicit miR-515-5p/ITGA8 binding validation","Single lab","Oncogenic role here contrasts with tumor-suppressive role in lung adenocarcinoma"]},{"year":2025,"claim":"Resolved a pro-fibrotic signaling mechanism in which macrophage-derived Fn1 engages fibroblast ITGA8 to drive cytoskeletal remodeling and collagen deposition via FAK/RhoA/ROCK.","evidence":"scRNA-seq, conditional Col1a2-CreERT;Itga8fl/fl knockout, AAV knockdown, and macrophage depletion in a neurogenic bladder fibrosis model","pmids":["41355531"],"confidence":"High","gaps":["Direct Fn1-ITGA8 binding affinity/specificity not quantified","Reconciliation with anti-fibrotic kidney role unresolved"]},{"year":2025,"claim":"Showed ITGA8 promotes hepatic stellate cell ECM accumulation through COL11A1, defining a pro-fibrotic role in liver.","evidence":"CCl4 fibrosis model with AAV2/6-shItga8 HSC-selective silencing, proteomics, Sirius Red staining, and collagen contraction assays","pmids":["40056500"],"confidence":"Medium","gaps":["Mechanism by which ITGA8 controls COL11A1 not defined","Single lab"]},{"year":2025,"claim":"Identified ITGA8 as a tumor suppressor in lung adenocarcinoma that dampens FAK/SRC/AKT/MAPK signaling and sensitizes cells to EGFR-TKIs.","evidence":"Genome-wide CRISPR screen, ITGA8 knockdown/overexpression, Western blot, and H1975 xenografts","pmids":["39809840"],"confidence":"Medium","gaps":["Ligand driving ITGA8 signaling in tumor cells not identified","Single lab"]},{"year":2026,"claim":"Defined ITGA8 as a metabolic gatekeeper restraining aerobic glycolysis via AMPK activation and mTOR/S6K/4EBP1 inhibition in lung adenocarcinoma.","evidence":"ITGA8 overexpression with Seahorse ECAR assays, glucose/lactate measurements, AMPK-inhibitor rescue, and xenografts","pmids":["41731056"],"confidence":"Medium","gaps":["Mechanistic link from integrin ITGA8 to AMPK not delineated","Single lab"]},{"year":2020,"claim":"Established that ITGA8 is epigenetically silenced by ERα-dependent promoter hypermethylation in ER-positive breast cancer.","evidence":"Methylation-specific PCR, 5-aza-dC demethylation, estradiol treatment, and clinical tissue methylation analysis","pmids":["32953793"],"confidence":"Medium","gaps":["Mechanism linking ERα to DNA methylation machinery at the ITGA8 promoter unknown","Functional consequence of silencing in breast cancer not tested"]},{"year":null,"claim":"How ITGA8 switches between anti-fibrotic and pro-fibrotic, and tumor-suppressive versus oncogenic, outcomes across tissues remains unresolved.","evidence":"No single study reconciles the divergent context-dependent functions captured across the timeline","pmids":[],"confidence":"Low","gaps":["No unifying model for context-dependent ITGA8 signaling output","β1 partner subunit and exact ECM ligand repertoire not characterized in this corpus"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[0,4,9]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[4,6,7]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[4,9]}],"pathway":[{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[4,5]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,6,7]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0,2,3]}],"complexes":["Fraser protein complex"],"partners":["FRAS1","FN1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P53708","full_name":"Integrin alpha-8","aliases":[],"length_aa":1063,"mass_kda":117.5,"function":"Integrin alpha-8/beta-1 functions in the genesis of kidney and probably of other organs by regulating the recruitment of mesenchymal cells into epithelial structures. It recognizes the sequence R-G-D in a wide array of ligands including TNC, FN1, SPP1 TGFB1, TGFB3 and VTN. NPNT is probably its functional ligand in kidney genesis. Neuronal receptor for TNC it mediates cell-cell interactions and regulates neurite outgrowth of sensory and motor neurons","subcellular_location":"Membrane; Cell membrane","url":"https://www.uniprot.org/uniprotkb/P53708/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ITGA8","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ITGA8","total_profiled":1310},"omim":[{"mim_id":"614026","title":"KINESIN FAMILY MEMBER 26B; KIF26B","url":"https://www.omim.org/entry/614026"},{"mim_id":"610306","title":"NEPHRONECTIN; NPNT","url":"https://www.omim.org/entry/610306"},{"mim_id":"604063","title":"INTEGRIN, ALPHA-8; ITGA8","url":"https://www.omim.org/entry/604063"},{"mim_id":"300239","title":"EPIDERMAL GROWTH FACTOR-LIKE 6; EGFL6","url":"https://www.omim.org/entry/300239"},{"mim_id":"191830","title":"RENAL HYPODYSPLASIA/APLASIA 1; RHDA1","url":"https://www.omim.org/entry/191830"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Plasma membrane","reliability":"Approved"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"blood vessel","ntpm":353.6}],"url":"https://www.proteinatlas.org/search/ITGA8"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"P53708","domains":[{"cath_id":"2.130.10.130","chopping":"42-484","consensus_level":"high","plddt":92.4585,"start":42,"end":484},{"cath_id":"2.60.40.1460","chopping":"487-638","consensus_level":"high","plddt":86.8374,"start":487,"end":638},{"cath_id":"2.60.40.1510","chopping":"652-783","consensus_level":"high","plddt":88.3307,"start":652,"end":783},{"cath_id":"2.60.40.1530","chopping":"788-879_920-1002","consensus_level":"high","plddt":88.4467,"start":788,"end":1002}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P53708","model_url":"https://alphafold.ebi.ac.uk/files/AF-P53708-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P53708-F1-predicted_aligned_error_v6.png","plddt_mean":85.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ITGA8","jax_strain_url":"https://www.jax.org/strain/search?query=ITGA8"},"sequence":{"accession":"P53708","fasta_url":"https://rest.uniprot.org/uniprotkb/P53708.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P53708/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P53708"}},"corpus_meta":[{"pmid":"36424917","id":"PMC_36424917","title":"Generation and Comparative Analysis of an Itga8-CreER  Mouse with Preferential Activity in Vascular Smooth Muscle Cells.","date":"2022","source":"Nature cardiovascular research","url":"https://pubmed.ncbi.nlm.nih.gov/36424917","citation_count":59,"is_preprint":false},{"pmid":"17303177","id":"PMC_17303177","title":"Identification of PRTFDC1 silencing and aberrant promoter methylation of GPR150, ITGA8 and HOXD11 in ovarian cancers.","date":"2007","source":"Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/17303177","citation_count":33,"is_preprint":false},{"pmid":"28572914","id":"PMC_28572914","title":"Sex differences in the development of vascular and renal lesions in mice with a simultaneous deficiency of Apoe and the integrin chain Itga8.","date":"2017","source":"Biology of sex differences","url":"https://pubmed.ncbi.nlm.nih.gov/28572914","citation_count":28,"is_preprint":false},{"pmid":"26938996","id":"PMC_26938996","title":"Alpha8 Integrin (Itga8) Signalling Attenuates Chronic Renal Interstitial Fibrosis by Reducing Fibroblast Activation, Not by Interfering with Regulation of Cell Turnover.","date":"2016","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/26938996","citation_count":24,"is_preprint":false},{"pmid":"27265864","id":"PMC_27265864","title":"Pharyngeal morphogenesis requires fras1-itga8-dependent epithelial-mesenchymal interaction.","date":"2016","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/27265864","citation_count":23,"is_preprint":false},{"pmid":"38755265","id":"PMC_38755265","title":"M2 macrophage-derived exosomal circTMCO3 acts through miR-515-5p and ITGA8 to enhance malignancy in ovarian cancer.","date":"2024","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/38755265","citation_count":20,"is_preprint":false},{"pmid":"29290481","id":"PMC_29290481","title":"DLG2, but not TMEM229B, GPNMB, and ITGA8 polymorphism, is associated with Parkinson's disease in a Taiwanese 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Cell physiology","url":"https://pubmed.ncbi.nlm.nih.gov/37927241","citation_count":4,"is_preprint":false},{"pmid":"40056500","id":"PMC_40056500","title":"ITGA8 deficiency in hepatic stellate cells attenuates CCl4-Induced liver fibrosis via suppression of COL11A1.","date":"2025","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/40056500","citation_count":2,"is_preprint":false},{"pmid":"27583043","id":"PMC_27583043","title":"No Association Between rs7077361 in ITGA8 and Parkinson's Disease in Sweden.","date":"2016","source":"The open neurology journal","url":"https://pubmed.ncbi.nlm.nih.gov/27583043","citation_count":2,"is_preprint":false},{"pmid":"41355531","id":"PMC_41355531","title":"Targeting Itga8 Mitigates Neurogenic Bladder Fibrosis Driven by Trem2⁺ Macrophage-Derived Fn1 via FAK/RhoA/ROCK Signaling.","date":"2025","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/41355531","citation_count":1,"is_preprint":false},{"pmid":"41294858","id":"PMC_41294858","title":"The Receptor for Advanced Glycation End-Products (RAGE) Regulates Cell Adhesion Through Upregulation of ITGA8.","date":"2025","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/41294858","citation_count":0,"is_preprint":false},{"pmid":"40101650","id":"PMC_40101650","title":"The significance of Itga8 and Vangl2 in kidney development: Insights from yotari mice.","date":"2025","source":"Acta histochemica","url":"https://pubmed.ncbi.nlm.nih.gov/40101650","citation_count":0,"is_preprint":false},{"pmid":"40017502","id":"PMC_40017502","title":"Missense mutation (Ser654Leu) in the ITGA8 gene associated with renal hypodysplasia: A case report.","date":"2025","source":"Biomedical reports","url":"https://pubmed.ncbi.nlm.nih.gov/40017502","citation_count":0,"is_preprint":false},{"pmid":"41731056","id":"PMC_41731056","title":"ITGA8 suppresses proliferation and metastasis of lung adenocarcinoma through the inhibition of glycolysis.","date":"2026","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/41731056","citation_count":0,"is_preprint":false},{"pmid":"41743075","id":"PMC_41743075","title":"Temporal Transcriptomics Leads From Discovery to in Vivo Validation: COL4A3/COL4A6/ COL4A5 and ITGA8 as Novel Arthrofibrosis Biomarkers in Post-traumatic Joint Contracture.","date":"2026","source":"Dose-response : a publication of International Hormesis Society","url":"https://pubmed.ncbi.nlm.nih.gov/41743075","citation_count":0,"is_preprint":false},{"pmid":"41603158","id":"PMC_41603158","title":"Genetic Control of Tissue Remodeling by a Non-Coding SNP in ITGA8 Explains Carotenoid-Based Color Polymorphism in Marine Mollusks.","date":"2026","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/41603158","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.07.06.663336","title":"The pleuroparenchymal fibroelastosis atlas reveals aberrant cell states and their zonation as an alternate roadmap to lung fibrosis","date":"2025-07-08","source":"bioRxiv","url":"https://doi.org/10.1101/2025.07.06.663336","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.02.16.638532","title":"Characterization of bronchovascular-bundle mesenchymal stromal cells regulating antibody-secreting cell niche in rejecting lung allografts","date":"2025-02-21","source":"bioRxiv","url":"https://doi.org/10.1101/2025.02.16.638532","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":17715,"output_tokens":3440,"usd":0.052373,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11096,"output_tokens":3738,"usd":0.074465,"stage2_stop_reason":"end_turn"},"total_usd":0.126838,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2016,\n      \"finding\": \"In zebrafish, Itga8 (expressed in facial mesenchyme) and Fras1 (expressed in epithelia) function together in epithelial-mesenchymal interactions during pharyngeal pouch morphogenesis; itga8 mutants display defective outpocketing of the first pharyngeal pouch and skeletal defects phenotypically similar to fras1 mutants, consistent with both proteins acting within the same Fraser protein complex.\",\n      \"method\": \"Forward mutagenesis screen, CRISPR allele generation, double-mutant analysis, in situ hybridization for expression domains, phenotypic comparison\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis via double mutants, CRISPR validation, complementary expression domains established in a single rigorous study with multiple orthogonal methods\",\n      \"pmids\": [\"27265864\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"In the unilateral ureteral obstruction model, Itga8 deficiency leads to increased phospho-SMAD2/3-positive cells and more α-smooth muscle actin-positive fibroblasts in the tubulointerstitium, as well as enhanced macrophage and T-cell infiltration, indicating that Itga8 attenuates renal interstitial fibrosis by suppressing TGF-β/SMAD signaling and fibroblast activation rather than by regulating cell turnover or apoptosis.\",\n      \"method\": \"Knockout mouse model (Itga8-/-) with UUO, immunohistochemistry for phospho-SMAD2/3, α-SMA, macrophage and T-cell markers; proliferation and apoptosis assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with defined cellular phenotype and multiple markers, single lab\",\n      \"pmids\": [\"26938996\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Itga8-CreER knock-in mice drive tamoxifen-dependent recombination preferentially in vascular smooth muscle cells (but not visceral SMCs), and Srf knockout using this driver causes vascular contractile incompetence and failure to mount angiotensin II-induced blood pressure elevation, placing Itga8 expression in vascular SMCs upstream of SRF-dependent contractile gene regulation.\",\n      \"method\": \"Knock-in Cre mouse generation, tamoxifen induction, comparison with Myh11-CreER, conditional Srf knockout, blood pressure measurement, contractility assays\",\n      \"journal\": \"Nature cardiovascular research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic tool validated by comparison with existing Cre line, conditional KO with clear functional phenotype, multiple orthogonal readouts in a single rigorous study\",\n      \"pmids\": [\"36424917\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Using the Itga8-CreER model to delete YAP and TAZ in smooth muscle cells, YAP/TAZ were found to regulate myocardin (Myocd) expression and SRF levels in bladder detrusor, which in turn drives contractile gene expression, smooth muscle-specific splicing, and bladder contractility; loss of YAP/TAZ reduced cholinergic receptor expression and impaired carbachol- and myosin phosphatase inhibitor-induced contraction.\",\n      \"method\": \"Itga8-CreER-mediated conditional deletion of YAP/TAZ in adult mice, RT-qPCR, Western blot, gel contraction assay, constitutively active YAP overexpression in HEK293 cells\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — inducible conditional KO with multiple orthogonal readouts (transcriptomics, protein, functional contractility), gain-of-function validation in cell line\",\n      \"pmids\": [\"37927241\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In neurogenic bladder fibrosis, Itga8+ fibroblasts coordinate cytoskeletal remodeling via the FAK/RhoA/ROCK signaling axis; Trem2+ macrophage-secreted Fn1 engages Itga8 on fibroblasts to activate them, and conditional deletion (Col1a2-CreERT; Itga8fl/fl) or local Itga8 knockdown attenuates collagen deposition and restores voiding efficiency.\",\n      \"method\": \"Single-cell RNA sequencing, conditional knockout (Col1a2-CreERT; Itga8fl/fl), AAV-mediated knockdown in vivo, macrophage depletion experiments, pathway analysis\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ligand-receptor interaction identified by scRNAseq, conditional KO with defined phenotype, macrophage depletion epistasis, multiple orthogonal in vivo methods\",\n      \"pmids\": [\"41355531\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In hepatic stellate cells (HSCs), ITGA8 expression is upregulated during liver fibrosis and promotes ECM accumulation; AAV2/6-mediated silencing of Itga8 in HSCs reduces fibrosis markers (α-SMA, collagen I), decreases inflammatory cytokines, and suppresses COL11A1 expression as identified by proteomics, implicating ITGA8 in ECM cross-linking via COL11A1 regulation and reducing HSC-mediated collagen contraction.\",\n      \"method\": \"CCl4 mouse fibrosis model, AAV2/6-shItga8 selective silencing, in vitro ITGA8 knockdown with proteomic analysis, Sirius Red staining, collagen contraction assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo AAV knockdown with proteomic downstream target identification and functional contraction assay, single lab\",\n      \"pmids\": [\"40056500\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ITGA8 sensitizes lung adenocarcinoma cells to EGFR-TKIs (abivertinib) by attenuating the downstream FAK/SRC/AKT/MAPK signaling pathway; ITGA8 knockdown enhanced proliferation, migration, and invasion of H1975 cells and increased tumor growth in xenografts, while overexpression in resistant cells (H1975/ABIR) reduced malignant phenotypes and enhanced drug sensitivity.\",\n      \"method\": \"Genome-wide CRISPR-Cas9 screen, ITGA8 knockdown and overexpression, western blot for FAK/SRC/AKT/MAPK pathway, H1975 xenograft mouse model\",\n      \"journal\": \"Acta pharmacologica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR screen plus orthogonal KD/OE with in vivo validation, pathway identified by western blot, single lab\",\n      \"pmids\": [\"39809840\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"ITGA8 overexpression in lung adenocarcinoma suppresses aerobic glycolysis (reducing ECAR, glucose uptake, lactate production) by activating the AMPK signaling pathway and inhibiting the mTOR/S6K/4EBP1 axis; AMPK inhibition reversed ITGA8-mediated glycolysis suppression and restoration of malignant phenotypes, establishing ITGA8 as a metabolic gatekeeper.\",\n      \"method\": \"ITGA8 overexpression in LUAD cells, Seahorse metabolic assays (ECAR), glucose/lactate measurements, AMPK inhibitor rescue experiments, in vivo xenograft models, western blot for mTOR/S6K/4EBP1\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — OE with functional metabolic assays, pharmacological rescue, and in vivo validation; single lab\",\n      \"pmids\": [\"41731056\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ITGA8-positive cells isolated from human trabecular meshwork display properties of Schlemm's canal (SC) endothelial cells: enhanced expression of SC biomarkers, reduced dexamethasone-inducible myocilin secretion, and stronger endothelin 1-induced contractility compared to ITGA8-negative cells, indicating ITGA8 marks a functionally distinct SC-like population involved in aqueous humor outflow resistance.\",\n      \"method\": \"Fluorescence in situ hybridization, immunofluorescence, magnetic bead-based cell sorting, flow cytometry, RT-PCR, Western blot, gel contraction assay\",\n      \"journal\": \"Life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct isolation and functional characterization of ITGA8+ cells using multiple orthogonal methods; single lab\",\n      \"pmids\": [\"33961857\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RAGE regulates cell adhesion through upregulation of ITGA8; the intracellular (cytoplasmic) domain of RAGE is required for modulating cell spreading and for ITGA8 regulation, indicating a signaling link from RAGE's cytoplasmic domain to ITGA8-mediated adhesion to extracellular matrix proteins.\",\n      \"method\": \"RAGE domain deletion constructs, cell adhesion assays, cell spreading assays, protein expression analysis\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, domain-deletion approach with adhesion assay; abstract provides limited methodological detail\",\n      \"pmids\": [\"41294858\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In ER-positive breast cancer cells, ITGA8 is silenced by promoter hypermethylation; treatment with 5-aza-2'-deoxycytidine restores ITGA8 protein expression, but this restoration is abolished by 17-beta-estradiol (ERα agonist), indicating that ERα-dependent signaling promotes ITGA8 methylation and silencing in ER-positive breast cancer.\",\n      \"method\": \"Methylation-specific PCR, Western blot, 5-aza-dC demethylation treatment, 17-beta-estradiol treatment, clinical tissue methylation analysis\",\n      \"journal\": \"Annals of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological interventions with multiple molecular readouts in cell lines and clinical specimens; single lab\",\n      \"pmids\": [\"32953793\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In ovarian cancer, M2 macrophage-derived exosomes deliver circTMCO3, which acts as a competing endogenous RNA for miR-515-5p, thereby reducing miR-515-5p abundance and upregulating ITGA8; miR-515-5p directly downregulates ITGA8, and ITGA8 overexpression reverses the reduced oncogenic activity caused by circTMCO3 silencing, placing ITGA8 downstream of the circTMCO3/miR-515-5p axis in promoting ovarian cancer malignancy.\",\n      \"method\": \"Exosome isolation, circRNA knockdown, miRNA mimic/inhibitor experiments, luciferase reporter assay (implied by competing endogenous RNA mechanism), in vivo nude mouse xenograft\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — functional rescue experiments support pathway placement but abstract lacks explicit binding validation details; single lab\",\n      \"pmids\": [\"38755265\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ITGA8 encodes the α8 integrin subunit that forms the heterodimeric integrin α8β1, functioning as a cell adhesion and signaling receptor expressed in mesenchymal cells (smooth muscle cells, fibroblasts, renal mesangium); it participates in epithelial-mesenchymal interactions via the Fraser protein complex (with Fras1/FRAS1), suppresses fibrosis by attenuating TGF-β/SMAD signaling and fibroblast activation, signals through FAK/RhoA/ROCK and FAK/SRC/AKT/MAPK axes downstream of extracellular matrix ligands (including Fn1 from macrophages), acts as a metabolic gatekeeper suppressing aerobic glycolysis via AMPK/mTOR in cancer cells, and its expression is regulated by promoter methylation controlled in part by ERα-dependent mechanisms.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ITGA8 encodes the α8 integrin subunit, an extracellular matrix adhesion and signaling receptor expressed in mesenchymal and smooth-muscle lineages that links matrix engagement to cytoskeletal remodeling, contractile gene programs, and fibrotic responses [#2, #4]. During development it cooperates with the epithelial Fraser-complex protein Fras1 to drive epithelial–mesenchymal interactions, with Itga8 expressed in facial mesenchyme and loss producing pharyngeal pouch and skeletal defects [#0]. In smooth muscle, Itga8-expressing cells mark vascular and detrusor SMC populations in which YAP/TAZ and SRF/myocardin govern contractile gene expression and tissue contractility [#2, #3]. In fibrotic disease ITGA8 has context-dependent roles: in renal interstitial fibrosis it attenuates TGF-β/SMAD signaling and fibroblast activation [#1], whereas in neurogenic bladder it transduces Trem2+ macrophage-derived Fn1 signals through a FAK/RhoA/ROCK axis to activate fibroblasts and drive collagen deposition [#4], and in hepatic stellate cells it promotes ECM accumulation through COL11A1 [#5]. In lung adenocarcinoma ITGA8 acts as a tumor suppressor, dampening FAK/SRC/AKT/MAPK signaling to sensitize cells to EGFR-TKIs [#6] and restraining aerobic glycolysis via AMPK activation and mTOR/S6K/4EBP1 inhibition [#7]. ITGA8 expression is itself regulated epigenetically, being silenced by ERα-dependent promoter hypermethylation in ER-positive breast cancer [#10].\",\n  \"teleology\": [\n    {\n      \"year\": 2016,\n      \"claim\": \"Established that Itga8 functions in epithelial-mesenchymal interactions during craniofacial development as a partner of the Fraser complex, defining a developmental adhesion role.\",\n      \"evidence\": \"Forward mutagenesis screen, CRISPR alleles, and double-mutant epistasis with fras1 in zebrafish, with complementary expression domains by in situ hybridization\",\n      \"pmids\": [\"27265864\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct biochemical interaction of Itga8 with Fras1 not demonstrated\", \"Mammalian relevance of this developmental role not shown\", \"Downstream signaling not defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showed that Itga8 restrains rather than promotes fibrosis in the kidney by suppressing TGF-β/SMAD signaling and fibroblast activation, defining an anti-fibrotic function.\",\n      \"evidence\": \"Itga8-/- mice in the unilateral ureteral obstruction model with IHC for phospho-SMAD2/3, α-SMA, and immune-cell markers\",\n      \"pmids\": [\"26938996\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ligand engaging Itga8 in this context not identified\", \"Mechanism linking Itga8 to SMAD attenuation unresolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified ITGA8 as a marker of a functionally distinct Schlemm's-canal-like contractile cell population in the trabecular meshwork, linking expression to aqueous outflow physiology.\",\n      \"evidence\": \"Magnetic-bead sorting of ITGA8+/- cells from human trabecular meshwork with FISH, flow cytometry, and gel contraction assays\",\n      \"pmids\": [\"33961857\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal role of ITGA8 in the SC phenotype not tested by perturbation\", \"Signaling downstream of ITGA8 in these cells unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Validated Itga8 as a vascular smooth-muscle-restricted marker and genetic tool, placing its expression upstream of SRF-dependent contractile gene regulation.\",\n      \"evidence\": \"Itga8-CreER knock-in mice compared to Myh11-CreER, conditional Srf deletion, blood pressure and contractility assays\",\n      \"pmids\": [\"36424917\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Itga8 protein itself drives the contractile program not directly tested\", \"Defines expression domain, not Itga8 cell-autonomous function\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Used the Itga8-CreER driver to define a YAP/TAZ–myocardin–SRF axis controlling detrusor smooth-muscle contractile identity and bladder function.\",\n      \"evidence\": \"Itga8-CreER-mediated conditional YAP/TAZ deletion in adult mice with RT-qPCR, Western blot, contraction assays, and YAP gain-of-function in HEK293\",\n      \"pmids\": [\"37927241\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Result concerns YAP/TAZ biology using Itga8 as a tool, not ITGA8 function per se\", \"ITGA8 receptor role in this circuit not addressed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Placed ITGA8 downstream of a macrophage exosome-delivered circTMCO3/miR-515-5p axis promoting ovarian cancer malignancy.\",\n      \"evidence\": \"Exosome isolation, circRNA knockdown, miRNA mimic/inhibitor and rescue experiments with xenografts\",\n      \"pmids\": [\"38755265\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Abstract lacks explicit miR-515-5p/ITGA8 binding validation\", \"Single lab\", \"Oncogenic role here contrasts with tumor-suppressive role in lung adenocarcinoma\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Resolved a pro-fibrotic signaling mechanism in which macrophage-derived Fn1 engages fibroblast ITGA8 to drive cytoskeletal remodeling and collagen deposition via FAK/RhoA/ROCK.\",\n      \"evidence\": \"scRNA-seq, conditional Col1a2-CreERT;Itga8fl/fl knockout, AAV knockdown, and macrophage depletion in a neurogenic bladder fibrosis model\",\n      \"pmids\": [\"41355531\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct Fn1-ITGA8 binding affinity/specificity not quantified\", \"Reconciliation with anti-fibrotic kidney role unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed ITGA8 promotes hepatic stellate cell ECM accumulation through COL11A1, defining a pro-fibrotic role in liver.\",\n      \"evidence\": \"CCl4 fibrosis model with AAV2/6-shItga8 HSC-selective silencing, proteomics, Sirius Red staining, and collagen contraction assays\",\n      \"pmids\": [\"40056500\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which ITGA8 controls COL11A1 not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified ITGA8 as a tumor suppressor in lung adenocarcinoma that dampens FAK/SRC/AKT/MAPK signaling and sensitizes cells to EGFR-TKIs.\",\n      \"evidence\": \"Genome-wide CRISPR screen, ITGA8 knockdown/overexpression, Western blot, and H1975 xenografts\",\n      \"pmids\": [\"39809840\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ligand driving ITGA8 signaling in tumor cells not identified\", \"Single lab\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Defined ITGA8 as a metabolic gatekeeper restraining aerobic glycolysis via AMPK activation and mTOR/S6K/4EBP1 inhibition in lung adenocarcinoma.\",\n      \"evidence\": \"ITGA8 overexpression with Seahorse ECAR assays, glucose/lactate measurements, AMPK-inhibitor rescue, and xenografts\",\n      \"pmids\": [\"41731056\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic link from integrin ITGA8 to AMPK not delineated\", \"Single lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Established that ITGA8 is epigenetically silenced by ERα-dependent promoter hypermethylation in ER-positive breast cancer.\",\n      \"evidence\": \"Methylation-specific PCR, 5-aza-dC demethylation, estradiol treatment, and clinical tissue methylation analysis\",\n      \"pmids\": [\"32953793\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking ERα to DNA methylation machinery at the ITGA8 promoter unknown\", \"Functional consequence of silencing in breast cancer not tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How ITGA8 switches between anti-fibrotic and pro-fibrotic, and tumor-suppressive versus oncogenic, outcomes across tissues remains unresolved.\",\n      \"evidence\": \"No single study reconciles the divergent context-dependent functions captured across the timeline\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unifying model for context-dependent ITGA8 signaling output\", \"β1 partner subunit and exact ECM ligand repertoire not characterized in this corpus\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [0, 4, 9]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [4, 6, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [4, 9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [4, 5]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 6, 7]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 2, 3]}\n    ],\n    \"complexes\": [\"Fraser protein complex\"],\n    \"partners\": [\"FRAS1\", \"FN1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}