{"gene":"NCOA5","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":2013,"finding":"Heterozygous deletion of Ncoa5 in mice causes spontaneous HCC exclusively in males, preceded by increased IL-6 expression, early-onset glucose intolerance, and progressive hepatic steatosis and dysplasia; blockading IL-6 overexpression averts glucose intolerance and partially deters HCC development, placing NCOA5 upstream of IL-6 in this pathway.","method":"Ncoa5+/- mouse model (haploinsufficiency), IL-6 blockade experiment, genetic epistasis","journal":"Cancer cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO mouse model with defined phenotypic readouts, IL-6 blockade rescue experiment, replicated across multiple downstream analyses in one rigorous study","pmids":["24332041"],"is_preprint":false},{"year":2015,"finding":"NCOA5 functions as an LXR corepressor at the Abca1 promoter in macrophages; TLR3 signaling promotes recruitment of NCOA5 to the Abca1 promoter together with loss of RNA polymerase II, resulting in reduced cholesterol efflux, thereby mediating crosstalk between pro-inflammatory and anti-inflammatory pathways.","method":"Promoter enrichment-quantitative mass spectrometry (PE-QMS), ChIP, loss-of-function experiments, cholesterol efflux assay","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — PE-QMS identification of complex components, ChIP confirmation of promoter binding, functional efflux assay, multiple orthogonal methods in one study","pmids":["25755249"],"is_preprint":false},{"year":2019,"finding":"Heterozygous deletion of Ncoa5 in mice leads to increased IL-6 expression in epididymal epithelial cells, causing decreased sperm motility and male infertility; heterozygous deletion of Il-6 in Ncoa5+/- mice partially rescued spermatozoa motility and infertility, establishing NCOA5 as an upstream regulator of IL-6 in epididymal sperm maturation.","method":"Ncoa5+/- mouse model, immunohistochemistry for IL-6, genetic rescue by Il-6 heterozygous deletion","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean haploinsufficiency mouse model, genetic epistasis rescue experiment, IHC validation of IL-6 upregulation, multiple methods","pmids":["31664153"],"is_preprint":false},{"year":2020,"finding":"NCOA5 deficiency in mice leads to p21WAF1/CIP1 overexpression in liver; heterozygous deletion of p21WAF1/CIP1 in Ncoa5+/- mice alleviated key features of the protumorigenic niche, placing p21WAF1/CIP1 downstream of NCOA5 in the development of the HCC-associated liver microenvironment.","method":"Ncoa5+/- mouse model, p21WAF1/CIP1 heterozygous deletion genetic rescue, transcriptomic analysis, metformin pharmacological intervention","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis via double-mutant rescue, transcriptomic analysis, pharmacological validation, multiple orthogonal methods","pmids":["32203160"],"is_preprint":false},{"year":2023,"finding":"Myeloid-lineage-specific deletion of Ncoa5 is sufficient to cause spontaneous NASH and HCC in male mice; NCOA5-deficient intrahepatic macrophages overexpress PF4, which triggers lipid accumulation in hepatocytes by inducing lipogenesis-promoting gene expression, establishing a NCOA5-PF4 axis in macrophages as a driver of NAFLD/NASH.","method":"Myeloid-lineage-specific Ncoa5 conditional knockout mice, transcriptomic analysis of intrahepatic macrophages, in vitro and in vivo PF4 functional studies","journal":"Cellular and molecular gastroenterology and hepatology","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific conditional KO, in vitro and in vivo PF4 mechanistic studies, transcriptomic validation, multiple orthogonal methods","pmids":["37734594"],"is_preprint":false},{"year":2017,"finding":"NCOA5 promotes colorectal cancer cell proliferation, migration, and invasion by upregulating p-AKT, Cyclin D1, and MMP9 while downregulating P27 via the PI3K/AKT signaling pathway; PI3K inhibitor LY294002 blocked these NCOA5-mediated effects, and knockdown of Cyclin D1 or MMP9 blocked the tumor-promoting activity of NCOA5.","method":"NCOA5 knockdown/overexpression in CRC cell lines, PI3K inhibitor rescue, xenograft tumor model, western blotting for pathway components","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD and OE with defined cellular phenotype, pharmacological epistasis with PI3K inhibitor, single lab","pmids":["29296214"],"is_preprint":false},{"year":2017,"finding":"Wild-type NCOA5 suppresses HCC cell proliferation via induction of G2/M arrest and increases DNA damage and cell senescence; the T445A amino acid substitution (Thr to Ala) significantly impairs these activities, as shown by reduced G2/M arrest, decreased DNA damage/senescence induction, and loss of tumor growth inhibitory function in xenograft models.","method":"Tet-On inducible expression of NCOA5wt vs NCOA5T445A in HCC cells, xenograft tumor model, cell cycle analysis, DNA damage and senescence assays","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — inducible expression system with mutagenesis comparison, xenograft validation, multiple cellular readouts, single lab","pmids":["28137631"],"is_preprint":false},{"year":2018,"finding":"CRISPR/Cas9-mediated knockout of NCOA5 in HCC cells inhibits proliferation, tumor microsphere formation, migration, and suppresses epithelial-mesenchymal transition (EMT).","method":"CRISPR/Cas9 NCOA5 knockout in HCC cell lines, proliferation assay, tumor microsphere formation, migration assay, EMT marker analysis","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean CRISPR KO with defined cellular phenotype, multiple readouts, single lab","pmids":["29626478"],"is_preprint":false},{"year":2020,"finding":"In bovine mammary epithelial cells, NCOA5 binds directly to the mTOR promoter (confirmed by ChIP-qPCR); NCOA5 overexpression increases mTOR phosphorylation and β-casein synthesis, while knockdown has opposite effects; PI3K inhibition abolishes amino acid-induced NCOA5 upregulation, placing NCOA5 downstream of PI3K and upstream of mTOR in amino acid signaling.","method":"ChIP-qPCR (NCOA5 binding to mTOR promoter), NCOA5 overexpression/knockdown, PI3K inhibition, measurement of mTOR phosphorylation and β-casein synthesis","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-qPCR for direct promoter binding, gain/loss-of-function, pharmacological epistasis, single lab in bovine cells","pmids":["32736675"],"is_preprint":false},{"year":2025,"finding":"NCOA5 inhibits ferroptosis in HCC cells by maintaining GPX4 levels via the transcription factor MYC; NCOA5 knockdown decreases GPX4 expression, sensitizes sorafenib-resistant HCC cells to sorafenib, and induces ferroptosis; overexpression of GPX4 rescues the ferroptosis induced by NCOA5 knockdown.","method":"NCOA5 knockdown in sorafenib-resistant HCC cell lines, GPX4 expression analysis, MYC transcription factor studies, in vivo xenograft validation, rescue by GPX4 overexpression","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD with defined ferroptosis phenotype, rescue experiment with GPX4, in vivo validation, single lab","pmids":["40316542"],"is_preprint":false},{"year":2025,"finding":"NCOA5 represses PRDX6 expression by interfering with NRF2-mediated transactivation; loss of PRDX6 phenocopies NCOA5 overexpression (increased ROS, increased cisplatin sensitivity), and enforced PRDX6 expression reverses the effects of NCOA5 on ROS production and cisplatin sensitivity in NSCLC cells.","method":"NCOA5 overexpression/knockdown in NSCLC cells, PRDX6 expression analysis, ROS measurement, NRF2-mediated transactivation assay, rescue by PRDX6 overexpression, in vivo validation","journal":"Biochemical pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain/loss-of-function with defined molecular pathway, epistasis rescue experiment, in vivo validation, single lab","pmids":["40619029"],"is_preprint":false},{"year":2013,"finding":"An ortholog of NCOA5 is essential for maintenance of the pluripotent stem cell population in planarians; NCOA5 was identified as enriched in planarian stem cells by in vivo SILAC proteomics comparing normal vs. stem cell-depleted planarians.","method":"In vivo SILAC proteomics in planarians, stem cell depletion comparison, functional knockdown of Ncoa5 in planarians","journal":"Cell reports","confidence":"Low","confidence_rationale":"Tier 3 / Weak — planarian ortholog study, single lab, indirect relevance to mammalian NCOA5 mechanism","pmids":["24268775"],"is_preprint":false},{"year":2023,"finding":"TPX2 interacts with NCOA5 (confirmed by co-immunoprecipitation); NCOA5 acts as a downstream target of TPX2 in promoting proliferation, migration, invasion, and angiogenesis in breast cancer cells, as NCOA5 overexpression reversed the suppressive effects of TPX2 knockdown.","method":"Co-immunoprecipitation (TPX2–NCOA5 interaction), NCOA5/TPX2 knockdown and overexpression in breast cancer cell lines, rescue epistasis experiment","journal":"Experimental and therapeutic medicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP for interaction, epistasis by rescue, single lab, limited mechanistic depth","pmids":["37229326"],"is_preprint":false}],"current_model":"NCOA5 is a nuclear receptor coactivator/corepressor that suppresses IL-6 expression (in liver and epididymis), acts as an LXR corepressor to repress Abca1-mediated cholesterol efflux in macrophages upon TLR3 signaling, directly binds the mTOR promoter to activate mTOR signaling downstream of PI3K, regulates cell cycle progression and EMT in cancer cells, inhibits ferroptosis via a MYC-GPX4 axis, and represses PRDX6 via NRF2 interference; haploinsufficiency of NCOA5 in mice causes male-specific spontaneous HCC through elevated IL-6, p21WAF1/CIP1 overexpression, and a protumorigenic microenvironment, with myeloid-lineage NCOA5 loss sufficient to drive NASH/HCC via macrophage PF4 overexpression."},"narrative":{"mechanistic_narrative":"NCOA5 is a nuclear receptor coregulator that gates inflammatory and metabolic gene programs and, through them, suppresses tumorigenesis in a tissue- and sex-dependent manner [PMID:24332041, PMID:25755249]. Its best-defined activity is transcriptional repression of IL-6: heterozygous loss of Ncoa5 in mice elevates IL-6 and drives male-specific spontaneous hepatocellular carcinoma preceded by glucose intolerance and hepatic steatosis, with IL-6 blockade averting these phenotypes and placing NCOA5 genetically upstream of IL-6 [PMID:24332041], and the same NCOA5→IL-6 axis governs epididymal epithelial function and sperm maturation [PMID:31664153]. NCOA5 also acts as an LXR corepressor, being recruited to the Abca1 promoter upon TLR3 signaling to displace RNA polymerase II and reduce macrophage cholesterol efflux, thereby coupling pro- and anti-inflammatory programs [PMID:25755249]. The protumorigenic liver microenvironment caused by NCOA5 deficiency operates through downstream p21WAF1/CIP1 overexpression [PMID:32203160], and myeloid-lineage-specific deletion alone is sufficient to cause NASH and HCC via macrophage PF4 overexpression that induces hepatocyte lipogenesis [PMID:37734594]. In cancer cells NCOA5 has context-dependent roles: it can suppress HCC proliferation by inducing G2/M arrest, DNA damage, and senescence, an activity lost by the T445A substitution [PMID:28137631], yet in other settings it promotes proliferation, migration, and EMT and sustains tumor growth [PMID:29296214, PMID:29626478]. Additional reported activities include direct binding of the mTOR promoter to activate mTOR signaling downstream of PI3K [PMID:32736675], inhibition of ferroptosis via a MYC–GPX4 axis [PMID:40316542], and repression of PRDX6 through interference with NRF2-mediated transactivation [PMID:40619029].","teleology":[{"year":2013,"claim":"Established NCOA5 as a tumor suppressor in liver and defined IL-6 as its key downstream effector, answering whether NCOA5 dosage causally controls a carcinogenic inflammatory program.","evidence":"Ncoa5+/- haploinsufficient mice with IL-6 blockade rescue and genetic epistasis","pmids":["24332041"],"confidence":"High","gaps":["Molecular mechanism by which NCOA5 represses IL-6 transcription not resolved","Basis of the strict male specificity of HCC not explained","Direct DNA/receptor binding events at IL-6 locus not shown"]},{"year":2015,"claim":"Defined a direct biochemical mechanism for NCOA5 as an LXR corepressor recruited to a target promoter, showing how it links inflammatory signaling to lipid metabolism.","evidence":"Promoter enrichment-quantitative mass spectrometry, ChIP, cholesterol efflux assay in macrophages with TLR3 stimulation","pmids":["25755249"],"confidence":"High","gaps":["Whether NCOA5 acts as corepressor at other LXR targets unknown","Structural basis of NCOA5-LXR interaction not determined","Relationship between corepressor activity and IL-6 repression not connected"]},{"year":2017,"claim":"Tested NCOA5's role within cancer cells directly, revealing context-dependent functions ranging from growth suppression to growth promotion.","evidence":"Tet-On NCOA5wt vs T445A in HCC cells with xenografts (cell cycle/DNA damage/senescence readouts); separately, knockdown/overexpression in CRC cells with PI3K inhibitor rescue","pmids":["28137631","29296214"],"confidence":"Medium","gaps":["Opposing pro- and anti-tumorigenic roles not reconciled mechanistically","Functional importance of the T445 residue at the molecular level unknown","Single-lab cell-line studies without cross-validation"]},{"year":2018,"claim":"Confirmed NCOA5 supports HCC malignant phenotypes including EMT via clean genetic ablation, complementing dosage models.","evidence":"CRISPR/Cas9 NCOA5 knockout in HCC cell lines with proliferation, microsphere, migration, and EMT marker assays","pmids":["29626478"],"confidence":"Medium","gaps":["Transcriptional targets driving EMT not identified","Apparent contradiction with growth-suppressive role in same tissue unresolved"]},{"year":2019,"claim":"Generalized the NCOA5→IL-6 axis beyond liver, showing it controls a distinct physiological process (sperm maturation) through the same effector.","evidence":"Ncoa5+/- mice with Il-6 heterozygous deletion rescue and IL-6 IHC in epididymis","pmids":["31664153"],"confidence":"High","gaps":["Mechanism of IL-6 repression in epididymal epithelium not defined","Cell-autonomous vs systemic contribution not separated"]},{"year":2020,"claim":"Placed p21WAF1/CIP1 downstream of NCOA5 in building the protumorigenic liver niche, extending the pathway beyond IL-6.","evidence":"Ncoa5+/- ; p21+/- double-mutant genetic rescue with transcriptomics and metformin intervention","pmids":["32203160"],"confidence":"High","gaps":["Whether p21 induction is direct or downstream of IL-6 not resolved","Cell type responsible for p21 overexpression not pinpointed"]},{"year":2020,"claim":"Introduced a direct transcriptional-activation function, showing NCOA5 binds the mTOR promoter to relay PI3K signaling, broadening its mechanistic repertoire beyond corepression.","evidence":"ChIP-qPCR, gain/loss-of-function, and PI3K inhibition in bovine mammary epithelial cells","pmids":["32736675"],"confidence":"Medium","gaps":["Whether NCOA5 binds the mTOR promoter in human/mammalian cancer cells unknown","Coactivator/corepressor cofactors at the mTOR promoter not identified","Single-lab study in a non-mammalian-cancer system"]},{"year":2023,"claim":"Demonstrated cell-type-specific sufficiency, proving myeloid NCOA5 loss alone drives NASH/HCC through macrophage PF4-mediated hepatocyte lipogenesis.","evidence":"Myeloid-specific conditional Ncoa5 knockout mice with macrophage transcriptomics and PF4 functional studies","pmids":["37734594"],"confidence":"High","gaps":["How NCOA5 represses PF4 transcription in macrophages not defined","Relationship between PF4 axis and the earlier IL-6 axis not integrated"]},{"year":2025,"claim":"Linked NCOA5 to redox/cell-death control, identifying ferroptosis inhibition via MYC-GPX4 and PRDX6 repression via NRF2 interference as additional effector pathways.","evidence":"Knockdown/overexpression with rescue (GPX4 or PRDX6) and in vivo validation in sorafenib-resistant HCC and NSCLC cells","pmids":["40316542","40619029"],"confidence":"Medium","gaps":["Whether NCOA5 regulates MYC and NRF2 targets directly or indirectly unclear","Single-lab studies for each axis without independent replication","Connection between these redox roles and the IL-6/tumor-suppressor model unaddressed"]},{"year":null,"claim":"How a single coregulator switches between corepressor (IL-6, Abca1/LXR, PRDX6/NRF2) and activator (mTOR, GPX4) functions, and what determines its tissue- and sex-specific tumor-suppressive versus tumor-promoting outputs, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model or defined recruitment logic for NCOA5 at target promoters","Determinants of context-dependent pro- vs anti-tumor activity unknown","Mechanistic basis of male-specific phenotypes unexplained"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,1,8,10]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[1,8]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,10]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,8]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[1,8]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,1,4]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,8]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0,4]}],"complexes":[],"partners":["LXR","TPX2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9HCD5","full_name":"Nuclear receptor coactivator 5","aliases":["Coactivator independent of AF-2","CIA"],"length_aa":579,"mass_kda":65.5,"function":"Nuclear receptor coregulator that can have both coactivator and corepressor functions. Interacts with nuclear receptors for steroids (ESR1 and ESR2) independently of the steroid binding domain (AF-2) of the ESR receptors, and with the orphan nuclear receptor NR1D2. Involved in the coactivation of nuclear steroid receptors (ER) as well as the corepression of MYC in response to 17-beta-estradiol (E2)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9HCD5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/NCOA5","classification":"Not Classified","n_dependent_lines":68,"n_total_lines":1208,"dependency_fraction":0.056291390728476824},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"ATG13","stoichiometry":4.0},{"gene":"ATG101","stoichiometry":0.2},{"gene":"CPSF6","stoichiometry":0.2},{"gene":"PAIP1","stoichiometry":0.2},{"gene":"RBM14","stoichiometry":0.2},{"gene":"SNRPA","stoichiometry":0.2},{"gene":"SNRPB","stoichiometry":0.2},{"gene":"SSRP1","stoichiometry":0.2},{"gene":"TNPO3","stoichiometry":0.2},{"gene":"TOP1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/NCOA5","total_profiled":1310},"omim":[{"mim_id":"616825","title":"NUCLEAR RECEPTOR COACTIVATOR 5; NCOA5","url":"https://www.omim.org/entry/616825"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Actin filaments","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/NCOA5"},"hgnc":{"alias_symbol":["bA465L10.6","CIA"],"prev_symbol":[]},"alphafold":{"accession":"Q9HCD5","domains":[{"cath_id":"3.40.50.800","chopping":"188-323","consensus_level":"high","plddt":86.612,"start":188,"end":323},{"cath_id":"-","chopping":"338-373","consensus_level":"medium","plddt":83.8511,"start":338,"end":373}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9HCD5","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9HCD5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9HCD5-F1-predicted_aligned_error_v6.png","plddt_mean":58.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NCOA5","jax_strain_url":"https://www.jax.org/strain/search?query=NCOA5"},"sequence":{"accession":"Q9HCD5","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9HCD5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9HCD5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9HCD5"}},"corpus_meta":[{"pmid":"24332041","id":"PMC_24332041","title":"NCOA5 haploinsufficiency results in glucose intolerance and subsequent hepatocellular carcinoma.","date":"2013","source":"Cancer cell","url":"https://pubmed.ncbi.nlm.nih.gov/24332041","citation_count":58,"is_preprint":false},{"pmid":"24268775","id":"PMC_24268775","title":"SILAC proteomics of planarians identifies Ncoa5 as a conserved component of pluripotent stem cells.","date":"2013","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/24268775","citation_count":39,"is_preprint":false},{"pmid":"29296214","id":"PMC_29296214","title":"NCOA5 promotes proliferation, migration and invasion of colorectal cancer cells via activation of PI3K/AKT pathway.","date":"2017","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/29296214","citation_count":33,"is_preprint":false},{"pmid":"25755249","id":"PMC_25755249","title":"An LXR-NCOA5 gene regulatory complex directs inflammatory crosstalk-dependent repression of macrophage cholesterol efflux.","date":"2015","source":"The EMBO 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metformin.","date":"2020","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/32203160","citation_count":19,"is_preprint":false},{"pmid":"25416054","id":"PMC_25416054","title":"NCOA5 low expression correlates with survival in esophageal squamous cell carcinoma.","date":"2014","source":"Medical oncology (Northwood, London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/25416054","citation_count":15,"is_preprint":false},{"pmid":"21645569","id":"PMC_21645569","title":"A CD40 and an NCOA5 gene polymorphism confer susceptibility to psoriasis in a Southern European population: a case-control study.","date":"2011","source":"Human immunology","url":"https://pubmed.ncbi.nlm.nih.gov/21645569","citation_count":15,"is_preprint":false},{"pmid":"32736675","id":"PMC_32736675","title":"NCOA5 is a master regulator of amino acid-induced mTOR activation and β-casein synthesis in bovine mammary epithelial cells.","date":"2020","source":"Biochemical and biophysical research 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a novel candidate gene for multiple sclerosis susceptibility?","date":"2023","source":"Molecular biology reports","url":"https://pubmed.ncbi.nlm.nih.gov/37817021","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":12318,"output_tokens":3431,"usd":0.044209,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11060,"output_tokens":3593,"usd":0.072563,"stage2_stop_reason":"end_turn"},"total_usd":0.116772,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2013,\n      \"finding\": \"Heterozygous deletion of Ncoa5 in mice causes spontaneous HCC exclusively in males, preceded by increased IL-6 expression, early-onset glucose intolerance, and progressive hepatic steatosis and dysplasia; blockading IL-6 overexpression averts glucose intolerance and partially deters HCC development, placing NCOA5 upstream of IL-6 in this pathway.\",\n      \"method\": \"Ncoa5+/- mouse model (haploinsufficiency), IL-6 blockade experiment, genetic epistasis\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO mouse model with defined phenotypic readouts, IL-6 blockade rescue experiment, replicated across multiple downstream analyses in one rigorous study\",\n      \"pmids\": [\"24332041\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"NCOA5 functions as an LXR corepressor at the Abca1 promoter in macrophages; TLR3 signaling promotes recruitment of NCOA5 to the Abca1 promoter together with loss of RNA polymerase II, resulting in reduced cholesterol efflux, thereby mediating crosstalk between pro-inflammatory and anti-inflammatory pathways.\",\n      \"method\": \"Promoter enrichment-quantitative mass spectrometry (PE-QMS), ChIP, loss-of-function experiments, cholesterol efflux assay\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — PE-QMS identification of complex components, ChIP confirmation of promoter binding, functional efflux assay, multiple orthogonal methods in one study\",\n      \"pmids\": [\"25755249\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Heterozygous deletion of Ncoa5 in mice leads to increased IL-6 expression in epididymal epithelial cells, causing decreased sperm motility and male infertility; heterozygous deletion of Il-6 in Ncoa5+/- mice partially rescued spermatozoa motility and infertility, establishing NCOA5 as an upstream regulator of IL-6 in epididymal sperm maturation.\",\n      \"method\": \"Ncoa5+/- mouse model, immunohistochemistry for IL-6, genetic rescue by Il-6 heterozygous deletion\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean haploinsufficiency mouse model, genetic epistasis rescue experiment, IHC validation of IL-6 upregulation, multiple methods\",\n      \"pmids\": [\"31664153\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"NCOA5 deficiency in mice leads to p21WAF1/CIP1 overexpression in liver; heterozygous deletion of p21WAF1/CIP1 in Ncoa5+/- mice alleviated key features of the protumorigenic niche, placing p21WAF1/CIP1 downstream of NCOA5 in the development of the HCC-associated liver microenvironment.\",\n      \"method\": \"Ncoa5+/- mouse model, p21WAF1/CIP1 heterozygous deletion genetic rescue, transcriptomic analysis, metformin pharmacological intervention\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis via double-mutant rescue, transcriptomic analysis, pharmacological validation, multiple orthogonal methods\",\n      \"pmids\": [\"32203160\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Myeloid-lineage-specific deletion of Ncoa5 is sufficient to cause spontaneous NASH and HCC in male mice; NCOA5-deficient intrahepatic macrophages overexpress PF4, which triggers lipid accumulation in hepatocytes by inducing lipogenesis-promoting gene expression, establishing a NCOA5-PF4 axis in macrophages as a driver of NAFLD/NASH.\",\n      \"method\": \"Myeloid-lineage-specific Ncoa5 conditional knockout mice, transcriptomic analysis of intrahepatic macrophages, in vitro and in vivo PF4 functional studies\",\n      \"journal\": \"Cellular and molecular gastroenterology and hepatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific conditional KO, in vitro and in vivo PF4 mechanistic studies, transcriptomic validation, multiple orthogonal methods\",\n      \"pmids\": [\"37734594\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"NCOA5 promotes colorectal cancer cell proliferation, migration, and invasion by upregulating p-AKT, Cyclin D1, and MMP9 while downregulating P27 via the PI3K/AKT signaling pathway; PI3K inhibitor LY294002 blocked these NCOA5-mediated effects, and knockdown of Cyclin D1 or MMP9 blocked the tumor-promoting activity of NCOA5.\",\n      \"method\": \"NCOA5 knockdown/overexpression in CRC cell lines, PI3K inhibitor rescue, xenograft tumor model, western blotting for pathway components\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD and OE with defined cellular phenotype, pharmacological epistasis with PI3K inhibitor, single lab\",\n      \"pmids\": [\"29296214\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Wild-type NCOA5 suppresses HCC cell proliferation via induction of G2/M arrest and increases DNA damage and cell senescence; the T445A amino acid substitution (Thr to Ala) significantly impairs these activities, as shown by reduced G2/M arrest, decreased DNA damage/senescence induction, and loss of tumor growth inhibitory function in xenograft models.\",\n      \"method\": \"Tet-On inducible expression of NCOA5wt vs NCOA5T445A in HCC cells, xenograft tumor model, cell cycle analysis, DNA damage and senescence assays\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — inducible expression system with mutagenesis comparison, xenograft validation, multiple cellular readouts, single lab\",\n      \"pmids\": [\"28137631\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CRISPR/Cas9-mediated knockout of NCOA5 in HCC cells inhibits proliferation, tumor microsphere formation, migration, and suppresses epithelial-mesenchymal transition (EMT).\",\n      \"method\": \"CRISPR/Cas9 NCOA5 knockout in HCC cell lines, proliferation assay, tumor microsphere formation, migration assay, EMT marker analysis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean CRISPR KO with defined cellular phenotype, multiple readouts, single lab\",\n      \"pmids\": [\"29626478\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In bovine mammary epithelial cells, NCOA5 binds directly to the mTOR promoter (confirmed by ChIP-qPCR); NCOA5 overexpression increases mTOR phosphorylation and β-casein synthesis, while knockdown has opposite effects; PI3K inhibition abolishes amino acid-induced NCOA5 upregulation, placing NCOA5 downstream of PI3K and upstream of mTOR in amino acid signaling.\",\n      \"method\": \"ChIP-qPCR (NCOA5 binding to mTOR promoter), NCOA5 overexpression/knockdown, PI3K inhibition, measurement of mTOR phosphorylation and β-casein synthesis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-qPCR for direct promoter binding, gain/loss-of-function, pharmacological epistasis, single lab in bovine cells\",\n      \"pmids\": [\"32736675\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NCOA5 inhibits ferroptosis in HCC cells by maintaining GPX4 levels via the transcription factor MYC; NCOA5 knockdown decreases GPX4 expression, sensitizes sorafenib-resistant HCC cells to sorafenib, and induces ferroptosis; overexpression of GPX4 rescues the ferroptosis induced by NCOA5 knockdown.\",\n      \"method\": \"NCOA5 knockdown in sorafenib-resistant HCC cell lines, GPX4 expression analysis, MYC transcription factor studies, in vivo xenograft validation, rescue by GPX4 overexpression\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD with defined ferroptosis phenotype, rescue experiment with GPX4, in vivo validation, single lab\",\n      \"pmids\": [\"40316542\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NCOA5 represses PRDX6 expression by interfering with NRF2-mediated transactivation; loss of PRDX6 phenocopies NCOA5 overexpression (increased ROS, increased cisplatin sensitivity), and enforced PRDX6 expression reverses the effects of NCOA5 on ROS production and cisplatin sensitivity in NSCLC cells.\",\n      \"method\": \"NCOA5 overexpression/knockdown in NSCLC cells, PRDX6 expression analysis, ROS measurement, NRF2-mediated transactivation assay, rescue by PRDX6 overexpression, in vivo validation\",\n      \"journal\": \"Biochemical pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain/loss-of-function with defined molecular pathway, epistasis rescue experiment, in vivo validation, single lab\",\n      \"pmids\": [\"40619029\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"An ortholog of NCOA5 is essential for maintenance of the pluripotent stem cell population in planarians; NCOA5 was identified as enriched in planarian stem cells by in vivo SILAC proteomics comparing normal vs. stem cell-depleted planarians.\",\n      \"method\": \"In vivo SILAC proteomics in planarians, stem cell depletion comparison, functional knockdown of Ncoa5 in planarians\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — planarian ortholog study, single lab, indirect relevance to mammalian NCOA5 mechanism\",\n      \"pmids\": [\"24268775\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TPX2 interacts with NCOA5 (confirmed by co-immunoprecipitation); NCOA5 acts as a downstream target of TPX2 in promoting proliferation, migration, invasion, and angiogenesis in breast cancer cells, as NCOA5 overexpression reversed the suppressive effects of TPX2 knockdown.\",\n      \"method\": \"Co-immunoprecipitation (TPX2–NCOA5 interaction), NCOA5/TPX2 knockdown and overexpression in breast cancer cell lines, rescue epistasis experiment\",\n      \"journal\": \"Experimental and therapeutic medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP for interaction, epistasis by rescue, single lab, limited mechanistic depth\",\n      \"pmids\": [\"37229326\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NCOA5 is a nuclear receptor coactivator/corepressor that suppresses IL-6 expression (in liver and epididymis), acts as an LXR corepressor to repress Abca1-mediated cholesterol efflux in macrophages upon TLR3 signaling, directly binds the mTOR promoter to activate mTOR signaling downstream of PI3K, regulates cell cycle progression and EMT in cancer cells, inhibits ferroptosis via a MYC-GPX4 axis, and represses PRDX6 via NRF2 interference; haploinsufficiency of NCOA5 in mice causes male-specific spontaneous HCC through elevated IL-6, p21WAF1/CIP1 overexpression, and a protumorigenic microenvironment, with myeloid-lineage NCOA5 loss sufficient to drive NASH/HCC via macrophage PF4 overexpression.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"NCOA5 is a nuclear receptor coregulator that gates inflammatory and metabolic gene programs and, through them, suppresses tumorigenesis in a tissue- and sex-dependent manner [#0, #1]. Its best-defined activity is transcriptional repression of IL-6: heterozygous loss of Ncoa5 in mice elevates IL-6 and drives male-specific spontaneous hepatocellular carcinoma preceded by glucose intolerance and hepatic steatosis, with IL-6 blockade averting these phenotypes and placing NCOA5 genetically upstream of IL-6 [#0], and the same NCOA5\\u2192IL-6 axis governs epididymal epithelial function and sperm maturation [#2]. NCOA5 also acts as an LXR corepressor, being recruited to the Abca1 promoter upon TLR3 signaling to displace RNA polymerase II and reduce macrophage cholesterol efflux, thereby coupling pro- and anti-inflammatory programs [#1]. The protumorigenic liver microenvironment caused by NCOA5 deficiency operates through downstream p21WAF1/CIP1 overexpression [#3], and myeloid-lineage-specific deletion alone is sufficient to cause NASH and HCC via macrophage PF4 overexpression that induces hepatocyte lipogenesis [#4]. In cancer cells NCOA5 has context-dependent roles: it can suppress HCC proliferation by inducing G2/M arrest, DNA damage, and senescence, an activity lost by the T445A substitution [#6], yet in other settings it promotes proliferation, migration, and EMT and sustains tumor growth [#5, #7]. Additional reported activities include direct binding of the mTOR promoter to activate mTOR signaling downstream of PI3K [#8], inhibition of ferroptosis via a MYC\\u2013GPX4 axis [#9], and repression of PRDX6 through interference with NRF2-mediated transactivation [#10].\",\n  \"teleology\": [\n    {\n      \"year\": 2013,\n      \"claim\": \"Established NCOA5 as a tumor suppressor in liver and defined IL-6 as its key downstream effector, answering whether NCOA5 dosage causally controls a carcinogenic inflammatory program.\",\n      \"evidence\": \"Ncoa5+/- haploinsufficient mice with IL-6 blockade rescue and genetic epistasis\",\n      \"pmids\": [\"24332041\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Molecular mechanism by which NCOA5 represses IL-6 transcription not resolved\",\n        \"Basis of the strict male specificity of HCC not explained\",\n        \"Direct DNA/receptor binding events at IL-6 locus not shown\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined a direct biochemical mechanism for NCOA5 as an LXR corepressor recruited to a target promoter, showing how it links inflammatory signaling to lipid metabolism.\",\n      \"evidence\": \"Promoter enrichment-quantitative mass spectrometry, ChIP, cholesterol efflux assay in macrophages with TLR3 stimulation\",\n      \"pmids\": [\"25755249\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether NCOA5 acts as corepressor at other LXR targets unknown\",\n        \"Structural basis of NCOA5-LXR interaction not determined\",\n        \"Relationship between corepressor activity and IL-6 repression not connected\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Tested NCOA5's role within cancer cells directly, revealing context-dependent functions ranging from growth suppression to growth promotion.\",\n      \"evidence\": \"Tet-On NCOA5wt vs T445A in HCC cells with xenografts (cell cycle/DNA damage/senescence readouts); separately, knockdown/overexpression in CRC cells with PI3K inhibitor rescue\",\n      \"pmids\": [\"28137631\", \"29296214\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Opposing pro- and anti-tumorigenic roles not reconciled mechanistically\",\n        \"Functional importance of the T445 residue at the molecular level unknown\",\n        \"Single-lab cell-line studies without cross-validation\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Confirmed NCOA5 supports HCC malignant phenotypes including EMT via clean genetic ablation, complementing dosage models.\",\n      \"evidence\": \"CRISPR/Cas9 NCOA5 knockout in HCC cell lines with proliferation, microsphere, migration, and EMT marker assays\",\n      \"pmids\": [\"29626478\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Transcriptional targets driving EMT not identified\",\n        \"Apparent contradiction with growth-suppressive role in same tissue unresolved\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Generalized the NCOA5\\u2192IL-6 axis beyond liver, showing it controls a distinct physiological process (sperm maturation) through the same effector.\",\n      \"evidence\": \"Ncoa5+/- mice with Il-6 heterozygous deletion rescue and IL-6 IHC in epididymis\",\n      \"pmids\": [\"31664153\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanism of IL-6 repression in epididymal epithelium not defined\",\n        \"Cell-autonomous vs systemic contribution not separated\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Placed p21WAF1/CIP1 downstream of NCOA5 in building the protumorigenic liver niche, extending the pathway beyond IL-6.\",\n      \"evidence\": \"Ncoa5+/- ; p21+/- double-mutant genetic rescue with transcriptomics and metformin intervention\",\n      \"pmids\": [\"32203160\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether p21 induction is direct or downstream of IL-6 not resolved\",\n        \"Cell type responsible for p21 overexpression not pinpointed\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Introduced a direct transcriptional-activation function, showing NCOA5 binds the mTOR promoter to relay PI3K signaling, broadening its mechanistic repertoire beyond corepression.\",\n      \"evidence\": \"ChIP-qPCR, gain/loss-of-function, and PI3K inhibition in bovine mammary epithelial cells\",\n      \"pmids\": [\"32736675\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether NCOA5 binds the mTOR promoter in human/mammalian cancer cells unknown\",\n        \"Coactivator/corepressor cofactors at the mTOR promoter not identified\",\n        \"Single-lab study in a non-mammalian-cancer system\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrated cell-type-specific sufficiency, proving myeloid NCOA5 loss alone drives NASH/HCC through macrophage PF4-mediated hepatocyte lipogenesis.\",\n      \"evidence\": \"Myeloid-specific conditional Ncoa5 knockout mice with macrophage transcriptomics and PF4 functional studies\",\n      \"pmids\": [\"37734594\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"How NCOA5 represses PF4 transcription in macrophages not defined\",\n        \"Relationship between PF4 axis and the earlier IL-6 axis not integrated\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Linked NCOA5 to redox/cell-death control, identifying ferroptosis inhibition via MYC-GPX4 and PRDX6 repression via NRF2 interference as additional effector pathways.\",\n      \"evidence\": \"Knockdown/overexpression with rescue (GPX4 or PRDX6) and in vivo validation in sorafenib-resistant HCC and NSCLC cells\",\n      \"pmids\": [\"40316542\", \"40619029\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether NCOA5 regulates MYC and NRF2 targets directly or indirectly unclear\",\n        \"Single-lab studies for each axis without independent replication\",\n        \"Connection between these redox roles and the IL-6/tumor-suppressor model unaddressed\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single coregulator switches between corepressor (IL-6, Abca1/LXR, PRDX6/NRF2) and activator (mTOR, GPX4) functions, and what determines its tissue- and sex-specific tumor-suppressive versus tumor-promoting outputs, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No structural model or defined recruitment logic for NCOA5 at target promoters\",\n        \"Determinants of context-dependent pro- vs anti-tumor activity unknown\",\n        \"Mechanistic basis of male-specific phenotypes unexplained\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 1, 8, 10]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [1, 8]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [1, 8]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 1, 4]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 8]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 4]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"LXR\", \"TPX2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}