{"gene":"CRTAC1","run_date":"2026-06-09T22:57:19","timeline":{"discoveries":[{"year":2024,"finding":"X-ray crystallography at 1.6 Å resolution revealed that CRTAC1 consists of a three-domain fold comprising a compact β-propeller-TTR combination, in which an extended loop of the TTR domain plugs the β-propeller core. Ten bound ions were observed: six calcium, three potassium, and one sodium. Potassium ions bind between the blades of the β-propeller and are essential for structural stability; low potassium concentrations cause changes in tryptophan environment and exposure of two buried free cysteines located on a β-blade and in the β-propeller-plugging TTR loop. Mutating the two free cysteines to serines prevents covalent intermolecular interactions but not aggregation in the absence of potassium.","method":"X-ray crystallography (1.6 Å resolution) with active-site/cysteine mutagenesis and tryptophan fluorescence assay","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution crystal structure combined with mutagenesis and biochemical validation in a single rigorous study","pmids":["39029889"],"is_preprint":false},{"year":2006,"finding":"CRTAC1-A isoform is secreted by cultured human chondrocytes and localizes to the extracellular matrix of articular cartilage. Its secretion is stimulated by BMP4. Of five putative O-glycosylation motifs in the last exon of CRTAC1-A, the most C-terminal one is functionally modified, as determined by serial C-terminal deletion mutants exposed to the O-glycosylation inhibitor Benzyl-alpha-GalNAc. Both CRTAC1 isoforms contain four FG-GAP repeat domains and an RGD integrin-binding motif.","method":"Serial C-terminal deletion mutants + O-glycosylation inhibitor treatment; immunolocalization in articular cartilage sections; BMP4 stimulation assay","journal":"Matrix biology : journal of the International Society for Matrix Biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct biochemical mutagenesis/inhibitor approach for glycosylation site mapping plus localization, single lab with multiple orthogonal methods","pmids":["17074475"],"is_preprint":false},{"year":2001,"finding":"CEP-68 (CRTAC1) encodes a secreted protein with an N-terminal leader peptide and an EGF-like calcium-binding domain, defining a new protein family. It functions as a marker gene distinguishing chondrocytes from osteoblasts and mesenchymal stem cells in culture.","method":"Gene characterization, sequence analysis, and cell-culture marker assays comparing chondrocytes, osteoblasts, and mesenchymal stem cells","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct characterization of protein domain structure and cell-type-specific expression by experimental comparison, single lab","pmids":["11139377"],"is_preprint":false},{"year":2010,"finding":"Structural prediction analysis identified the N-terminal region of CRTAC1/CRTAC2 family members as a potential seven-bladed β-propeller structure closely related to those of integrin alpha chains and glycosylphosphatidylinositol-specific phospholipase D1 protein families, supported by phylogenetic analysis. A CRTAC2 paralog lacking the EGF-like calcium-binding domain was identified in teleost fish pituitary gland.","method":"Structural prediction, phylogenetic analysis, database searches, and sequence analysis of pituitary-expressed transcripts","journal":"Gene","confidence":"Low","confidence_rationale":"Tier 4 / Weak — primarily computational structural prediction and phylogenetic analysis without experimental biochemical validation","pmids":["20171266"],"is_preprint":false},{"year":2021,"finding":"CRTAC1 overexpression in bladder cancer cells inhibited cell viability, proliferation, migration, invasion, and EMT. Mechanistically, CRTAC1 co-localizes with and co-immunoprecipitates YY1, negatively modulates YY1 mRNA and protein expression, and inactivates the TGF-β pathway by downregulating YY1. Chromatin immunoprecipitation and luciferase reporter assays confirmed the interaction between CRTAC1 and YY1 at the transcriptional level.","method":"Co-immunoprecipitation, immunofluorescence co-localization, ChIP, luciferase reporter assays, western blotting, CCK-8, colony formation, wound healing, Transwell assays","journal":"Bioengineered","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and multiple orthogonal functional assays in single lab; no independent replication","pmids":["34818994"],"is_preprint":false},{"year":2020,"finding":"CRTAC1 promotes pyroptosis in human lens epithelial cells (HLECs) under UVB irradiation via ROS production. Downregulation of CRTAC1 reversed UVB-induced pyroptosis (reduced NLRP3, active Caspase-1, GSDMD-N, IL-1β, IL-18), while CRTAC1 overexpression promoted pyroptosis. The ROS inhibitor N-acetyl-l-cysteine blocked the effects of CRTAC1 overexpression, placing CRTAC1 upstream of ROS in the pyroptosis pathway.","method":"siRNA knockdown and overexpression of CRTAC1 in HLECs, western blotting for pyroptosis markers, ROS inhibitor rescue experiment","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function and gain-of-function with defined molecular readouts plus pharmacological rescue, single lab","pmids":["32838966"],"is_preprint":false},{"year":2023,"finding":"CRTAC1 overexpression in NSCLC cells increased intracellular Ca2+ levels by eliciting ryanodine receptor (RyR)-mediated calcium release, which promoted NFAT transcriptional activation, induced STUB1 mRNA transcription and protein expression, accelerated Akt1 protein degradation, and thereby enhanced cisplatin-induced apoptosis. In vivo mouse experiments confirmed that CRTAC1 overexpression increased the antitumor effects of cisplatin.","method":"CRTAC1 overexpression and knockdown in NSCLC cells, intracellular Ca2+ measurement, NFAT reporter assay, western blotting for STUB1 and Akt1, in vivo mouse tumor model","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (Ca2+ assay, reporter, western blot, in vivo) in single lab defining a mechanistic pathway","pmids":["37633993"],"is_preprint":false},{"year":2025,"finding":"Secreted CRTAC1 derived from senescent fibroblast-like synoviocytes (FLS) binds NRF2 in chondrocytes, suppresses NRF2-dependent transcription of SIRT3, reduces SIRT3 expression, promotes acetylation of FOXO3a, suppresses mitophagy, and induces mitochondrial dysfunction, ultimately contributing to chondrocyte degradation and OA progression. Intra-articular AAV-SIRT3 delivery alleviated OA in mice.","method":"Single-cell RNA sequencing, in vitro binding assay (CRTAC1-NRF2 interaction), western blotting, SIRT3 conditional knockout mouse, intra-articular AAV injection in vivo","journal":"Acta pharmaceutica Sinica. B","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding experiment for CRTAC1-NRF2, multiple in vitro and in vivo functional assays in single lab","pmids":["41311393"],"is_preprint":false},{"year":2022,"finding":"CRTAC1 expression in bladder urothelial carcinoma is epigenetically silenced by the lncRNA TPRG1-AS1, which recruits DNA methyltransferase DNMT3A to the CRTAC1 promoter, increasing promoter DNA methylation and suppressing CRTAC1 transcription downstream of TFAP2A-driven TPRG1-AS1 transcription.","method":"ChIP-qPCR, luciferase reporter assay, methylation analysis, microarray, rescue/knockdown experiments in BLCA cells, in vivo tumor model","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-qPCR and reporter assays establish mechanism of CRTAC1 promoter methylation; single lab","pmids":["36410635"],"is_preprint":false},{"year":2024,"finding":"In degenerative spinal ligaments, SPP1+ macrophages interact with CRTAC1+ chondrocyte-like cells. SPP1 activates ATF3 (identified as a key transcription factor by SCENIC analysis and further experiments) in CRTAC1+ cells, which drives the CRTAC1/MGP/CLU axis to promote ligament calcification.","method":"Single-cell RNA sequencing, SCENIC transcription factor analysis, CellChat cell-cell interaction analysis, further experimental validation (not fully detailed in abstract)","journal":"Aging cell","confidence":"Low","confidence_rationale":"Tier 3 / Weak — scRNA-seq and computational inference with limited experimental follow-up detail in abstract; single lab","pmids":["39158018"],"is_preprint":false},{"year":2026,"finding":"CRTAC1 inhibits proliferation, migration, and invasion of lung adenocarcinoma (LUAD) cells in vitro and in vivo by suppressing integrin/FAK signaling.","method":"CRTAC1 overexpression/knockdown in LUAD cells, in vitro proliferation/migration/invasion assays, in vivo mouse tumor model, western blotting for integrin/FAK pathway components","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function and gain-of-function with defined signaling pathway readout plus in vivo validation, single lab","pmids":["41708954"],"is_preprint":false},{"year":2024,"finding":"In gastric cancer cells (HGC-27 and MKN-74), CRTAC1 knockdown inhibited proliferation and migration, promoted apoptosis, increased E-cadherin expression, and reduced vimentin, p-PI3K, AKT2, p-AKT, and p-mTOR expression, placing CRTAC1 upstream of EMT and the PI3K/AKT/mTOR signaling pathway in gastric cancer.","method":"siRNA knockdown of CRTAC1, CCK-8, EdU, colony formation, flow cytometry, wound healing, Transwell assays, western blotting for PI3K/AKT pathway","journal":"Nan fang yi ke da xue xue bao = Journal of Southern Medical University","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single knockdown approach with pathway western blotting but no reconstitution or rescue","pmids":["39725632"],"is_preprint":false}],"current_model":"CRTAC1 is a secreted, glycosylated extracellular matrix protein with a structurally characterized three-domain fold (β-propeller-TTR) stabilized by potassium and calcium ions; it bears an RGD integrin-binding motif and EGF-like calcium-binding domain, is O-glycosylated at its C-terminal exon, localizes to articular cartilage ECM, and functions as a context-dependent signaling regulator that—depending on cell type—suppresses tumor progression by blocking integrin/FAK signaling and Akt1 (via Ca²⁺/NFAT/STUB1), promotes pyroptosis via ROS in lens epithelial cells, binds NRF2 to suppress SIRT3 and induce mitochondrial dysfunction in chondrocytes, and interacts with YY1 to inactivate TGF-β signaling in bladder cancer."},"narrative":{"mechanistic_narrative":"CRTAC1 is a secreted, glycosylated extracellular matrix protein originally defined as a chondrocyte marker distinguishing chondrocytes from osteoblasts and mesenchymal stem cells, and it localizes to the extracellular matrix of articular cartilage [PMID:17074475, PMID:11139377]. High-resolution crystallography established its architecture as a compact three-domain β-propeller–TTR fold in which an extended TTR loop plugs the β-propeller core; the structure binds ten ions, with potassium ions wedged between propeller blades being essential for stability, such that potassium depletion exposes buried cysteines and promotes covalent intermolecular interactions and aggregation [PMID:39029889]. The protein carries an N-terminal leader peptide, an EGF-like calcium-binding domain, FG-GAP repeat domains, an RGD integrin-binding motif, and a functionally O-glycosylated C-terminal exon, and its secretion by chondrocytes is induced by BMP4 [PMID:17074475, PMID:11139377]. Functionally, CRTAC1 acts as a context-dependent regulator of cell signaling and survival across multiple cell types: it suppresses tumor progression in lung adenocarcinoma by blocking integrin/FAK signaling [PMID:41708954], enhances cisplatin-induced apoptosis in NSCLC by triggering ryanodine-receptor–mediated Ca²⁺ release that activates NFAT, induces STUB1, and accelerates Akt1 degradation [PMID:37633993], and inhibits proliferation, migration, and EMT in bladder cancer by binding and downregulating YY1 to inactivate TGF-β signaling [PMID:34818994]. In non-cancer contexts, CRTAC1 promotes ROS-dependent pyroptosis in UVB-irradiated lens epithelial cells [PMID:32838966], and secreted CRTAC1 from senescent synoviocytes binds NRF2 in chondrocytes to suppress SIRT3 transcription, promote FOXO3a acetylation, impair mitophagy, and drive mitochondrial dysfunction in osteoarthritis [PMID:41311393]. Its own expression is epigenetically silenced in bladder carcinoma through lncRNA TPRG1-AS1–directed recruitment of DNMT3A to the CRTAC1 promoter [PMID:36410635].","teleology":[{"year":2001,"claim":"Established CRTAC1 (CEP-68) as a secreted, EGF-like calcium-binding-domain protein and a chondrocyte-specific marker, defining a new protein family and its baseline cell-type identity.","evidence":"Gene characterization, sequence analysis, and marker comparison across chondrocytes, osteoblasts, and mesenchymal stem cells","pmids":["11139377"],"confidence":"Medium","gaps":["No structural model of the protein","Functional role beyond cell-type marker undefined","No interacting partners identified"]},{"year":2006,"claim":"Localized CRTAC1-A to articular cartilage ECM, mapped a functional C-terminal O-glycosylation site, and showed BMP4-induced secretion, defining its secretory and post-translational biology.","evidence":"Serial C-terminal deletion mutants with O-glycosylation inhibitor, immunolocalization in cartilage, and BMP4 stimulation in cultured chondrocytes","pmids":["17074475"],"confidence":"Medium","gaps":["Function of the RGD motif not tested","Role of FG-GAP repeats not defined","Binding partners in ECM unknown"]},{"year":2010,"claim":"Predicted the N-terminal region as a seven-bladed β-propeller related to integrin alpha chains, providing the first structural hypothesis linking CRTAC1 to integrin-type folds.","evidence":"Computational structural prediction, phylogenetic analysis, and database searches","pmids":["20171266"],"confidence":"Low","gaps":["Purely computational with no experimental validation","β-propeller fold not confirmed biochemically at this stage","Functional consequence of fold relationship unaddressed"]},{"year":2020,"claim":"Placed CRTAC1 upstream of ROS in a pyroptosis pathway, the first demonstration of a cell-signaling function for the protein.","evidence":"siRNA knockdown and overexpression in human lens epithelial cells with pyroptosis-marker western blotting and ROS-inhibitor rescue under UVB","pmids":["32838966"],"confidence":"Medium","gaps":["Molecular mechanism linking CRTAC1 to ROS generation unknown","No receptor or direct binding partner identified","Generalizability beyond lens epithelial cells untested"]},{"year":2021,"claim":"Identified YY1 as a direct CRTAC1 partner and defined a tumor-suppressive axis in bladder cancer through YY1 downregulation and TGF-β inactivation.","evidence":"Reciprocal Co-IP, co-localization, ChIP, luciferase reporter, and functional proliferation/migration/invasion assays in bladder cancer cells","pmids":["34818994"],"confidence":"Medium","gaps":["No independent replication of the CRTAC1-YY1 interaction","How a secreted ECM protein modulates a nuclear transcription factor mechanistically unclear","Direct binding interface not mapped"]},{"year":2022,"claim":"Explained how CRTAC1 is silenced in cancer, showing epigenetic repression via lncRNA-directed promoter methylation.","evidence":"ChIP-qPCR, luciferase reporter, methylation analysis, and rescue/knockdown experiments in bladder carcinoma cells with in vivo model","pmids":["36410635"],"confidence":"Medium","gaps":["Generalizability of this silencing mechanism to other tumors untested","Upstream signals controlling TPRG1-AS1 only partly defined","No structural detail of DNMT3A recruitment"]},{"year":2023,"claim":"Defined a mechanistic chemosensitization pathway in NSCLC linking CRTAC1 to RyR-mediated Ca²⁺ release, NFAT, STUB1, and Akt1 degradation.","evidence":"Overexpression/knockdown, intracellular Ca²⁺ measurement, NFAT reporter, western blotting, and in vivo cisplatin tumor model","pmids":["37633993"],"confidence":"Medium","gaps":["How CRTAC1 triggers RyR-mediated calcium release mechanistically unknown","Direct molecular partner upstream of Ca²⁺ flux unidentified","Single-lab pathway without independent confirmation"]},{"year":2024,"claim":"Determined the high-resolution three-domain β-propeller–TTR structure and its dependence on potassium for stability, providing the definitive structural framework for CRTAC1.","evidence":"X-ray crystallography at 1.6 Å with cysteine mutagenesis and tryptophan fluorescence","pmids":["39029889"],"confidence":"High","gaps":["Structural basis for partner binding (YY1, NRF2, integrins) not resolved","Physiological consequence of potassium-dependent cysteine exposure in vivo unknown","Role of bound calcium ions in function untested"]},{"year":2024,"claim":"Extended CRTAC1 functions to gastric cancer and to a ligament calcification cell-cell axis, broadening its disease contexts.","evidence":"siRNA knockdown with PI3K/AKT/mTOR pathway western blotting in gastric cancer cells; scRNA-seq and SCENIC inference of an SPP1-ATF3-CRTAC1/MGP/CLU axis in spinal ligaments","pmids":["39725632","39158018"],"confidence":"Low","gaps":["Gastric cancer findings rest on single knockdown without rescue","Ligament axis is largely computational with limited experimental follow-up","Direct mechanistic links remain unestablished"]},{"year":2025,"claim":"Identified NRF2 as a direct CRTAC1 binding partner and defined a senescence-driven NRF2–SIRT3–FOXO3a–mitophagy axis driving chondrocyte dysfunction in osteoarthritis.","evidence":"scRNA-seq, in vitro CRTAC1-NRF2 binding assay, western blotting, SIRT3 conditional knockout, and intra-articular AAV-SIRT3 rescue in mice","pmids":["41311393"],"confidence":"Medium","gaps":["Structural basis of CRTAC1-NRF2 binding unresolved","How extracellular CRTAC1 accesses intracellular NRF2 unclear","Single-lab mechanism without independent replication"]},{"year":2026,"claim":"Demonstrated that CRTAC1 suppresses lung adenocarcinoma progression through integrin/FAK signaling, connecting its RGD/integrin-related features to tumor suppression.","evidence":"Overexpression/knockdown in LUAD cells with proliferation/migration/invasion assays, integrin/FAK western blotting, and in vivo tumor model","pmids":["41708954"],"confidence":"Medium","gaps":["Direct CRTAC1-integrin binding not demonstrated","Role of the RGD motif in this signaling untested","Single-lab finding without independent confirmation"]},{"year":null,"claim":"It remains unknown how a single secreted ECM protein engages such mechanistically distinct intracellular targets (YY1, NRF2, RyR/Ca²⁺, integrin/FAK) and what unifying receptor or entry mechanism governs its context-dependent actions.","evidence":"","pmids":[],"confidence":"Low","gaps":["No defined cell-surface receptor linking secreted CRTAC1 to intracellular signaling","Structural interfaces for named partners not mapped","Determinants of cell-type-specific (tumor-suppressive vs degenerative) outcomes unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,1]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[1,2]},{"term_id":"GO:0031012","term_label":"extracellular matrix","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,6,10]},{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[1]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[5,6]}],"complexes":[],"partners":["YY1","NRF2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9NQ79","full_name":"Cartilage acidic protein 1","aliases":["68 kDa chondrocyte-expressed protein","CEP-68","ASPIC"],"length_aa":661,"mass_kda":71.4,"function":"","subcellular_location":"Secreted, extracellular space, extracellular matrix","url":"https://www.uniprot.org/uniprotkb/Q9NQ79/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CRTAC1","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/CRTAC1","total_profiled":1310},"omim":[{"mim_id":"614189","title":"GOLGIN A7 FAMILY, MEMBER B; GOLGA7B","url":"https://www.omim.org/entry/614189"},{"mim_id":"606276","title":"CARTILAGE ACIDIC PROTEIN 1; CRTAC1","url":"https://www.omim.org/entry/606276"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"blood vessel","ntpm":61.8},{"tissue":"lung","ntpm":47.1},{"tissue":"urinary bladder","ntpm":50.4}],"url":"https://www.proteinatlas.org/search/CRTAC1"},"hgnc":{"alias_symbol":["FLJ10320","CEP-68","ASPIC1"],"prev_symbol":[]},"alphafold":{"accession":"Q9NQ79","domains":[{"cath_id":"2.130.10.130","chopping":"46-451","consensus_level":"medium","plddt":94.9409,"start":46,"end":451},{"cath_id":"-","chopping":"562-594","consensus_level":"medium","plddt":90.3539,"start":562,"end":594}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NQ79","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NQ79-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NQ79-F1-predicted_aligned_error_v6.png","plddt_mean":85.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CRTAC1","jax_strain_url":"https://www.jax.org/strain/search?query=CRTAC1"},"sequence":{"accession":"Q9NQ79","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NQ79.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NQ79/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NQ79"}},"corpus_meta":[{"pmid":"17074475","id":"PMC_17074475","title":"Chondrocyte secreted CRTAC1: a glycosylated extracellular matrix molecule of human articular cartilage.","date":"2006","source":"Matrix biology : journal of the International Society for Matrix Biology","url":"https://pubmed.ncbi.nlm.nih.gov/17074475","citation_count":69,"is_preprint":false},{"pmid":"33982893","id":"PMC_33982893","title":"The CRTAC1 Protein in Plasma Is Associated With Osteoarthritis and Predicts Progression to Joint Replacement: A Large-Scale Proteomics Scan in Iceland.","date":"2021","source":"Arthritis & rheumatology (Hoboken, N.J.)","url":"https://pubmed.ncbi.nlm.nih.gov/33982893","citation_count":53,"is_preprint":false},{"pmid":"35924962","id":"PMC_35924962","title":"Plasma proteomics identifies CRTAC1 as a biomarker for osteoarthritis severity and progression.","date":"2023","source":"Rheumatology (Oxford, England)","url":"https://pubmed.ncbi.nlm.nih.gov/35924962","citation_count":44,"is_preprint":false},{"pmid":"11139377","id":"PMC_11139377","title":"Chondrocyte expressed protein-68 (CEP-68), a novel human marker gene for cultured chondrocytes.","date":"2001","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/11139377","citation_count":38,"is_preprint":false},{"pmid":"34818994","id":"PMC_34818994","title":"CRTAC1 (Cartilage acidic protein 1) inhibits cell proliferation, migration, invasion and epithelial-mesenchymal transition (EMT) process in bladder cancer by downregulating Yin Yang 1 (YY1) to inactivate the TGF-β pathway.","date":"2021","source":"Bioengineered","url":"https://pubmed.ncbi.nlm.nih.gov/34818994","citation_count":26,"is_preprint":false},{"pmid":"32838966","id":"PMC_32838966","title":"Down-regulation of CRTAC1 attenuates UVB-induced pyroptosis in HLECs through inhibiting ROS production.","date":"2020","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/32838966","citation_count":25,"is_preprint":false},{"pmid":"36410635","id":"PMC_36410635","title":"The oncogenic role of TFAP2A in bladder urothelial carcinoma via a novel long noncoding RNA TPRG1-AS1/DNMT3A/CRTAC1 axis.","date":"2022","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/36410635","citation_count":17,"is_preprint":false},{"pmid":"20171266","id":"PMC_20171266","title":"CRTAC1 homolog proteins are conserved from cyanobacteria to man and secreted by the teleost fish pituitary gland.","date":"2010","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/20171266","citation_count":13,"is_preprint":false},{"pmid":"37633993","id":"PMC_37633993","title":"CRTAC1 enhances the chemosensitivity of non-small cell lung cancer to cisplatin by eliciting RyR-mediated calcium release and inhibiting Akt1 expression.","date":"2023","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/37633993","citation_count":11,"is_preprint":false},{"pmid":"39158018","id":"PMC_39158018","title":"Single-cell RNA sequencing reveals the CRTAC1+ population actively contributes to the pathogenesis of spinal ligament degeneration by SPP1+ macrophage.","date":"2024","source":"Aging cell","url":"https://pubmed.ncbi.nlm.nih.gov/39158018","citation_count":9,"is_preprint":false},{"pmid":"41311393","id":"PMC_41311393","title":"CRTAC1 derived from senescent FLSs induces chondrocyte mitochondrial dysfunction via modulating NRF2/SIRT3 axis in osteoarthritis progression.","date":"2025","source":"Acta pharmaceutica Sinica. B","url":"https://pubmed.ncbi.nlm.nih.gov/41311393","citation_count":3,"is_preprint":false},{"pmid":"39682792","id":"PMC_39682792","title":"Polymorphisms Within the IQGAP2 and CRTAC1 Genes of Gannan Yaks and Their Association with Milk Quality Characteristics.","date":"2024","source":"Foods (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/39682792","citation_count":3,"is_preprint":false},{"pmid":"39029889","id":"PMC_39029889","title":"CRTAC1 has a Compact β-propeller-TTR Core Stabilized by Potassium Ions.","date":"2024","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/39029889","citation_count":2,"is_preprint":false},{"pmid":"40408237","id":"PMC_40408237","title":"CRTAC1: a novel indicator of lung involvement in SSc.","date":"2025","source":"Rheumatology (Oxford, England)","url":"https://pubmed.ncbi.nlm.nih.gov/40408237","citation_count":0,"is_preprint":false},{"pmid":"41708954","id":"PMC_41708954","title":"CRTAC1 inhibits progression of lung adenocarcinoma by suppressing integrin/FAK signaling.","date":"2026","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/41708954","citation_count":0,"is_preprint":false},{"pmid":"39725632","id":"PMC_39725632","title":"[High expression of CRTAC1 promotes proliferation, migration and immune cell infiltration of gastric cancer by regulating the PI3K/AKT signaling pathway].","date":"2024","source":"Nan fang yi ke da xue xue bao = Journal of Southern Medical University","url":"https://pubmed.ncbi.nlm.nih.gov/39725632","citation_count":0,"is_preprint":false},{"pmid":"41580236","id":"PMC_41580236","title":"CRTAC1 as a biomarker for osteoarthritis: Link to inflammation and microRNA regulation.","date":"2026","source":"Osteoarthritis and cartilage","url":"https://pubmed.ncbi.nlm.nih.gov/41580236","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.02.17.638761","title":"Proteomic characterisation of the early rheumatoid arthritis-cardiovascular disease multimorbid axis","date":"2025-02-23","source":"bioRxiv","url":"https://doi.org/10.1101/2025.02.17.638761","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.09.04.24313052","title":"Pharmacogenetic Study of Antipsychotic-Induced Lipid and BMI Changes in Chinese Schizophrenia Patients: A Genome-Wide Association Study","date":"2024-09-04","source":"bioRxiv","url":"https://doi.org/10.1101/2024.09.04.24313052","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":12629,"output_tokens":3458,"usd":0.044879,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11060,"output_tokens":4075,"usd":0.078588,"stage2_stop_reason":"end_turn"},"total_usd":0.123467,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2024,\n      \"finding\": \"X-ray crystallography at 1.6 Å resolution revealed that CRTAC1 consists of a three-domain fold comprising a compact β-propeller-TTR combination, in which an extended loop of the TTR domain plugs the β-propeller core. Ten bound ions were observed: six calcium, three potassium, and one sodium. Potassium ions bind between the blades of the β-propeller and are essential for structural stability; low potassium concentrations cause changes in tryptophan environment and exposure of two buried free cysteines located on a β-blade and in the β-propeller-plugging TTR loop. Mutating the two free cysteines to serines prevents covalent intermolecular interactions but not aggregation in the absence of potassium.\",\n      \"method\": \"X-ray crystallography (1.6 Å resolution) with active-site/cysteine mutagenesis and tryptophan fluorescence assay\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution crystal structure combined with mutagenesis and biochemical validation in a single rigorous study\",\n      \"pmids\": [\"39029889\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"CRTAC1-A isoform is secreted by cultured human chondrocytes and localizes to the extracellular matrix of articular cartilage. Its secretion is stimulated by BMP4. Of five putative O-glycosylation motifs in the last exon of CRTAC1-A, the most C-terminal one is functionally modified, as determined by serial C-terminal deletion mutants exposed to the O-glycosylation inhibitor Benzyl-alpha-GalNAc. Both CRTAC1 isoforms contain four FG-GAP repeat domains and an RGD integrin-binding motif.\",\n      \"method\": \"Serial C-terminal deletion mutants + O-glycosylation inhibitor treatment; immunolocalization in articular cartilage sections; BMP4 stimulation assay\",\n      \"journal\": \"Matrix biology : journal of the International Society for Matrix Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct biochemical mutagenesis/inhibitor approach for glycosylation site mapping plus localization, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"17074475\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"CEP-68 (CRTAC1) encodes a secreted protein with an N-terminal leader peptide and an EGF-like calcium-binding domain, defining a new protein family. It functions as a marker gene distinguishing chondrocytes from osteoblasts and mesenchymal stem cells in culture.\",\n      \"method\": \"Gene characterization, sequence analysis, and cell-culture marker assays comparing chondrocytes, osteoblasts, and mesenchymal stem cells\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct characterization of protein domain structure and cell-type-specific expression by experimental comparison, single lab\",\n      \"pmids\": [\"11139377\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Structural prediction analysis identified the N-terminal region of CRTAC1/CRTAC2 family members as a potential seven-bladed β-propeller structure closely related to those of integrin alpha chains and glycosylphosphatidylinositol-specific phospholipase D1 protein families, supported by phylogenetic analysis. A CRTAC2 paralog lacking the EGF-like calcium-binding domain was identified in teleost fish pituitary gland.\",\n      \"method\": \"Structural prediction, phylogenetic analysis, database searches, and sequence analysis of pituitary-expressed transcripts\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — primarily computational structural prediction and phylogenetic analysis without experimental biochemical validation\",\n      \"pmids\": [\"20171266\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CRTAC1 overexpression in bladder cancer cells inhibited cell viability, proliferation, migration, invasion, and EMT. Mechanistically, CRTAC1 co-localizes with and co-immunoprecipitates YY1, negatively modulates YY1 mRNA and protein expression, and inactivates the TGF-β pathway by downregulating YY1. Chromatin immunoprecipitation and luciferase reporter assays confirmed the interaction between CRTAC1 and YY1 at the transcriptional level.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence co-localization, ChIP, luciferase reporter assays, western blotting, CCK-8, colony formation, wound healing, Transwell assays\",\n      \"journal\": \"Bioengineered\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and multiple orthogonal functional assays in single lab; no independent replication\",\n      \"pmids\": [\"34818994\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CRTAC1 promotes pyroptosis in human lens epithelial cells (HLECs) under UVB irradiation via ROS production. Downregulation of CRTAC1 reversed UVB-induced pyroptosis (reduced NLRP3, active Caspase-1, GSDMD-N, IL-1β, IL-18), while CRTAC1 overexpression promoted pyroptosis. The ROS inhibitor N-acetyl-l-cysteine blocked the effects of CRTAC1 overexpression, placing CRTAC1 upstream of ROS in the pyroptosis pathway.\",\n      \"method\": \"siRNA knockdown and overexpression of CRTAC1 in HLECs, western blotting for pyroptosis markers, ROS inhibitor rescue experiment\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function and gain-of-function with defined molecular readouts plus pharmacological rescue, single lab\",\n      \"pmids\": [\"32838966\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CRTAC1 overexpression in NSCLC cells increased intracellular Ca2+ levels by eliciting ryanodine receptor (RyR)-mediated calcium release, which promoted NFAT transcriptional activation, induced STUB1 mRNA transcription and protein expression, accelerated Akt1 protein degradation, and thereby enhanced cisplatin-induced apoptosis. In vivo mouse experiments confirmed that CRTAC1 overexpression increased the antitumor effects of cisplatin.\",\n      \"method\": \"CRTAC1 overexpression and knockdown in NSCLC cells, intracellular Ca2+ measurement, NFAT reporter assay, western blotting for STUB1 and Akt1, in vivo mouse tumor model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (Ca2+ assay, reporter, western blot, in vivo) in single lab defining a mechanistic pathway\",\n      \"pmids\": [\"37633993\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Secreted CRTAC1 derived from senescent fibroblast-like synoviocytes (FLS) binds NRF2 in chondrocytes, suppresses NRF2-dependent transcription of SIRT3, reduces SIRT3 expression, promotes acetylation of FOXO3a, suppresses mitophagy, and induces mitochondrial dysfunction, ultimately contributing to chondrocyte degradation and OA progression. Intra-articular AAV-SIRT3 delivery alleviated OA in mice.\",\n      \"method\": \"Single-cell RNA sequencing, in vitro binding assay (CRTAC1-NRF2 interaction), western blotting, SIRT3 conditional knockout mouse, intra-articular AAV injection in vivo\",\n      \"journal\": \"Acta pharmaceutica Sinica. B\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding experiment for CRTAC1-NRF2, multiple in vitro and in vivo functional assays in single lab\",\n      \"pmids\": [\"41311393\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CRTAC1 expression in bladder urothelial carcinoma is epigenetically silenced by the lncRNA TPRG1-AS1, which recruits DNA methyltransferase DNMT3A to the CRTAC1 promoter, increasing promoter DNA methylation and suppressing CRTAC1 transcription downstream of TFAP2A-driven TPRG1-AS1 transcription.\",\n      \"method\": \"ChIP-qPCR, luciferase reporter assay, methylation analysis, microarray, rescue/knockdown experiments in BLCA cells, in vivo tumor model\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-qPCR and reporter assays establish mechanism of CRTAC1 promoter methylation; single lab\",\n      \"pmids\": [\"36410635\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In degenerative spinal ligaments, SPP1+ macrophages interact with CRTAC1+ chondrocyte-like cells. SPP1 activates ATF3 (identified as a key transcription factor by SCENIC analysis and further experiments) in CRTAC1+ cells, which drives the CRTAC1/MGP/CLU axis to promote ligament calcification.\",\n      \"method\": \"Single-cell RNA sequencing, SCENIC transcription factor analysis, CellChat cell-cell interaction analysis, further experimental validation (not fully detailed in abstract)\",\n      \"journal\": \"Aging cell\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — scRNA-seq and computational inference with limited experimental follow-up detail in abstract; single lab\",\n      \"pmids\": [\"39158018\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"CRTAC1 inhibits proliferation, migration, and invasion of lung adenocarcinoma (LUAD) cells in vitro and in vivo by suppressing integrin/FAK signaling.\",\n      \"method\": \"CRTAC1 overexpression/knockdown in LUAD cells, in vitro proliferation/migration/invasion assays, in vivo mouse tumor model, western blotting for integrin/FAK pathway components\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function and gain-of-function with defined signaling pathway readout plus in vivo validation, single lab\",\n      \"pmids\": [\"41708954\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In gastric cancer cells (HGC-27 and MKN-74), CRTAC1 knockdown inhibited proliferation and migration, promoted apoptosis, increased E-cadherin expression, and reduced vimentin, p-PI3K, AKT2, p-AKT, and p-mTOR expression, placing CRTAC1 upstream of EMT and the PI3K/AKT/mTOR signaling pathway in gastric cancer.\",\n      \"method\": \"siRNA knockdown of CRTAC1, CCK-8, EdU, colony formation, flow cytometry, wound healing, Transwell assays, western blotting for PI3K/AKT pathway\",\n      \"journal\": \"Nan fang yi ke da xue xue bao = Journal of Southern Medical University\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single knockdown approach with pathway western blotting but no reconstitution or rescue\",\n      \"pmids\": [\"39725632\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CRTAC1 is a secreted, glycosylated extracellular matrix protein with a structurally characterized three-domain fold (β-propeller-TTR) stabilized by potassium and calcium ions; it bears an RGD integrin-binding motif and EGF-like calcium-binding domain, is O-glycosylated at its C-terminal exon, localizes to articular cartilage ECM, and functions as a context-dependent signaling regulator that—depending on cell type—suppresses tumor progression by blocking integrin/FAK signaling and Akt1 (via Ca²⁺/NFAT/STUB1), promotes pyroptosis via ROS in lens epithelial cells, binds NRF2 to suppress SIRT3 and induce mitochondrial dysfunction in chondrocytes, and interacts with YY1 to inactivate TGF-β signaling in bladder cancer.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CRTAC1 is a secreted, glycosylated extracellular matrix protein originally defined as a chondrocyte marker distinguishing chondrocytes from osteoblasts and mesenchymal stem cells, and it localizes to the extracellular matrix of articular cartilage [#1, #2]. High-resolution crystallography established its architecture as a compact three-domain β-propeller–TTR fold in which an extended TTR loop plugs the β-propeller core; the structure binds ten ions, with potassium ions wedged between propeller blades being essential for stability, such that potassium depletion exposes buried cysteines and promotes covalent intermolecular interactions and aggregation [#0]. The protein carries an N-terminal leader peptide, an EGF-like calcium-binding domain, FG-GAP repeat domains, an RGD integrin-binding motif, and a functionally O-glycosylated C-terminal exon, and its secretion by chondrocytes is induced by BMP4 [#1, #2]. Functionally, CRTAC1 acts as a context-dependent regulator of cell signaling and survival across multiple cell types: it suppresses tumor progression in lung adenocarcinoma by blocking integrin/FAK signaling [#10], enhances cisplatin-induced apoptosis in NSCLC by triggering ryanodine-receptor–mediated Ca²⁺ release that activates NFAT, induces STUB1, and accelerates Akt1 degradation [#6], and inhibits proliferation, migration, and EMT in bladder cancer by binding and downregulating YY1 to inactivate TGF-β signaling [#4]. In non-cancer contexts, CRTAC1 promotes ROS-dependent pyroptosis in UVB-irradiated lens epithelial cells [#5], and secreted CRTAC1 from senescent synoviocytes binds NRF2 in chondrocytes to suppress SIRT3 transcription, promote FOXO3a acetylation, impair mitophagy, and drive mitochondrial dysfunction in osteoarthritis [#7]. Its own expression is epigenetically silenced in bladder carcinoma through lncRNA TPRG1-AS1–directed recruitment of DNMT3A to the CRTAC1 promoter [#8].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established CRTAC1 (CEP-68) as a secreted, EGF-like calcium-binding-domain protein and a chondrocyte-specific marker, defining a new protein family and its baseline cell-type identity.\",\n      \"evidence\": \"Gene characterization, sequence analysis, and marker comparison across chondrocytes, osteoblasts, and mesenchymal stem cells\",\n      \"pmids\": [\"11139377\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of the protein\", \"Functional role beyond cell-type marker undefined\", \"No interacting partners identified\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Localized CRTAC1-A to articular cartilage ECM, mapped a functional C-terminal O-glycosylation site, and showed BMP4-induced secretion, defining its secretory and post-translational biology.\",\n      \"evidence\": \"Serial C-terminal deletion mutants with O-glycosylation inhibitor, immunolocalization in cartilage, and BMP4 stimulation in cultured chondrocytes\",\n      \"pmids\": [\"17074475\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Function of the RGD motif not tested\", \"Role of FG-GAP repeats not defined\", \"Binding partners in ECM unknown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Predicted the N-terminal region as a seven-bladed β-propeller related to integrin alpha chains, providing the first structural hypothesis linking CRTAC1 to integrin-type folds.\",\n      \"evidence\": \"Computational structural prediction, phylogenetic analysis, and database searches\",\n      \"pmids\": [\"20171266\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Purely computational with no experimental validation\", \"β-propeller fold not confirmed biochemically at this stage\", \"Functional consequence of fold relationship unaddressed\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Placed CRTAC1 upstream of ROS in a pyroptosis pathway, the first demonstration of a cell-signaling function for the protein.\",\n      \"evidence\": \"siRNA knockdown and overexpression in human lens epithelial cells with pyroptosis-marker western blotting and ROS-inhibitor rescue under UVB\",\n      \"pmids\": [\"32838966\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism linking CRTAC1 to ROS generation unknown\", \"No receptor or direct binding partner identified\", \"Generalizability beyond lens epithelial cells untested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified YY1 as a direct CRTAC1 partner and defined a tumor-suppressive axis in bladder cancer through YY1 downregulation and TGF-β inactivation.\",\n      \"evidence\": \"Reciprocal Co-IP, co-localization, ChIP, luciferase reporter, and functional proliferation/migration/invasion assays in bladder cancer cells\",\n      \"pmids\": [\"34818994\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No independent replication of the CRTAC1-YY1 interaction\", \"How a secreted ECM protein modulates a nuclear transcription factor mechanistically unclear\", \"Direct binding interface not mapped\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Explained how CRTAC1 is silenced in cancer, showing epigenetic repression via lncRNA-directed promoter methylation.\",\n      \"evidence\": \"ChIP-qPCR, luciferase reporter, methylation analysis, and rescue/knockdown experiments in bladder carcinoma cells with in vivo model\",\n      \"pmids\": [\"36410635\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Generalizability of this silencing mechanism to other tumors untested\", \"Upstream signals controlling TPRG1-AS1 only partly defined\", \"No structural detail of DNMT3A recruitment\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined a mechanistic chemosensitization pathway in NSCLC linking CRTAC1 to RyR-mediated Ca²⁺ release, NFAT, STUB1, and Akt1 degradation.\",\n      \"evidence\": \"Overexpression/knockdown, intracellular Ca²⁺ measurement, NFAT reporter, western blotting, and in vivo cisplatin tumor model\",\n      \"pmids\": [\"37633993\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How CRTAC1 triggers RyR-mediated calcium release mechanistically unknown\", \"Direct molecular partner upstream of Ca²⁺ flux unidentified\", \"Single-lab pathway without independent confirmation\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Determined the high-resolution three-domain β-propeller–TTR structure and its dependence on potassium for stability, providing the definitive structural framework for CRTAC1.\",\n      \"evidence\": \"X-ray crystallography at 1.6 Å with cysteine mutagenesis and tryptophan fluorescence\",\n      \"pmids\": [\"39029889\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for partner binding (YY1, NRF2, integrins) not resolved\", \"Physiological consequence of potassium-dependent cysteine exposure in vivo unknown\", \"Role of bound calcium ions in function untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended CRTAC1 functions to gastric cancer and to a ligament calcification cell-cell axis, broadening its disease contexts.\",\n      \"evidence\": \"siRNA knockdown with PI3K/AKT/mTOR pathway western blotting in gastric cancer cells; scRNA-seq and SCENIC inference of an SPP1-ATF3-CRTAC1/MGP/CLU axis in spinal ligaments\",\n      \"pmids\": [\"39725632\", \"39158018\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Gastric cancer findings rest on single knockdown without rescue\", \"Ligament axis is largely computational with limited experimental follow-up\", \"Direct mechanistic links remain unestablished\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified NRF2 as a direct CRTAC1 binding partner and defined a senescence-driven NRF2–SIRT3–FOXO3a–mitophagy axis driving chondrocyte dysfunction in osteoarthritis.\",\n      \"evidence\": \"scRNA-seq, in vitro CRTAC1-NRF2 binding assay, western blotting, SIRT3 conditional knockout, and intra-articular AAV-SIRT3 rescue in mice\",\n      \"pmids\": [\"41311393\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of CRTAC1-NRF2 binding unresolved\", \"How extracellular CRTAC1 accesses intracellular NRF2 unclear\", \"Single-lab mechanism without independent replication\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Demonstrated that CRTAC1 suppresses lung adenocarcinoma progression through integrin/FAK signaling, connecting its RGD/integrin-related features to tumor suppression.\",\n      \"evidence\": \"Overexpression/knockdown in LUAD cells with proliferation/migration/invasion assays, integrin/FAK western blotting, and in vivo tumor model\",\n      \"pmids\": [\"41708954\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct CRTAC1-integrin binding not demonstrated\", \"Role of the RGD motif in this signaling untested\", \"Single-lab finding without independent confirmation\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown how a single secreted ECM protein engages such mechanistically distinct intracellular targets (YY1, NRF2, RyR/Ca²⁺, integrin/FAK) and what unifying receptor or entry mechanism governs its context-dependent actions.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No defined cell-surface receptor linking secreted CRTAC1 to intracellular signaling\", \"Structural interfaces for named partners not mapped\", \"Determinants of cell-type-specific (tumor-suppressive vs degenerative) outcomes unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0005509\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"GO:0031012\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 6, 10]},\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [5, 6]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"YY1\",\n      \"NRF2\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":6,"faith_total":6,"faith_pct":100.0}}