{"gene":"ASPH","run_date":"2026-06-09T22:02:44","timeline":{"discoveries":[{"year":2000,"finding":"The mouse ASPH (BAH) gene encodes aspartyl β-hydroxylase, a catalytic enzyme, and shares exons with junctin (a calsequestrin-binding protein) and a noncatalytic isoform called humbug (lacking the catalytic domain); all three genes use separate promoters and alternative splicing from the same genomic locus of ~200 kb with 24 exons.","method":"Gene cloning, Northern blot, Western blot, monoclonal antibody epitope mapping, genomic characterization","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct molecular cloning, protein-level validation with monoclonal antibodies, and genomic characterization of exon sharing across three gene products in one rigorous study","pmids":["10956665"],"is_preprint":false},{"year":2014,"finding":"Homozygous loss-of-function mutations in ASPH (truncating and missense) cause Traboulsi syndrome (facial dysmorphism, lens dislocation, anterior-segment abnormalities, spontaneous filtering blebs); the mutations are predicted to severely impair the enzymatic hydroxylase function of ASPH, and Asph-knockout mice show foreshortened snout phenotype consistent with the human syndrome.","method":"Autozygosity mapping, whole-exome sequencing, Sanger sequencing, Asph-knockout mouse model, developmental expression analysis","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic mapping, human mutations, and orthogonal knockout mouse model all independently confirm loss-of-function phenotype","pmids":["24768550"],"is_preprint":false},{"year":2018,"finding":"The hydroxylase catalytic activity of ASPH (not merely its expression) is required for promoting hepatocellular carcinoma (HCC) cell migration and EMT in vitro and intrahepatic/distant metastasis in vivo; a hydroxylase-dead ASPH mutant fails to promote migration. ASPH physically interacts with vimentin, an EMT regulator, and this interaction mediates its pro-migratory effect.","method":"Wild-type vs. hydroxylase mutant overexpression, cell migration assay, in vivo metastasis model, co-immunoprecipitation with vimentin","journal":"EBioMedicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — catalytic mutant rescue experiment plus co-IP with vimentin, single lab","pmids":["29764768"],"is_preprint":false},{"year":2019,"finding":"ASPH physically interacts with Notch receptors, Notch ligands (JAGs), and Notch regulators (ADAM10/17) to activate the Notch signaling cascade; this activation provides substrates (especially MMPs/ADAMs) for synthesis and release of pro-metastatic exosomes. Small molecule inhibitors (SMIs) of ASPH's β-hydroxylase activity abrogate these effects.","method":"Co-immunoprecipitation, Western blot, lentiviral overexpression and CRISPR-KO stable lines, luciferase reporter, 2D/3D invasion assay, orthotopic and tail vein mouse models","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP for physical interactions and CRISPR-KO with in vivo validation, single lab with multiple orthogonal methods","pmids":["31694640"],"is_preprint":false},{"year":2022,"finding":"Rare heterozygous pathogenic variants in ASPH, which encodes junctin (a regulator of excitation-contraction coupling), cause exertional heat illness and malignant hyperthermia susceptibility; pathogenicity was validated in CRISPR-edited C2C12 myotubes and transgenic zebrafish.","method":"Genomic sequencing, CRISPR-edited C2C12 myotubes, transgenic zebrafish models","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — orthogonal pre-clinical models (cell and zebrafish) validate human variant pathogenicity","pmids":["35697689"],"is_preprint":false},{"year":2019,"finding":"Bioinformatic analysis identified 105 putative ASPH hydroxylation substrates in the human proteome; among these, fibrillin-1 (FBN1) and LTBP2—both associated with inherited ectopia lentis—contain the ASPH hydroxylation motif and are essential for microfibril and ciliary zonule development, implicating ASPH-mediated hydroxylation in zonule formation and lens stability.","method":"Exome sequencing of proband, bioinformatic motif search in SwissProt database","journal":"Ophthalmic genetics","confidence":"Low","confidence_rationale":"Tier 4 / Weak — computational substrate prediction without in vitro hydroxylation validation","pmids":["30600741"],"is_preprint":false},{"year":2024,"finding":"AspH (ASPH) catalyzes stereoselective (3R)-hydroxylation of aspartyl- and asparaginyl-residues via a dioxygen activation–HAT–rebound hydroxylation mechanism. Unusually for 2OG hydroxylases, AspH lacks the standard Asp/Glu of the His-His-Asp/Glu Fe-binding triad; instead, a water molecule stabilized by second-coordination-sphere residue Asp721 coordinates Fe(II). The rebound hydroxylation step (not HAT) is rate-limiting. The TPR domain influences substrate binding and undergoes dynamic motions during catalysis.","method":"Molecular dynamics (MD), quantum mechanics/molecular mechanics (QM/MM), analysis of published crystal structures","journal":"Chemical science","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — QM/MM mechanistic modeling with structural validation from crystallography, single computational study","pmids":["38455014"],"is_preprint":false},{"year":2024,"finding":"Clinical mutations in second-coordination-sphere (R735W, R735Q, R688Q) and long-range (G434V) residues of AspH alter binding interactions with co-substrate 2-oxoglutarate and substrate in ferryl complexes, and change activation energies for the HAT step, compared to wild-type. These mutations are linked to Traboulsi syndrome and chronic kidney disease.","method":"QM/MM and MD computational analysis of mutant vs. wild-type AspH","journal":"Chemphyschem","confidence":"Low","confidence_rationale":"Tier 4 / Weak — computational study only, no in vitro biochemical validation reported","pmids":["38839574"],"is_preprint":false},{"year":2022,"finding":"INPP5F interacts physically with ASPH (co-immunoprecipitation) and activates the Notch signaling pathway via this interaction to upregulate c-MYC and cyclin E1, promoting HCC cell proliferation; cytoplasmic translocation of INPP5F (regulated by NES/NLS signals) is required for this ASPH-mediated Notch activation.","method":"Co-immunoprecipitation, mass spectrometry, immunofluorescence, transcriptome sequencing, nuclear export inhibitor (LMB) treatment, NLS/NES mutagenesis","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP plus mass spectrometry, multiple orthogonal methods in single lab","pmids":["34996491"],"is_preprint":false},{"year":2024,"finding":"ASPH upregulates SQSTM1/P62 and the SLC7A11-GPX4 axis, thereby promoting autophagy but blocking ferroptosis in HCC cells; ASPH knockout sensitizes HCC cells to sorafenib by attenuating autophagy and enabling senescence, apoptosis, and ferroptosis. ASPH promotes tumor growth and metastasis in vivo.","method":"ASPH knockout (KO), Western blot, cell viability assay, in vivo HCC mouse models (intrahepatic, pulmonary, splenic metastasis)","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO with defined molecular pathway readouts plus in vivo validation, single lab","pmids":["39706251"],"is_preprint":false},{"year":2020,"finding":"ASPH regulates osteogenic differentiation and cellular senescence of bone marrow mesenchymal stem cells (BMSCs) through Wnt signaling mediated by GSK3β; depletion of Asph suppressed osteogenic differentiation and accelerated senescence, while overexpression had the opposite effect.","method":"Asph depletion and overexpression in BMSCs, osteogenic differentiation assay, Western blot for GSK3β/Wnt pathway components","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function and gain-of-function with pathway-level molecular readout, single lab","pmids":["33015050"],"is_preprint":false},{"year":2023,"finding":"ASPH overexpression promotes epithelial-to-mesenchymal transition (EMT) and metastasis in intrahepatic cholangiocarcinoma cells via a GSK3β/SHH/GLI2 axis: ASPH overexpression decreases phospho-GSK3β and upregulates SHH signaling elements GLI2 and SUFU. Knockdown of ASPH inhibits migration and invasion.","method":"Western blot, wound healing assay, transwell assay, immunofluorescence, nude mouse lung metastasis model","journal":"Current protein & peptide science","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, correlative Western blot-based pathway analysis without direct mechanistic validation of ASPH–GSK3β interaction","pmids":["37132101"],"is_preprint":false},{"year":2025,"finding":"ASPH interacts physically with RUVBL2 (identified by immunoprecipitation combined with mass spectrometry) and enhances activation of MAPK and Notch signaling pathways through this interaction to promote lung adenocarcinoma cell migration and metastasis.","method":"Immunoprecipitation combined with mass spectrometry (IP-MS), transcriptome sequencing, Transwell/scratch healing assay, murine lung metastasis model","journal":"Frontiers of medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — IP-MS identification of binding partner with in vivo functional validation, single lab","pmids":["41454078"],"is_preprint":false},{"year":2025,"finding":"HRASLS2 interacts with ASPH protein (co-immunoprecipitation) and increases ASPH protein stability; ASPH overexpression reverses the inhibitory effects of HRASLS2 knockdown on pancreatic cancer cell growth and glycolysis, placing ASPH downstream of HRASLS2 in a stability-dependent pathway.","method":"Co-immunoprecipitation, HRASLS2 knockdown and ASPH overexpression rescue, cell growth and glycolysis assays (glucose consumption, lactate, ECAR), xenograft model","journal":"Naunyn-Schmiedeberg's archives of pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus epistasis rescue experiment and in vivo xenograft, single lab","pmids":["40833600"],"is_preprint":false}],"current_model":"ASPH (aspartyl/asparaginyl β-hydroxylase) is a type II transmembrane, non-heme Fe(II)/2-oxoglutarate-dependent dioxygenase that stereoselectively hydroxylates aspartyl and asparaginyl residues in EGF-domain-containing proteins (including fibrillin-1, coagulation factors, and Notch pathway ligands/receptors) via an unusual two-His/water Fe-coordination mechanism with rate-limiting rebound hydroxylation; its catalytic activity activates Notch signaling (through physical interactions with Notch receptors, JAG ligands, and ADAM10/17), drives EMT via vimentin interaction, promotes autophagy while suppressing ferroptosis through the SQSTM1/P62 and SLC7A11-GPX4 axes, and regulates Wnt/GSK3β signaling in mesenchymal stem cells; loss-of-function mutations cause Traboulsi syndrome (ectopia lentis, facial dysmorphism) and, through its junctin isoform, malignant hyperthermia susceptibility, underscoring its dual roles in development and oncogenesis."},"narrative":{"mechanistic_narrative":"ASPH is the catalytic aspartyl/asparaginyl β-hydroxylase encoded together with the calsequestrin-binding isoform junctin and the noncatalytic isoform humbug from a single ~200 kb locus that uses separate promoters and alternative splicing [PMID:10956665]. As a 2-oxoglutarate-dependent dioxygenase, ASPH performs stereoselective (3R)-hydroxylation of aspartyl/asparaginyl residues through dioxygen activation, hydrogen-atom transfer, and a rate-limiting rebound step, employing an atypical Fe(II) coordination in which a water molecule stabilized by the second-sphere residue Asp721 substitutes for the usual His-His-Asp/Glu triad, with the TPR domain shaping substrate binding [PMID:38455014]. This catalytic activity, not mere expression, drives cancer cell migration, EMT, and metastasis, as a hydroxylase-dead mutant fails to promote migration and ASPH physically engages the EMT regulator vimentin [PMID:29764768]. Mechanistically, ASPH operates as a hub for oncogenic signaling: it interacts with Notch receptors, JAG ligands, and ADAM10/17 to activate Notch and license pro-metastatic exosome release [PMID:31694640], cooperates with INPP5F to amplify Notch-driven c-MYC/cyclin E1 expression and proliferation [PMID:34996491], and partners with RUVBL2 to enhance MAPK and Notch signaling in lung adenocarcinoma [PMID:41454078]. ASPH additionally upregulates SQSTM1/p62 and the SLC7A11-GPX4 axis to promote autophagy while suppressing ferroptosis, and its loss sensitizes hepatocellular carcinoma to sorafenib [PMID:39706251], and it regulates osteogenic differentiation and senescence of mesenchymal stem cells through GSK3β/Wnt signaling [PMID:33015050]. Genetically, homozygous loss-of-function mutations that impair hydroxylase activity cause Traboulsi syndrome (facial dysmorphism, lens dislocation, anterior-segment abnormalities), recapitulated by Asph-knockout mice [PMID:24768550], while rare heterozygous variants acting through the junctin isoform cause exertional heat illness and malignant hyperthermia susceptibility [PMID:35697689].","teleology":[{"year":2000,"claim":"Established that one genomic locus produces three functionally distinct products—the catalytic hydroxylase ASPH, the calsequestrin-binding junctin, and the noncatalytic humbug—resolving how a single gene contributes to both enzymatic and structural roles.","evidence":"Gene cloning, Northern/Western blot, monoclonal antibody epitope mapping, and genomic characterization in mouse","pmids":["10956665"],"confidence":"High","gaps":["Tissue-specific regulation of the three promoters not defined","Physiological substrates of the catalytic isoform not identified at this stage"]},{"year":2014,"claim":"Demonstrated that loss of ASPH hydroxylase function causes a defined human developmental disorder, linking the enzyme to anterior-segment and craniofacial development.","evidence":"Autozygosity mapping, whole-exome sequencing, and an Asph-knockout mouse with foreshortened-snout phenotype","pmids":["24768550"],"confidence":"High","gaps":["Direct hydroxylation substrates responsible for the lens/zonule phenotype not biochemically validated","Mechanism connecting hydroxylase loss to ectopia lentis unresolved"]},{"year":2018,"claim":"Distinguished catalytic activity from expression as the driver of metastatic behavior, showing the enzyme's hydroxylase function is required for migration and EMT.","evidence":"Wild-type vs. hydroxylase-dead mutant overexpression with migration/metastasis assays and co-IP with vimentin in HCC","pmids":["29764768"],"confidence":"Medium","gaps":["Whether vimentin is a direct hydroxylation substrate unproven","Single-lab co-IP without reciprocal structural mapping"]},{"year":2019,"claim":"Defined ASPH as an upstream activator of Notch signaling via physical engagement of receptors, JAG ligands, and ADAM10/17, linking it to a druggable pro-metastatic exosome program.","evidence":"Co-IP, CRISPR-KO and overexpression lines, luciferase reporter, invasion assays, and orthotopic/tail-vein mouse models with small-molecule inhibitors","pmids":["31694640"],"confidence":"Medium","gaps":["Direct hydroxylation of Notch-pathway substrates not demonstrated","Single lab; SMI specificity not orthogonally confirmed"]},{"year":2019,"claim":"Proposed FBN1 and LTBP2 as ASPH substrates linking hydroxylation to microfibril and ciliary zonule formation, offering a molecular hypothesis for the lens phenotype.","evidence":"Exome sequencing of a proband plus bioinformatic hydroxylation-motif search in SwissProt","pmids":["30600741"],"confidence":"Low","gaps":["Computational prediction without in vitro hydroxylation validation","No demonstration that ASPH hydroxylates FBN1/LTBP2 in cells"]},{"year":2020,"claim":"Extended ASPH function to stem-cell biology, showing it controls osteogenic differentiation and senescence through GSK3β/Wnt signaling.","evidence":"Asph depletion and overexpression in BMSCs with differentiation assays and GSK3β/Wnt Western blots","pmids":["33015050"],"confidence":"Medium","gaps":["Direct molecular link between ASPH and GSK3β not established","Whether the effect requires hydroxylase activity untested"]},{"year":2022,"claim":"Identified INPP5F as a partner that requires cytoplasmic translocation to drive ASPH-mediated Notch activation and proliferation, adding a regulatory layer to ASPH-Notch signaling.","evidence":"Reciprocal co-IP, mass spectrometry, immunofluorescence, NLS/NES mutagenesis, and LMB treatment in HCC","pmids":["34996491"],"confidence":"Medium","gaps":["How INPP5F mechanistically potentiates ASPH catalysis unknown","Single-lab interaction data"]},{"year":2022,"claim":"Established that heterozygous ASPH variants acting through the junctin isoform cause exertional heat illness and malignant hyperthermia susceptibility, demonstrating a distinct excitation-contraction-coupling disease mechanism.","evidence":"Genomic sequencing with validation in CRISPR-edited C2C12 myotubes and transgenic zebrafish","pmids":["35697689"],"confidence":"High","gaps":["Precise effect of variants on junctin-calsequestrin/RyR coupling not fully resolved","Relationship to the catalytic isoform's functions not addressed"]},{"year":2023,"claim":"Linked ASPH to a GSK3β/SHH/GLI2 axis driving EMT and metastasis in cholangiocarcinoma, broadening its oncogenic signaling reach.","evidence":"Western blot, wound-healing/transwell assays, and a nude-mouse lung metastasis model","pmids":["37132101"],"confidence":"Low","gaps":["Correlative Western-blot analysis without direct ASPH-GSK3β interaction validation","Causality of the SHH/GLI2 axis not mechanistically dissected"]},{"year":2024,"claim":"Resolved the atypical catalytic mechanism, showing ASPH uses a water-mediated Fe(II) coordination via second-sphere Asp721 in place of the canonical triad, with rebound hydroxylation rate-limiting.","evidence":"MD and QM/MM modeling built on published crystal structures","pmids":["38455014"],"confidence":"Medium","gaps":["Computational model not confirmed by enzyme kinetics or mutagenesis here","TPR-domain dynamics during substrate turnover not experimentally validated"]},{"year":2024,"claim":"Connected ASPH to redox and survival control, showing it promotes autophagy and suppresses ferroptosis via SQSTM1/p62 and SLC7A11-GPX4, with loss sensitizing tumors to sorafenib.","evidence":"ASPH knockout with Western blot, viability assays, and intrahepatic/pulmonary/splenic metastasis mouse models","pmids":["39706251"],"confidence":"Medium","gaps":["Whether the autophagy/ferroptosis effects depend on hydroxylase activity untested","Direct substrate within the SLC7A11-GPX4 axis not identified"]},{"year":2024,"claim":"Modeled how clinical second-sphere and long-range mutations perturb 2OG/substrate binding and HAT activation energies, offering a structural rationale for disease-linked variants.","evidence":"QM/MM and MD computational analysis of mutant vs. wild-type AspH","pmids":["38839574"],"confidence":"Low","gaps":["No in vitro biochemical validation of altered activity","Clinical genotype-phenotype correlations not experimentally tested"]},{"year":2025,"claim":"Identified RUVBL2 and HRASLS2 as new ASPH partners, the former amplifying MAPK/Notch signaling and the latter stabilizing ASPH protein, expanding the regulatory network around ASPH in lung and pancreatic cancers.","evidence":"IP-MS and co-IP with epistasis rescue, metabolic/glycolysis assays, and murine metastasis/xenograft models","pmids":["41454078","40833600"],"confidence":"Medium","gaps":["Mechanism by which RUVBL2 enhances signaling not defined","How HRASLS2 stabilizes ASPH (e.g., ubiquitination) not resolved","Single-lab interaction data each"]},{"year":null,"claim":"The direct physiological hydroxylation substrates that link ASPH catalysis to its developmental phenotypes and oncogenic signaling outputs remain experimentally unconfirmed.","evidence":"","pmids":[],"confidence":"Low","gaps":["No validated endogenous substrate ties hydroxylase activity to Notch, EMT, or zonule defects","Whether protein-interaction effects require catalytic activity largely untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016491","term_label":"oxidoreductase activity","supporting_discovery_ids":[0,6]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[2,6]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[6]}],"localization":[],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,8,12]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[1,10]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[1,4]}],"complexes":[],"partners":["VIM","NOTCH","JAG1","ADAM10","ADAM17","INPP5F","RUVBL2","HRASLS2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q12797","full_name":"Aspartyl/asparaginyl beta-hydroxylase","aliases":["Aspartate beta-hydroxylase","ASP beta-hydroxylase","Peptide-aspartate beta-dioxygenase"],"length_aa":758,"mass_kda":85.9,"function":"Specifically hydroxylates an Asp or Asn residue in certain epidermal growth factor-like (EGF) domains of a number of proteins Membrane-bound Ca(2+)-sensing protein, which is a structural component of the ER-plasma membrane junctions. Isoform 8 regulates the activity of Ca(+2) released-activated Ca(+2) (CRAC) channels in T-cells","subcellular_location":"Endoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/Q12797/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ASPH","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":[{"gene":"CANX","stoichiometry":0.2},{"gene":"CDS2","stoichiometry":0.2},{"gene":"DDOST","stoichiometry":0.2},{"gene":"OST4","stoichiometry":0.2},{"gene":"RPS16","stoichiometry":0.2},{"gene":"SEC61B","stoichiometry":0.2},{"gene":"SRPRA","stoichiometry":0.2},{"gene":"TMED10","stoichiometry":0.2},{"gene":"VAPA","stoichiometry":0.2},{"gene":"VAPB","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/ASPH","total_profiled":1310},"omim":[{"mim_id":"615441","title":"CARDIAC ARRHYTHMIA SYNDROME, WITH OR WITHOUT SKELETAL MUSCLE WEAKNESS; CARDAR","url":"https://www.omim.org/entry/615441"},{"mim_id":"603283","title":"TRIADIN; TRDN","url":"https://www.omim.org/entry/603283"},{"mim_id":"601552","title":"TRABOULSI SYNDROME","url":"https://www.omim.org/entry/601552"},{"mim_id":"600582","title":"ASPARTATE BETA-HYDROXYLASE; ASPH","url":"https://www.omim.org/entry/600582"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Endoplasmic reticulum","reliability":"Enhanced"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"adipose tissue","ntpm":362.0}],"url":"https://www.proteinatlas.org/search/ASPH"},"hgnc":{"alias_symbol":["CASQ2BP1","BAH","JCTN","HAAH"],"prev_symbol":[]},"alphafold":{"accession":"Q12797","domains":[{"cath_id":"1.25.40.10","chopping":"342-554","consensus_level":"medium","plddt":95.5228,"start":342,"end":554},{"cath_id":"2.60.120.330","chopping":"576-755","consensus_level":"high","plddt":96.2754,"start":576,"end":755}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q12797","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q12797-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q12797-F1-predicted_aligned_error_v6.png","plddt_mean":71.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ASPH","jax_strain_url":"https://www.jax.org/strain/search?query=ASPH"},"sequence":{"accession":"Q12797","fasta_url":"https://rest.uniprot.org/uniprotkb/Q12797.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q12797/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q12797"}},"corpus_meta":[{"pmid":"22398447","id":"PMC_22398447","title":"The BAH domain of ORC1 links H4K20me2 to DNA replication licensing and Meier-Gorlin syndrome.","date":"2012","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/22398447","citation_count":285,"is_preprint":false},{"pmid":"22096199","id":"PMC_22096199","title":"Structural basis of silencing: Sir3 BAH domain in complex with a nucleosome at 3.0 Å resolution.","date":"2011","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/22096199","citation_count":208,"is_preprint":false},{"pmid":"10619019","id":"PMC_10619019","title":"Two functionally distinct forms of the RSC nucleosome-remodeling complex, containing essential AT hook, BAH, and bromodomains.","date":"1999","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/10619019","citation_count":182,"is_preprint":false},{"pmid":"10100640","id":"PMC_10100640","title":"The BAH (bromo-adjacent homology) domain: a link between DNA methylation, replication and transcriptional regulation.","date":"1999","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/10100640","citation_count":161,"is_preprint":false},{"pmid":"10956665","id":"PMC_10956665","title":"Aspartyl beta -hydroxylase (Asph) and an evolutionarily conserved isoform of Asph missing the catalytic domain share exons with junctin.","date":"2000","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10956665","citation_count":96,"is_preprint":false},{"pmid":"30082786","id":"PMC_30082786","title":"Polycomb-mediated gene silencing by the BAH-EMF1 complex in plants.","date":"2018","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/30082786","citation_count":84,"is_preprint":false},{"pmid":"33139953","id":"PMC_33139953","title":"BAHCC1 binds H3K27me3 via a conserved BAH module to mediate gene silencing and oncogenesis.","date":"2020","source":"Nature 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journal of the International Society on Toxinology","url":"https://pubmed.ncbi.nlm.nih.gov/8053003","citation_count":47,"is_preprint":false},{"pmid":"11368894","id":"PMC_11368894","title":"The BAH domain, polybromo and the RSC chromatin remodelling complex.","date":"2001","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/11368894","citation_count":39,"is_preprint":false},{"pmid":"30179586","id":"PMC_30179586","title":"Recent advances in research on aspartate β-hydroxylase (ASPH) in pancreatic cancer: A brief update.","date":"2018","source":"Bosnian journal of basic medical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/30179586","citation_count":38,"is_preprint":false},{"pmid":"19273586","id":"PMC_19273586","title":"Mutational analysis of the Sir3 BAH domain reveals multiple points of interaction with nucleosomes.","date":"2009","source":"Molecular and cellular 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Yi xue ban = Journal of Sichuan University. 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zi mian yi xue za zhi = Chinese journal of cellular and molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/20423655","citation_count":0,"is_preprint":false},{"pmid":"36425649","id":"PMC_36425649","title":"The inhibitory effect of human umbilical cord mesenchymal stem cells expressing anti-HAAH scFv-sTRAIL fusion protein on glioma.","date":"2022","source":"Frontiers in bioengineering and biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/36425649","citation_count":0,"is_preprint":false},{"pmid":"41993253","id":"PMC_41993253","title":"Enteroviral epitope mimicry enables NK cell-mediated targeting of ASPH in hepatocellular carcinoma.","date":"2026","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/41993253","citation_count":0,"is_preprint":false},{"pmid":"40571906","id":"PMC_40571906","title":"Opposite Effects of Added AsPh3 Reveal a Drastic Mechanistic Switch in RhI/AuI Transmetalations via Rh-Au Bonded 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~200 kb with 24 exons.\",\n      \"method\": \"Gene cloning, Northern blot, Western blot, monoclonal antibody epitope mapping, genomic characterization\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct molecular cloning, protein-level validation with monoclonal antibodies, and genomic characterization of exon sharing across three gene products in one rigorous study\",\n      \"pmids\": [\"10956665\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Homozygous loss-of-function mutations in ASPH (truncating and missense) cause Traboulsi syndrome (facial dysmorphism, lens dislocation, anterior-segment abnormalities, spontaneous filtering blebs); the mutations are predicted to severely impair the enzymatic hydroxylase function of ASPH, and Asph-knockout mice show foreshortened snout phenotype consistent with the human syndrome.\",\n      \"method\": \"Autozygosity mapping, whole-exome sequencing, Sanger sequencing, Asph-knockout mouse model, developmental expression analysis\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic mapping, human mutations, and orthogonal knockout mouse model all independently confirm loss-of-function phenotype\",\n      \"pmids\": [\"24768550\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The hydroxylase catalytic activity of ASPH (not merely its expression) is required for promoting hepatocellular carcinoma (HCC) cell migration and EMT in vitro and intrahepatic/distant metastasis in vivo; a hydroxylase-dead ASPH mutant fails to promote migration. ASPH physically interacts with vimentin, an EMT regulator, and this interaction mediates its pro-migratory effect.\",\n      \"method\": \"Wild-type vs. hydroxylase mutant overexpression, cell migration assay, in vivo metastasis model, co-immunoprecipitation with vimentin\",\n      \"journal\": \"EBioMedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — catalytic mutant rescue experiment plus co-IP with vimentin, single lab\",\n      \"pmids\": [\"29764768\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ASPH physically interacts with Notch receptors, Notch ligands (JAGs), and Notch regulators (ADAM10/17) to activate the Notch signaling cascade; this activation provides substrates (especially MMPs/ADAMs) for synthesis and release of pro-metastatic exosomes. Small molecule inhibitors (SMIs) of ASPH's β-hydroxylase activity abrogate these effects.\",\n      \"method\": \"Co-immunoprecipitation, Western blot, lentiviral overexpression and CRISPR-KO stable lines, luciferase reporter, 2D/3D invasion assay, orthotopic and tail vein mouse models\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP for physical interactions and CRISPR-KO with in vivo validation, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"31694640\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Rare heterozygous pathogenic variants in ASPH, which encodes junctin (a regulator of excitation-contraction coupling), cause exertional heat illness and malignant hyperthermia susceptibility; pathogenicity was validated in CRISPR-edited C2C12 myotubes and transgenic zebrafish.\",\n      \"method\": \"Genomic sequencing, CRISPR-edited C2C12 myotubes, transgenic zebrafish models\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — orthogonal pre-clinical models (cell and zebrafish) validate human variant pathogenicity\",\n      \"pmids\": [\"35697689\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Bioinformatic analysis identified 105 putative ASPH hydroxylation substrates in the human proteome; among these, fibrillin-1 (FBN1) and LTBP2—both associated with inherited ectopia lentis—contain the ASPH hydroxylation motif and are essential for microfibril and ciliary zonule development, implicating ASPH-mediated hydroxylation in zonule formation and lens stability.\",\n      \"method\": \"Exome sequencing of proband, bioinformatic motif search in SwissProt database\",\n      \"journal\": \"Ophthalmic genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — computational substrate prediction without in vitro hydroxylation validation\",\n      \"pmids\": [\"30600741\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"AspH (ASPH) catalyzes stereoselective (3R)-hydroxylation of aspartyl- and asparaginyl-residues via a dioxygen activation–HAT–rebound hydroxylation mechanism. Unusually for 2OG hydroxylases, AspH lacks the standard Asp/Glu of the His-His-Asp/Glu Fe-binding triad; instead, a water molecule stabilized by second-coordination-sphere residue Asp721 coordinates Fe(II). The rebound hydroxylation step (not HAT) is rate-limiting. The TPR domain influences substrate binding and undergoes dynamic motions during catalysis.\",\n      \"method\": \"Molecular dynamics (MD), quantum mechanics/molecular mechanics (QM/MM), analysis of published crystal structures\",\n      \"journal\": \"Chemical science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — QM/MM mechanistic modeling with structural validation from crystallography, single computational study\",\n      \"pmids\": [\"38455014\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Clinical mutations in second-coordination-sphere (R735W, R735Q, R688Q) and long-range (G434V) residues of AspH alter binding interactions with co-substrate 2-oxoglutarate and substrate in ferryl complexes, and change activation energies for the HAT step, compared to wild-type. These mutations are linked to Traboulsi syndrome and chronic kidney disease.\",\n      \"method\": \"QM/MM and MD computational analysis of mutant vs. wild-type AspH\",\n      \"journal\": \"Chemphyschem\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — computational study only, no in vitro biochemical validation reported\",\n      \"pmids\": [\"38839574\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"INPP5F interacts physically with ASPH (co-immunoprecipitation) and activates the Notch signaling pathway via this interaction to upregulate c-MYC and cyclin E1, promoting HCC cell proliferation; cytoplasmic translocation of INPP5F (regulated by NES/NLS signals) is required for this ASPH-mediated Notch activation.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, immunofluorescence, transcriptome sequencing, nuclear export inhibitor (LMB) treatment, NLS/NES mutagenesis\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP plus mass spectrometry, multiple orthogonal methods in single lab\",\n      \"pmids\": [\"34996491\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ASPH upregulates SQSTM1/P62 and the SLC7A11-GPX4 axis, thereby promoting autophagy but blocking ferroptosis in HCC cells; ASPH knockout sensitizes HCC cells to sorafenib by attenuating autophagy and enabling senescence, apoptosis, and ferroptosis. ASPH promotes tumor growth and metastasis in vivo.\",\n      \"method\": \"ASPH knockout (KO), Western blot, cell viability assay, in vivo HCC mouse models (intrahepatic, pulmonary, splenic metastasis)\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO with defined molecular pathway readouts plus in vivo validation, single lab\",\n      \"pmids\": [\"39706251\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ASPH regulates osteogenic differentiation and cellular senescence of bone marrow mesenchymal stem cells (BMSCs) through Wnt signaling mediated by GSK3β; depletion of Asph suppressed osteogenic differentiation and accelerated senescence, while overexpression had the opposite effect.\",\n      \"method\": \"Asph depletion and overexpression in BMSCs, osteogenic differentiation assay, Western blot for GSK3β/Wnt pathway components\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function and gain-of-function with pathway-level molecular readout, single lab\",\n      \"pmids\": [\"33015050\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ASPH overexpression promotes epithelial-to-mesenchymal transition (EMT) and metastasis in intrahepatic cholangiocarcinoma cells via a GSK3β/SHH/GLI2 axis: ASPH overexpression decreases phospho-GSK3β and upregulates SHH signaling elements GLI2 and SUFU. Knockdown of ASPH inhibits migration and invasion.\",\n      \"method\": \"Western blot, wound healing assay, transwell assay, immunofluorescence, nude mouse lung metastasis model\",\n      \"journal\": \"Current protein & peptide science\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, correlative Western blot-based pathway analysis without direct mechanistic validation of ASPH–GSK3β interaction\",\n      \"pmids\": [\"37132101\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ASPH interacts physically with RUVBL2 (identified by immunoprecipitation combined with mass spectrometry) and enhances activation of MAPK and Notch signaling pathways through this interaction to promote lung adenocarcinoma cell migration and metastasis.\",\n      \"method\": \"Immunoprecipitation combined with mass spectrometry (IP-MS), transcriptome sequencing, Transwell/scratch healing assay, murine lung metastasis model\",\n      \"journal\": \"Frontiers of medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — IP-MS identification of binding partner with in vivo functional validation, single lab\",\n      \"pmids\": [\"41454078\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"HRASLS2 interacts with ASPH protein (co-immunoprecipitation) and increases ASPH protein stability; ASPH overexpression reverses the inhibitory effects of HRASLS2 knockdown on pancreatic cancer cell growth and glycolysis, placing ASPH downstream of HRASLS2 in a stability-dependent pathway.\",\n      \"method\": \"Co-immunoprecipitation, HRASLS2 knockdown and ASPH overexpression rescue, cell growth and glycolysis assays (glucose consumption, lactate, ECAR), xenograft model\",\n      \"journal\": \"Naunyn-Schmiedeberg's archives of pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus epistasis rescue experiment and in vivo xenograft, single lab\",\n      \"pmids\": [\"40833600\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ASPH (aspartyl/asparaginyl β-hydroxylase) is a type II transmembrane, non-heme Fe(II)/2-oxoglutarate-dependent dioxygenase that stereoselectively hydroxylates aspartyl and asparaginyl residues in EGF-domain-containing proteins (including fibrillin-1, coagulation factors, and Notch pathway ligands/receptors) via an unusual two-His/water Fe-coordination mechanism with rate-limiting rebound hydroxylation; its catalytic activity activates Notch signaling (through physical interactions with Notch receptors, JAG ligands, and ADAM10/17), drives EMT via vimentin interaction, promotes autophagy while suppressing ferroptosis through the SQSTM1/P62 and SLC7A11-GPX4 axes, and regulates Wnt/GSK3β signaling in mesenchymal stem cells; loss-of-function mutations cause Traboulsi syndrome (ectopia lentis, facial dysmorphism) and, through its junctin isoform, malignant hyperthermia susceptibility, underscoring its dual roles in development and oncogenesis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ASPH is the catalytic aspartyl/asparaginyl \\u03b2-hydroxylase encoded together with the calsequestrin-binding isoform junctin and the noncatalytic isoform humbug from a single ~200 kb locus that uses separate promoters and alternative splicing [#0]. As a 2-oxoglutarate-dependent dioxygenase, ASPH performs stereoselective (3R)-hydroxylation of aspartyl/asparaginyl residues through dioxygen activation, hydrogen-atom transfer, and a rate-limiting rebound step, employing an atypical Fe(II) coordination in which a water molecule stabilized by the second-sphere residue Asp721 substitutes for the usual His-His-Asp/Glu triad, with the TPR domain shaping substrate binding [#6]. This catalytic activity, not mere expression, drives cancer cell migration, EMT, and metastasis, as a hydroxylase-dead mutant fails to promote migration and ASPH physically engages the EMT regulator vimentin [#2]. Mechanistically, ASPH operates as a hub for oncogenic signaling: it interacts with Notch receptors, JAG ligands, and ADAM10/17 to activate Notch and license pro-metastatic exosome release [#3], cooperates with INPP5F to amplify Notch-driven c-MYC/cyclin E1 expression and proliferation [#8], and partners with RUVBL2 to enhance MAPK and Notch signaling in lung adenocarcinoma [#12]. ASPH additionally upregulates SQSTM1/p62 and the SLC7A11-GPX4 axis to promote autophagy while suppressing ferroptosis, and its loss sensitizes hepatocellular carcinoma to sorafenib [#9], and it regulates osteogenic differentiation and senescence of mesenchymal stem cells through GSK3\\u03b2/Wnt signaling [#10]. Genetically, homozygous loss-of-function mutations that impair hydroxylase activity cause Traboulsi syndrome (facial dysmorphism, lens dislocation, anterior-segment abnormalities), recapitulated by Asph-knockout mice [#1], while rare heterozygous variants acting through the junctin isoform cause exertional heat illness and malignant hyperthermia susceptibility [#4].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established that one genomic locus produces three functionally distinct products\\u2014the catalytic hydroxylase ASPH, the calsequestrin-binding junctin, and the noncatalytic humbug\\u2014resolving how a single gene contributes to both enzymatic and structural roles.\",\n      \"evidence\": \"Gene cloning, Northern/Western blot, monoclonal antibody epitope mapping, and genomic characterization in mouse\",\n      \"pmids\": [\"10956665\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tissue-specific regulation of the three promoters not defined\", \"Physiological substrates of the catalytic isoform not identified at this stage\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrated that loss of ASPH hydroxylase function causes a defined human developmental disorder, linking the enzyme to anterior-segment and craniofacial development.\",\n      \"evidence\": \"Autozygosity mapping, whole-exome sequencing, and an Asph-knockout mouse with foreshortened-snout phenotype\",\n      \"pmids\": [\"24768550\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct hydroxylation substrates responsible for the lens/zonule phenotype not biochemically validated\", \"Mechanism connecting hydroxylase loss to ectopia lentis unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Distinguished catalytic activity from expression as the driver of metastatic behavior, showing the enzyme's hydroxylase function is required for migration and EMT.\",\n      \"evidence\": \"Wild-type vs. hydroxylase-dead mutant overexpression with migration/metastasis assays and co-IP with vimentin in HCC\",\n      \"pmids\": [\"29764768\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether vimentin is a direct hydroxylation substrate unproven\", \"Single-lab co-IP without reciprocal structural mapping\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined ASPH as an upstream activator of Notch signaling via physical engagement of receptors, JAG ligands, and ADAM10/17, linking it to a druggable pro-metastatic exosome program.\",\n      \"evidence\": \"Co-IP, CRISPR-KO and overexpression lines, luciferase reporter, invasion assays, and orthotopic/tail-vein mouse models with small-molecule inhibitors\",\n      \"pmids\": [\"31694640\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct hydroxylation of Notch-pathway substrates not demonstrated\", \"Single lab; SMI specificity not orthogonally confirmed\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Proposed FBN1 and LTBP2 as ASPH substrates linking hydroxylation to microfibril and ciliary zonule formation, offering a molecular hypothesis for the lens phenotype.\",\n      \"evidence\": \"Exome sequencing of a proband plus bioinformatic hydroxylation-motif search in SwissProt\",\n      \"pmids\": [\"30600741\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Computational prediction without in vitro hydroxylation validation\", \"No demonstration that ASPH hydroxylates FBN1/LTBP2 in cells\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Extended ASPH function to stem-cell biology, showing it controls osteogenic differentiation and senescence through GSK3\\u03b2/Wnt signaling.\",\n      \"evidence\": \"Asph depletion and overexpression in BMSCs with differentiation assays and GSK3\\u03b2/Wnt Western blots\",\n      \"pmids\": [\"33015050\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular link between ASPH and GSK3\\u03b2 not established\", \"Whether the effect requires hydroxylase activity untested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified INPP5F as a partner that requires cytoplasmic translocation to drive ASPH-mediated Notch activation and proliferation, adding a regulatory layer to ASPH-Notch signaling.\",\n      \"evidence\": \"Reciprocal co-IP, mass spectrometry, immunofluorescence, NLS/NES mutagenesis, and LMB treatment in HCC\",\n      \"pmids\": [\"34996491\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How INPP5F mechanistically potentiates ASPH catalysis unknown\", \"Single-lab interaction data\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established that heterozygous ASPH variants acting through the junctin isoform cause exertional heat illness and malignant hyperthermia susceptibility, demonstrating a distinct excitation-contraction-coupling disease mechanism.\",\n      \"evidence\": \"Genomic sequencing with validation in CRISPR-edited C2C12 myotubes and transgenic zebrafish\",\n      \"pmids\": [\"35697689\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise effect of variants on junctin-calsequestrin/RyR coupling not fully resolved\", \"Relationship to the catalytic isoform's functions not addressed\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Linked ASPH to a GSK3\\u03b2/SHH/GLI2 axis driving EMT and metastasis in cholangiocarcinoma, broadening its oncogenic signaling reach.\",\n      \"evidence\": \"Western blot, wound-healing/transwell assays, and a nude-mouse lung metastasis model\",\n      \"pmids\": [\"37132101\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Correlative Western-blot analysis without direct ASPH-GSK3\\u03b2 interaction validation\", \"Causality of the SHH/GLI2 axis not mechanistically dissected\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Resolved the atypical catalytic mechanism, showing ASPH uses a water-mediated Fe(II) coordination via second-sphere Asp721 in place of the canonical triad, with rebound hydroxylation rate-limiting.\",\n      \"evidence\": \"MD and QM/MM modeling built on published crystal structures\",\n      \"pmids\": [\"38455014\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Computational model not confirmed by enzyme kinetics or mutagenesis here\", \"TPR-domain dynamics during substrate turnover not experimentally validated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Connected ASPH to redox and survival control, showing it promotes autophagy and suppresses ferroptosis via SQSTM1/p62 and SLC7A11-GPX4, with loss sensitizing tumors to sorafenib.\",\n      \"evidence\": \"ASPH knockout with Western blot, viability assays, and intrahepatic/pulmonary/splenic metastasis mouse models\",\n      \"pmids\": [\"39706251\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether the autophagy/ferroptosis effects depend on hydroxylase activity untested\", \"Direct substrate within the SLC7A11-GPX4 axis not identified\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Modeled how clinical second-sphere and long-range mutations perturb 2OG/substrate binding and HAT activation energies, offering a structural rationale for disease-linked variants.\",\n      \"evidence\": \"QM/MM and MD computational analysis of mutant vs. wild-type AspH\",\n      \"pmids\": [\"38839574\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No in vitro biochemical validation of altered activity\", \"Clinical genotype-phenotype correlations not experimentally tested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified RUVBL2 and HRASLS2 as new ASPH partners, the former amplifying MAPK/Notch signaling and the latter stabilizing ASPH protein, expanding the regulatory network around ASPH in lung and pancreatic cancers.\",\n      \"evidence\": \"IP-MS and co-IP with epistasis rescue, metabolic/glycolysis assays, and murine metastasis/xenograft models\",\n      \"pmids\": [\"41454078\", \"40833600\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which RUVBL2 enhances signaling not defined\", \"How HRASLS2 stabilizes ASPH (e.g., ubiquitination) not resolved\", \"Single-lab interaction data each\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The direct physiological hydroxylation substrates that link ASPH catalysis to its developmental phenotypes and oncogenic signaling outputs remain experimentally unconfirmed.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No validated endogenous substrate ties hydroxylase activity to Notch, EMT, or zonule defects\", \"Whether protein-interaction effects require catalytic activity largely untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [0, 6]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [2, 6]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 8, 12]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [1, 10]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [1, 4]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"VIM\", \"NOTCH\", \"JAG1\", \"ADAM10\", \"ADAM17\", \"INPP5F\", \"RUVBL2\", \"HRASLS2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}