{"gene":"ITGA8","run_date":"2026-04-28T18:06:54","timeline":{"discoveries":[{"year":2016,"finding":"Itga8 attenuates tubulointerstitial fibrosis in unilateral ureteral obstruction not by regulating cell turnover, but by suppressing TGF-β signaling (reducing phospho-SMAD2/3-positive cells), fibroblast activation (reducing α-SMA-positive cells), and immune cell infiltration (macrophages and T-cells).","method":"Itga8 knockout mouse model with unilateral ureteral obstruction; immunostaining for phospho-SMAD2/3, α-SMA, macrophage and T-cell markers; proliferation and apoptosis assays","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — clean KO with defined cellular phenotype and pathway placement (TGF-β/SMAD2/3), single lab","pmids":["26938996"],"is_preprint":false},{"year":2016,"finding":"Zebrafish itga8 (expressed in facial mesenchyme) interacts with fras1 (expressed in epithelia) as part of the Fraser protein complex to mediate epithelial-mesenchymal interactions required for pharyngeal pouch morphogenesis and craniofacial skeletal development; itga8 and fras1 single and double mutants share similar craniofacial phenotypes.","method":"Forward mutagenesis screen; CRISPR-generated itga8 alleles; genetic epistasis (fras1/itga8 double mutants); in situ hybridization for expression patterns","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis with double mutants, orthologous zebrafish gene, replicated using CRISPR alleles","pmids":["27265864"],"is_preprint":false},{"year":2022,"finding":"Itga8-CreER knock-in mouse demonstrates preferential Cre recombinase activity in vascular smooth muscle cells (VSMCs) with minimal activity in visceral SMC-containing tissues (e.g., intestine), unlike Myh11-CreER; conditional knockout of Srf using Itga8-CreER yields viable mice with vascular contractile incompetence and blunted angiotensin II-induced blood pressure elevation.","method":"Knock-in mouse generation; comparison with Myh11-CreER; conditional knockout of Srf; vascular contractility assays; blood pressure measurement with angiotensin II","journal":"Nature cardiovascular research","confidence":"High","confidence_rationale":"Tier 2 — direct genetic loss-of-function with defined vascular phenotype and functional consequence; multiple orthogonal readouts","pmids":["36424917"],"is_preprint":false},{"year":2023,"finding":"Itga8-Cre-mediated deletion of YAP and TAZ in smooth muscle reduces myocardin (Myocd) and serum response factor (Srf) expression along with contractile genes (Myh11, Mylk) and muscarinic receptors (Chrm2, Chrm3), impairing bladder contractility and smooth muscle-specific splicing (including exon 2a of Myocd); constitutively active YAP overexpression in HEK293 cells increases myocardin expression >8-fold.","method":"Itga8-CreER conditional deletion of YAP/TAZ; RT-qPCR; Western blot; gel contraction assay; carbachol/myosin phosphatase inhibitor contractility assays; YAP overexpression in HEK293 cells","journal":"American journal of physiology. Cell physiology","confidence":"Medium","confidence_rationale":"Tier 2 — conditional KO with defined molecular and functional phenotype; uses Itga8-Cre as tool, not direct mechanistic study of ITGA8 itself","pmids":["37927241"],"is_preprint":false},{"year":2025,"finding":"In hepatic stellate cells (HSCs), ITGA8 promotes liver fibrosis by regulating ECM remodeling through upregulation of COL11A1; AAV2/6-shItga8-mediated silencing of HSC-derived ITGA8 reduced COL11A1 expression, HSC-mediated collagen contraction, and markers of fibrosis and inflammation in CCl4-induced liver fibrosis.","method":"CCl4 mouse model; AAV2/6-shItga8 knockdown; proteomic analysis; Sirius Red staining; α-SMA/collagen I immunostaining; in vitro collagen contraction assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo KD with defined molecular target (COL11A1) identified by proteomics, validated functionally in vitro; single lab","pmids":["40056500"],"is_preprint":false},{"year":2025,"finding":"ITGA8+ fibroblasts mediate neurogenic bladder fibrosis via FAK/RhoA/ROCK signaling-dependent cytoskeletal remodeling; Trem2+ macrophage-secreted Fn1 engages ITGA8 on fibroblasts to reinforce pro-fibrotic signaling; conditional deletion of Itga8 (Col1a2-CreERT; Itga8fl/fl) or local knockdown significantly attenuates collagen deposition and improves bladder voiding efficiency.","method":"Single-cell RNA sequencing; conditional knockout (Col1a2-CreERT; Itga8fl/fl); local Itga8 knockdown; macrophage depletion; FAK/RhoA/ROCK pathway analysis; bladder function assessment","journal":"Advanced science","confidence":"High","confidence_rationale":"Tier 2 — conditional KO with defined pathway (FAK/RhoA/ROCK), identified ligand (Fn1 from Trem2+ macrophages), and functional readout; multiple orthogonal methods","pmids":["41355531"],"is_preprint":false},{"year":2025,"finding":"ITGA8 sensitizes lung adenocarcinoma cells to EGFR-TKIs (abivertinib) by attenuating the FAK/SRC/AKT/MAPK downstream signaling pathway; ITGA8 knockdown increases proliferation, migration, and invasion of H1975 cells and reduces abivertinib sensitivity in xenograft models, while ITGA8 overexpression reverses these effects.","method":"Genome-wide CRISPR-Cas9 screen; ITGA8 knockdown and overexpression; xenograft mouse models; FAK/SRC/AKT/MAPK pathway analysis by Western blot","journal":"Acta pharmacologica Sinica","confidence":"Medium","confidence_rationale":"Tier 2 — CRISPR screen plus KD/OE with pathway placement and in vivo validation; single lab","pmids":["39809840"],"is_preprint":false},{"year":2026,"finding":"ITGA8 acts as a metabolic gatekeeper in lung adenocarcinoma by suppressing aerobic glycolysis (decreasing extracellular acidification rate, glucose uptake, and lactate production) through activation of the AMPK signaling pathway and subsequent inhibition of the mTOR/S6K/4EBP1 axis; AMPK inhibitor treatment reversed ITGA8-mediated suppression of glycolysis.","method":"ITGA8 overexpression; Seahorse metabolic assay (ECAR); glucose uptake and lactate assays; Western blot for AMPK/mTOR/S6K/4EBP1; pharmacological AMPK inhibition; xenograft models","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 — mechanistic pathway placement with pharmacological rescue experiment; single lab, multiple orthogonal metabolic readouts","pmids":["41731056"],"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 regulation of ITGA8 expression; RAGE displays substrate-specific adhesion to extracellular matrix proteins.","method":"RAGE domain deletion constructs; cell adhesion assays to ECM proteins; protein expression analysis; cell spreading assays","journal":"Cells","confidence":"Low","confidence_rationale":"Tier 3 — single lab, mechanistic follow-up partial; ITGA8 identified as downstream effector of RAGE without direct functional validation of ITGA8 itself","pmids":["41294858"],"is_preprint":false},{"year":2021,"finding":"ITGA8-positive cells isolated from conventional outflow tissue (trabecular meshwork/Schlemm's canal) exhibit Schlemm's canal endothelial cell properties, including stronger expression of SC biomarkers, lower dexamethasone-inducible myocilin expression, and stronger contractility in response to endothelin-1, implicating ITGA8 in aqueous humor outflow resistance regulation.","method":"Immunofluorescence and FISH for ITGA8 localization; magnetic bead-based cell isolation; flow cytometry; RT-PCR; Western blot; gel contraction assay","journal":"Life sciences","confidence":"Medium","confidence_rationale":"Tier 3 — direct localization tied to functional consequence (contractility, SC marker expression); single lab with multiple assays","pmids":["33961857"],"is_preprint":false},{"year":2024,"finding":"circTMCO3 (from M2 macrophage-derived exosomes) functions as a competing endogenous RNA for miR-515-5p, reducing its abundance and thereby upregulating ITGA8 in ovarian cancer cells; miR-515-5p directly downregulates ITGA8 to inhibit ovarian cancer malignancy; ITGA8 overexpression reverses the decreased oncogenic activity caused by circTMCO3 silencing.","method":"circTMCO3 knockdown; miR-515-5p manipulation; ITGA8 overexpression; luciferase reporter assay (implied); proliferation/migration/invasion assays; nude mouse xenograft model","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2 — rescue experiment with ITGA8 OE; miR-515-5p/ITGA8 axis validated in vivo; single lab","pmids":["38755265"],"is_preprint":false},{"year":2020,"finding":"ITGA8 promoter hypermethylation in ER-positive breast cancer cells silences ITGA8 expression; this hypermethylation is dependent on ERα, as 17-beta-estradiol (ERα antagonist) abolished 5-aza-dC-induced upregulation of ITGA8 specifically in ER-positive cells.","method":"Methylation-specific PCR; 5-aza-dC demethylation treatment; 17-beta-estradiol treatment; Western blot for ITGA8 protein; clinical tissue specimens analysis","journal":"Annals of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 — pharmacological manipulation of methylation and ERα signaling with protein-level readout; single lab, validated in clinical specimens","pmids":["32953793"],"is_preprint":false}],"current_model":"ITGA8 encodes integrin subunit α8, which forms the α8β1 heterodimer and functions as a cell adhesion and signaling receptor that: (1) interacts with the Fraser complex protein FRAS1 in epithelial-mesenchymal signaling during organogenesis (kidney, craniofacial); (2) attenuates TGF-β/SMAD2/3 signaling and fibroblast activation in renal and hepatic fibrosis, while in neurogenic bladder fibrosis it promotes fibroblast activation via FAK/RhoA/ROCK signaling upon engagement by macrophage-secreted Fn1; (3) acts as a tumor suppressor in lung adenocarcinoma by suppressing FAK/SRC/AKT/MAPK and glycolytic metabolism via AMPK/mTOR/S6K/4EBP1 signaling; and (4) is epigenetically silenced by promoter hypermethylation (regulated by ERα in breast cancer) in multiple tumor types."},"narrative":{"teleology":[{"year":2016,"claim":"Establishing that ITGA8 functions as an anti-fibrotic signal in the kidney by placing it upstream of TGF-β/SMAD2/3 suppression and fibroblast activation, answering how loss of this integrin exacerbates tubulointerstitial injury.","evidence":"Itga8 knockout mice subjected to unilateral ureteral obstruction; immunostaining for pSMAD2/3 and α-SMA","pmids":["26938996"],"confidence":"Medium","gaps":["Ligand that engages α8β1 in renal interstitium not identified","Mechanism by which ITGA8 suppresses SMAD2/3 phosphorylation not resolved","Single-lab study without independent replication"]},{"year":2016,"claim":"Demonstrating that ITGA8 is a functional receptor for the Fraser complex component FRAS1, establishing a direct epithelial–mesenchymal signaling axis required for craniofacial morphogenesis.","evidence":"Zebrafish forward genetic screen and CRISPR alleles; genetic epistasis between itga8 and fras1 single and double mutants","pmids":["27265864"],"confidence":"High","gaps":["Biochemical binding affinity between ITGA8 and FRAS1 not measured","Whether this interaction is conserved in mammalian craniofacial development not tested"]},{"year":2020,"claim":"Revealing that ITGA8 is epigenetically silenced by ERα-dependent promoter hypermethylation in ER-positive breast cancer, providing a mechanism for its loss in certain tumors.","evidence":"Methylation-specific PCR; 5-aza-dC demethylation and 17-beta-estradiol treatment in breast cancer cell lines; clinical tissue validation","pmids":["32953793"],"confidence":"Medium","gaps":["Functional consequence of ITGA8 re-expression in breast cancer cells not assessed","Identity of the methyltransferase(s) recruited by ERα not determined"]},{"year":2021,"claim":"Identifying ITGA8 as a surface marker of Schlemm's canal endothelial cells in the eye, linking it to contractile regulation of aqueous humor outflow resistance.","evidence":"Immunofluorescence, FISH, magnetic bead isolation of ITGA8+ cells from trabecular meshwork/Schlemm's canal; gel contraction assay with endothelin-1","pmids":["33961857"],"confidence":"Medium","gaps":["Whether ITGA8 directly mediates contractility or serves only as a marker not distinguished","Relevance to glaucoma pathogenesis not tested in vivo"]},{"year":2022,"claim":"Validating ITGA8 as a preferential vascular smooth muscle cell marker by generating an Itga8-CreER knock-in and showing that conditional Srf deletion produces vascular contractile incompetence, establishing tissue-selective expression distinct from visceral smooth muscle.","evidence":"Itga8-CreER knock-in mice compared with Myh11-CreER; conditional Srf knockout; vascular contractility and blood pressure assays","pmids":["36424917"],"confidence":"High","gaps":["Intrinsic role of ITGA8 in VSMC contractility (beyond its use as a Cre driver) not dissected","Regulation of Itga8 expression in vascular versus visceral SMC lineages unknown"]},{"year":2024,"claim":"Placing ITGA8 downstream of a circTMCO3/miR-515-5p competing endogenous RNA axis in ovarian cancer, where ITGA8 upregulation promotes tumor malignancy — revealing a pro-oncogenic role contrasting with its tumor-suppressive function in lung cancer.","evidence":"circTMCO3 knockdown and miR-515-5p manipulation; ITGA8 overexpression rescue; nude mouse xenograft","pmids":["38755265"],"confidence":"Medium","gaps":["Downstream signaling pathway activated by ITGA8 in ovarian cancer not characterized","Context-dependent oncogenic versus tumor-suppressive switch mechanism not explained"]},{"year":2025,"claim":"Identifying macrophage-secreted Fn1 as the ligand engaging ITGA8 on fibroblasts and delineating a FAK/RhoA/ROCK pro-fibrotic signaling cascade in neurogenic bladder fibrosis, answering how immune–stromal crosstalk drives ITGA8-dependent fibrosis.","evidence":"Single-cell RNA-seq; Col1a2-CreERT; Itga8fl/fl conditional knockout; macrophage depletion; FAK/RhoA/ROCK pathway analysis; bladder voiding assessment","pmids":["41355531"],"confidence":"High","gaps":["Whether Fn1-ITGA8 engagement is direct or requires co-receptors not resolved","How the same integrin attenuates fibrosis in kidney but promotes it in bladder remains unexplained"]},{"year":2025,"claim":"Demonstrating that ITGA8 promotes hepatic fibrosis via COL11A1 upregulation in stellate cells, extending the pro-fibrotic role beyond the bladder and identifying a specific ECM target.","evidence":"CCl4 liver fibrosis model; AAV2/6-shItga8 knockdown; proteomics identifying COL11A1; collagen contraction assay","pmids":["40056500"],"confidence":"Medium","gaps":["Signaling pathway connecting ITGA8 to COL11A1 transcription not identified","Single-lab study; independent validation needed"]},{"year":2025,"claim":"Establishing ITGA8 as a tumor suppressor in lung adenocarcinoma that dampens FAK/SRC/AKT/MAPK signaling and sensitizes cells to EGFR-TKIs, directly linking integrin signaling to therapeutic response.","evidence":"Genome-wide CRISPR-Cas9 screen; ITGA8 KD/OE in H1975 cells; xenograft models; Western blot for pathway components","pmids":["39809840"],"confidence":"Medium","gaps":["Mechanism by which ITGA8 inhibits rather than activates FAK not resolved","Patient stratification by ITGA8 expression for TKI response not validated clinically"]},{"year":2026,"claim":"Extending the tumor-suppressive mechanism by showing ITGA8 activates AMPK to inhibit mTOR/S6K/4EBP1 signaling and suppress aerobic glycolysis, providing a metabolic explanation for growth suppression in lung adenocarcinoma.","evidence":"ITGA8 overexpression; Seahorse ECAR; glucose uptake/lactate assays; AMPK pharmacological inhibition rescue; xenograft models","pmids":["41731056"],"confidence":"Medium","gaps":["How ITGA8 activates AMPK (direct interaction, calcium flux, or other) not determined","Whether metabolic suppression and FAK/SRC inhibition are parallel or sequential pathways unclear"]},{"year":null,"claim":"The fundamental question of how ITGA8 exerts opposing effects on fibrosis (anti-fibrotic in kidney, pro-fibrotic in bladder and liver) and opposing roles in cancer (tumor-suppressive in lung, oncogenic in ovary) remains mechanistically unexplained.","evidence":"","pmids":[],"confidence":"High","gaps":["No structural model of α8β1 engagement with different ligands (nephronectin, Fn1, FRAS1) to explain context-dependent signaling","Tissue-specific co-receptor or adaptor usage not characterized","Systematic comparison of ITGA8 signaling outputs across cell types not performed"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[1,9]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,6,7]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,5,9]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,5,6,7]},{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[4,5]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[1]}],"complexes":["α8β1 integrin heterodimer"],"partners":["FRAS1","ITGB1","FN1","COL11A1"],"other_free_text":[]},"mechanistic_narrative":"ITGA8 encodes integrin α8, which pairs with β1 to form a heterodimeric cell-surface receptor that mediates cell–extracellular matrix adhesion and transduces outside-in signals across diverse tissue contexts including kidney, liver, vasculature, bladder, and lung. During organogenesis, ITGA8 interacts with the Fraser complex component FRAS1 at the epithelial–mesenchymal interface to drive pharyngeal pouch morphogenesis and craniofacial skeletal development [PMID:27265864], and it marks vascular smooth muscle cells where it is used as a lineage-specific Cre driver that reveals contractile function distinct from visceral smooth muscle [PMID:36424917]. In fibrotic disease, ITGA8 exerts context-dependent effects: it attenuates renal fibrosis by suppressing TGF-β/SMAD2/3 signaling and fibroblast activation [PMID:26938996], promotes hepatic fibrosis through COL11A1-dependent ECM remodeling in stellate cells [PMID:40056500], and drives neurogenic bladder fibrosis upon engagement by macrophage-derived fibronectin (Fn1) via FAK/RhoA/ROCK signaling [PMID:41355531]. In lung adenocarcinoma, ITGA8 functions as a tumor suppressor by dampening FAK/SRC/AKT/MAPK signaling and suppressing aerobic glycolysis through AMPK-mediated inhibition of mTOR/S6K/4EBP1, thereby sensitizing cells to EGFR tyrosine kinase inhibitors [PMID:39809840, PMID:41731056]."},"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":55,"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":32,"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":27,"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":19,"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":3,"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":"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":"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":"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":"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":"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":"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":"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":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":16979,"output_tokens":3416,"usd":0.051089},"stage2":{"model":"claude-opus-4-6","input_tokens":6816,"output_tokens":2950,"usd":0.161745},"total_usd":0.212834,"stage1_batch_id":"msgbatch_01DzrsgVgYngY1hvM3DU1yF2","stage2_batch_id":"msgbatch_01KA9b7iRzKFdhoBUT7vCvSe","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2016,\n      \"finding\": \"Itga8 attenuates tubulointerstitial fibrosis in unilateral ureteral obstruction not by regulating cell turnover, but by suppressing TGF-β signaling (reducing phospho-SMAD2/3-positive cells), fibroblast activation (reducing α-SMA-positive cells), and immune cell infiltration (macrophages and T-cells).\",\n      \"method\": \"Itga8 knockout mouse model with unilateral ureteral obstruction; immunostaining 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 — clean KO with defined cellular phenotype and pathway placement (TGF-β/SMAD2/3), single lab\",\n      \"pmids\": [\"26938996\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Zebrafish itga8 (expressed in facial mesenchyme) interacts with fras1 (expressed in epithelia) as part of the Fraser protein complex to mediate epithelial-mesenchymal interactions required for pharyngeal pouch morphogenesis and craniofacial skeletal development; itga8 and fras1 single and double mutants share similar craniofacial phenotypes.\",\n      \"method\": \"Forward mutagenesis screen; CRISPR-generated itga8 alleles; genetic epistasis (fras1/itga8 double mutants); in situ hybridization for expression patterns\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with double mutants, orthologous zebrafish gene, replicated using CRISPR alleles\",\n      \"pmids\": [\"27265864\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Itga8-CreER knock-in mouse demonstrates preferential Cre recombinase activity in vascular smooth muscle cells (VSMCs) with minimal activity in visceral SMC-containing tissues (e.g., intestine), unlike Myh11-CreER; conditional knockout of Srf using Itga8-CreER yields viable mice with vascular contractile incompetence and blunted angiotensin II-induced blood pressure elevation.\",\n      \"method\": \"Knock-in mouse generation; comparison with Myh11-CreER; conditional knockout of Srf; vascular contractility assays; blood pressure measurement with angiotensin II\",\n      \"journal\": \"Nature cardiovascular research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct genetic loss-of-function with defined vascular phenotype and functional consequence; multiple orthogonal readouts\",\n      \"pmids\": [\"36424917\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Itga8-Cre-mediated deletion of YAP and TAZ in smooth muscle reduces myocardin (Myocd) and serum response factor (Srf) expression along with contractile genes (Myh11, Mylk) and muscarinic receptors (Chrm2, Chrm3), impairing bladder contractility and smooth muscle-specific splicing (including exon 2a of Myocd); constitutively active YAP overexpression in HEK293 cells increases myocardin expression >8-fold.\",\n      \"method\": \"Itga8-CreER conditional deletion of YAP/TAZ; RT-qPCR; Western blot; gel contraction assay; carbachol/myosin phosphatase inhibitor contractility assays; YAP overexpression in HEK293 cells\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO with defined molecular and functional phenotype; uses Itga8-Cre as tool, not direct mechanistic study of ITGA8 itself\",\n      \"pmids\": [\"37927241\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In hepatic stellate cells (HSCs), ITGA8 promotes liver fibrosis by regulating ECM remodeling through upregulation of COL11A1; AAV2/6-shItga8-mediated silencing of HSC-derived ITGA8 reduced COL11A1 expression, HSC-mediated collagen contraction, and markers of fibrosis and inflammation in CCl4-induced liver fibrosis.\",\n      \"method\": \"CCl4 mouse model; AAV2/6-shItga8 knockdown; proteomic analysis; Sirius Red staining; α-SMA/collagen I immunostaining; in vitro collagen contraction assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo KD with defined molecular target (COL11A1) identified by proteomics, validated functionally in vitro; single lab\",\n      \"pmids\": [\"40056500\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ITGA8+ fibroblasts mediate neurogenic bladder fibrosis via FAK/RhoA/ROCK signaling-dependent cytoskeletal remodeling; Trem2+ macrophage-secreted Fn1 engages ITGA8 on fibroblasts to reinforce pro-fibrotic signaling; conditional deletion of Itga8 (Col1a2-CreERT; Itga8fl/fl) or local knockdown significantly attenuates collagen deposition and improves bladder voiding efficiency.\",\n      \"method\": \"Single-cell RNA sequencing; conditional knockout (Col1a2-CreERT; Itga8fl/fl); local Itga8 knockdown; macrophage depletion; FAK/RhoA/ROCK pathway analysis; bladder function assessment\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO with defined pathway (FAK/RhoA/ROCK), identified ligand (Fn1 from Trem2+ macrophages), and functional readout; multiple orthogonal methods\",\n      \"pmids\": [\"41355531\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ITGA8 sensitizes lung adenocarcinoma cells to EGFR-TKIs (abivertinib) by attenuating the FAK/SRC/AKT/MAPK downstream signaling pathway; ITGA8 knockdown increases proliferation, migration, and invasion of H1975 cells and reduces abivertinib sensitivity in xenograft models, while ITGA8 overexpression reverses these effects.\",\n      \"method\": \"Genome-wide CRISPR-Cas9 screen; ITGA8 knockdown and overexpression; xenograft mouse models; FAK/SRC/AKT/MAPK pathway analysis by Western blot\",\n      \"journal\": \"Acta pharmacologica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — CRISPR screen plus KD/OE with pathway placement and in vivo validation; single lab\",\n      \"pmids\": [\"39809840\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"ITGA8 acts as a metabolic gatekeeper in lung adenocarcinoma by suppressing aerobic glycolysis (decreasing extracellular acidification rate, glucose uptake, and lactate production) through activation of the AMPK signaling pathway and subsequent inhibition of the mTOR/S6K/4EBP1 axis; AMPK inhibitor treatment reversed ITGA8-mediated suppression of glycolysis.\",\n      \"method\": \"ITGA8 overexpression; Seahorse metabolic assay (ECAR); glucose uptake and lactate assays; Western blot for AMPK/mTOR/S6K/4EBP1; pharmacological AMPK inhibition; xenograft models\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic pathway placement with pharmacological rescue experiment; single lab, multiple orthogonal metabolic readouts\",\n      \"pmids\": [\"41731056\"],\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 regulation of ITGA8 expression; RAGE displays substrate-specific adhesion to extracellular matrix proteins.\",\n      \"method\": \"RAGE domain deletion constructs; cell adhesion assays to ECM proteins; protein expression analysis; cell spreading assays\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, mechanistic follow-up partial; ITGA8 identified as downstream effector of RAGE without direct functional validation of ITGA8 itself\",\n      \"pmids\": [\"41294858\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ITGA8-positive cells isolated from conventional outflow tissue (trabecular meshwork/Schlemm's canal) exhibit Schlemm's canal endothelial cell properties, including stronger expression of SC biomarkers, lower dexamethasone-inducible myocilin expression, and stronger contractility in response to endothelin-1, implicating ITGA8 in aqueous humor outflow resistance regulation.\",\n      \"method\": \"Immunofluorescence and FISH for ITGA8 localization; magnetic bead-based cell isolation; flow cytometry; RT-PCR; Western blot; gel contraction assay\",\n      \"journal\": \"Life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — direct localization tied to functional consequence (contractility, SC marker expression); single lab with multiple assays\",\n      \"pmids\": [\"33961857\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"circTMCO3 (from M2 macrophage-derived exosomes) functions as a competing endogenous RNA for miR-515-5p, reducing its abundance and thereby upregulating ITGA8 in ovarian cancer cells; miR-515-5p directly downregulates ITGA8 to inhibit ovarian cancer malignancy; ITGA8 overexpression reverses the decreased oncogenic activity caused by circTMCO3 silencing.\",\n      \"method\": \"circTMCO3 knockdown; miR-515-5p manipulation; ITGA8 overexpression; luciferase reporter assay (implied); proliferation/migration/invasion assays; nude mouse xenograft model\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — rescue experiment with ITGA8 OE; miR-515-5p/ITGA8 axis validated in vivo; single lab\",\n      \"pmids\": [\"38755265\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ITGA8 promoter hypermethylation in ER-positive breast cancer cells silences ITGA8 expression; this hypermethylation is dependent on ERα, as 17-beta-estradiol (ERα antagonist) abolished 5-aza-dC-induced upregulation of ITGA8 specifically in ER-positive cells.\",\n      \"method\": \"Methylation-specific PCR; 5-aza-dC demethylation treatment; 17-beta-estradiol treatment; Western blot for ITGA8 protein; clinical tissue specimens analysis\",\n      \"journal\": \"Annals of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pharmacological manipulation of methylation and ERα signaling with protein-level readout; single lab, validated in clinical specimens\",\n      \"pmids\": [\"32953793\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ITGA8 encodes integrin subunit α8, which forms the α8β1 heterodimer and functions as a cell adhesion and signaling receptor that: (1) interacts with the Fraser complex protein FRAS1 in epithelial-mesenchymal signaling during organogenesis (kidney, craniofacial); (2) attenuates TGF-β/SMAD2/3 signaling and fibroblast activation in renal and hepatic fibrosis, while in neurogenic bladder fibrosis it promotes fibroblast activation via FAK/RhoA/ROCK signaling upon engagement by macrophage-secreted Fn1; (3) acts as a tumor suppressor in lung adenocarcinoma by suppressing FAK/SRC/AKT/MAPK and glycolytic metabolism via AMPK/mTOR/S6K/4EBP1 signaling; and (4) is epigenetically silenced by promoter hypermethylation (regulated by ERα in breast cancer) in multiple tumor types.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ITGA8 encodes integrin α8, which pairs with β1 to form a heterodimeric cell-surface receptor that mediates cell–extracellular matrix adhesion and transduces outside-in signals across diverse tissue contexts including kidney, liver, vasculature, bladder, and lung. During organogenesis, ITGA8 interacts with the Fraser complex component FRAS1 at the epithelial–mesenchymal interface to drive pharyngeal pouch morphogenesis and craniofacial skeletal development [PMID:27265864], and it marks vascular smooth muscle cells where it is used as a lineage-specific Cre driver that reveals contractile function distinct from visceral smooth muscle [PMID:36424917]. In fibrotic disease, ITGA8 exerts context-dependent effects: it attenuates renal fibrosis by suppressing TGF-β/SMAD2/3 signaling and fibroblast activation [PMID:26938996], promotes hepatic fibrosis through COL11A1-dependent ECM remodeling in stellate cells [PMID:40056500], and drives neurogenic bladder fibrosis upon engagement by macrophage-derived fibronectin (Fn1) via FAK/RhoA/ROCK signaling [PMID:41355531]. In lung adenocarcinoma, ITGA8 functions as a tumor suppressor by dampening FAK/SRC/AKT/MAPK signaling and suppressing aerobic glycolysis through AMPK-mediated inhibition of mTOR/S6K/4EBP1, thereby sensitizing cells to EGFR tyrosine kinase inhibitors [PMID:39809840, PMID:41731056].\",\n  \"teleology\": [\n    {\n      \"year\": 2016,\n      \"claim\": \"Establishing that ITGA8 functions as an anti-fibrotic signal in the kidney by placing it upstream of TGF-β/SMAD2/3 suppression and fibroblast activation, answering how loss of this integrin exacerbates tubulointerstitial injury.\",\n      \"evidence\": \"Itga8 knockout mice subjected to unilateral ureteral obstruction; immunostaining for pSMAD2/3 and α-SMA\",\n      \"pmids\": [\"26938996\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Ligand that engages α8β1 in renal interstitium not identified\",\n        \"Mechanism by which ITGA8 suppresses SMAD2/3 phosphorylation not resolved\",\n        \"Single-lab study without independent replication\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstrating that ITGA8 is a functional receptor for the Fraser complex component FRAS1, establishing a direct epithelial–mesenchymal signaling axis required for craniofacial morphogenesis.\",\n      \"evidence\": \"Zebrafish forward genetic screen and CRISPR alleles; genetic epistasis between itga8 and fras1 single and double mutants\",\n      \"pmids\": [\"27265864\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Biochemical binding affinity between ITGA8 and FRAS1 not measured\",\n        \"Whether this interaction is conserved in mammalian craniofacial development not tested\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Revealing that ITGA8 is epigenetically silenced by ERα-dependent promoter hypermethylation in ER-positive breast cancer, providing a mechanism for its loss in certain tumors.\",\n      \"evidence\": \"Methylation-specific PCR; 5-aza-dC demethylation and 17-beta-estradiol treatment in breast cancer cell lines; clinical tissue validation\",\n      \"pmids\": [\"32953793\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Functional consequence of ITGA8 re-expression in breast cancer cells not assessed\",\n        \"Identity of the methyltransferase(s) recruited by ERα not determined\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identifying ITGA8 as a surface marker of Schlemm's canal endothelial cells in the eye, linking it to contractile regulation of aqueous humor outflow resistance.\",\n      \"evidence\": \"Immunofluorescence, FISH, magnetic bead isolation of ITGA8+ cells from trabecular meshwork/Schlemm's canal; gel contraction assay with endothelin-1\",\n      \"pmids\": [\"33961857\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether ITGA8 directly mediates contractility or serves only as a marker not distinguished\",\n        \"Relevance to glaucoma pathogenesis not tested in vivo\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Validating ITGA8 as a preferential vascular smooth muscle cell marker by generating an Itga8-CreER knock-in and showing that conditional Srf deletion produces vascular contractile incompetence, establishing tissue-selective expression distinct from visceral smooth muscle.\",\n      \"evidence\": \"Itga8-CreER knock-in mice compared with Myh11-CreER; conditional Srf knockout; vascular contractility and blood pressure assays\",\n      \"pmids\": [\"36424917\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Intrinsic role of ITGA8 in VSMC contractility (beyond its use as a Cre driver) not dissected\",\n        \"Regulation of Itga8 expression in vascular versus visceral SMC lineages unknown\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Placing ITGA8 downstream of a circTMCO3/miR-515-5p competing endogenous RNA axis in ovarian cancer, where ITGA8 upregulation promotes tumor malignancy — revealing a pro-oncogenic role contrasting with its tumor-suppressive function in lung cancer.\",\n      \"evidence\": \"circTMCO3 knockdown and miR-515-5p manipulation; ITGA8 overexpression rescue; nude mouse xenograft\",\n      \"pmids\": [\"38755265\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Downstream signaling pathway activated by ITGA8 in ovarian cancer not characterized\",\n        \"Context-dependent oncogenic versus tumor-suppressive switch mechanism not explained\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identifying macrophage-secreted Fn1 as the ligand engaging ITGA8 on fibroblasts and delineating a FAK/RhoA/ROCK pro-fibrotic signaling cascade in neurogenic bladder fibrosis, answering how immune–stromal crosstalk drives ITGA8-dependent fibrosis.\",\n      \"evidence\": \"Single-cell RNA-seq; Col1a2-CreERT; Itga8fl/fl conditional knockout; macrophage depletion; FAK/RhoA/ROCK pathway analysis; bladder voiding assessment\",\n      \"pmids\": [\"41355531\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether Fn1-ITGA8 engagement is direct or requires co-receptors not resolved\",\n        \"How the same integrin attenuates fibrosis in kidney but promotes it in bladder remains unexplained\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrating that ITGA8 promotes hepatic fibrosis via COL11A1 upregulation in stellate cells, extending the pro-fibrotic role beyond the bladder and identifying a specific ECM target.\",\n      \"evidence\": \"CCl4 liver fibrosis model; AAV2/6-shItga8 knockdown; proteomics identifying COL11A1; collagen contraction assay\",\n      \"pmids\": [\"40056500\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Signaling pathway connecting ITGA8 to COL11A1 transcription not identified\",\n        \"Single-lab study; independent validation needed\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Establishing ITGA8 as a tumor suppressor in lung adenocarcinoma that dampens FAK/SRC/AKT/MAPK signaling and sensitizes cells to EGFR-TKIs, directly linking integrin signaling to therapeutic response.\",\n      \"evidence\": \"Genome-wide CRISPR-Cas9 screen; ITGA8 KD/OE in H1975 cells; xenograft models; Western blot for pathway components\",\n      \"pmids\": [\"39809840\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism by which ITGA8 inhibits rather than activates FAK not resolved\",\n        \"Patient stratification by ITGA8 expression for TKI response not validated clinically\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Extending the tumor-suppressive mechanism by showing ITGA8 activates AMPK to inhibit mTOR/S6K/4EBP1 signaling and suppress aerobic glycolysis, providing a metabolic explanation for growth suppression in lung adenocarcinoma.\",\n      \"evidence\": \"ITGA8 overexpression; Seahorse ECAR; glucose uptake/lactate assays; AMPK pharmacological inhibition rescue; xenograft models\",\n      \"pmids\": [\"41731056\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"How ITGA8 activates AMPK (direct interaction, calcium flux, or other) not determined\",\n        \"Whether metabolic suppression and FAK/SRC inhibition are parallel or sequential pathways unclear\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The fundamental question of how ITGA8 exerts opposing effects on fibrosis (anti-fibrotic in kidney, pro-fibrotic in bladder and liver) and opposing roles in cancer (tumor-suppressive in lung, oncogenic in ovary) remains mechanistically unexplained.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No structural model of α8β1 engagement with different ligands (nephronectin, Fn1, FRAS1) to explain context-dependent signaling\",\n        \"Tissue-specific co-receptor or adaptor usage not characterized\",\n        \"Systematic comparison of ITGA8 signaling outputs across cell types not performed\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [1, 9]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 6, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 5, 9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 5, 6, 7]},\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [4, 5]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"complexes\": [\n      \"α8β1 integrin heterodimer\"\n    ],\n    \"partners\": [\n      \"FRAS1\",\n      \"ITGB1\",\n      \"FN1\",\n      \"COL11A1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}