{"gene":"PTGES3","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":2007,"finding":"cPGES/p23 (PTGES3) is required for glucocorticoid receptor (GR) function in vivo: cPGES/p23-knockout mice display retarded lung development and failure to induce GR-sensitive gluconeogenic enzymes prenatally, phenocopying GR-deficient neonates, establishing PTGES3 as a stabilizer of the GR complex. However, analysis of arachidonic acid metabolites in embryonic tissues and primary fibroblasts failed to support a role for this protein in PGE2 biosynthesis in vivo.","method":"Knockout mouse generation; analysis of GR-sensitive gluconeogenic enzyme induction; arachidonic acid metabolite profiling in embryonic tissues and primary fibroblasts","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO with defined cellular and developmental phenotypes, multiple orthogonal readouts (lung morphology, enzyme induction, metabolite profiling), replicated by independent lab (PMID:17719010)","pmids":["17438133"],"is_preprint":false},{"year":2007,"finding":"cPGES/p23-null embryos are smaller and primary fibroblasts show a proliferation defect, revealing a role for PTGES3 in cell proliferation beyond GR stabilization.","method":"Knockout mouse generation; body weight measurements; primary fibroblast proliferation assay","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO with defined phenotypic readout (proliferation), single lab, two orthogonal measurements","pmids":["17438133"],"is_preprint":false},{"year":2007,"finding":"cPGES/p23-null pups die perinatally with abnormal skin and lung morphology and lower lung PGE2 content, indicating that cPGES (PTGES3) contributes to PGE2 biosynthesis in lung development in vivo.","method":"Knockout mouse generation targeting catalytic Tyr9-containing exons; PGE2 measurement in lung tissue by ELISA/mass spectrometry","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO with defined phenotype and biochemical readout (PGE2 levels), single lab; partially contradicts PMID:17438133 on PGE2 synthesis role","pmids":["17719010"],"is_preprint":false},{"year":2011,"finding":"PTGES3 (cPGES/p23) positively regulates expression of the PGE2-inactivating enzyme 15-PGDH: cPGES/p23-null fibroblasts show decreased 15-PGDH expression; siRNA knockdown of cPGES/p23 in 3Y1 cells reduces 15-PGDH expression; and forced overexpression of cPGES/p23 in 3Y1 cells increases 15-PGDH promoter activity.","method":"Knockout fibroblast analysis; siRNA knockdown; forced overexpression with luciferase promoter reporter assay","journal":"Prostaglandins & other lipid mediators","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function and gain-of-function with reporter assay, single lab, multiple orthogonal approaches","pmids":["21334450"],"is_preprint":false},{"year":2025,"finding":"PTGES3 binds directly to the androgen receptor (AR), forms a protein complex with AR in the nucleus, regulates AR protein stability, and is necessary for AR function at AR target genes in prostate cancer cells; PTGES3 repression causes loss of AR protein, cell-cycle arrest, and cell death in AR-driven prostate cancer models.","method":"Genome-scale CRISPRi screen with live-cell AR fluorescent reporter; co-immunoprecipitation/direct binding assays; AR protein stability assays in vitro and in vivo; chromatin-associated AR target gene analysis; cell-cycle and viability assays after PTGES3 knockdown","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-scale functional screen validated with direct binding, protein stability, nuclear function, and cell phenotype assays; peer-reviewed, multiple orthogonal methods","pmids":["41193657"],"is_preprint":false},{"year":2026,"finding":"Andrographolide covalently binds Cys58 of PTGES3 at an allosteric site distinct from both its catalytic and Hsp90-binding regions; this inhibits PTGES3 enzymatic (PGE2 synthase) activity and disrupts the PTGES3-Hsp90 chaperone complex, leading to suppressed NF-κB signaling; genetic knockdown of Ptges3 attenuates the anti-inflammatory/antifibrotic effects of andrographolide in vitro and in vivo.","method":"Activity-based protein profiling (ABPP) for covalent target identification; site-specific mutagenesis (Cys58); enzymatic PGE2 synthase assay; molecular docking; biophysical analyses; siRNA knockdown in vitro and lung-specific Ptges3 knockdown in bleomycin/LPS mouse models","journal":"Journal of advanced research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — ABPP-based covalent site identification with mutagenesis validation, enzymatic assay, and in vivo knockdown with functional consequence; multiple orthogonal methods in single study","pmids":["42144059"],"is_preprint":false},{"year":2007,"finding":"Hsp90 regulates both cPGES/p23 (PTGES3) and its client protein kinase CK2, identifying PTGES3 as an Hsp90-associated co-chaperone (p23) that participates in Hsp90 client regulation.","method":"Cited as prior finding within the cPGES/p23 knockout study; biochemical characterization of Hsp90 complex","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — referenced as prior finding within abstract without detailed methods described; single lab","pmids":["17719010"],"is_preprint":false},{"year":2024,"finding":"PTGES3 knockdown by siRNA in breast cancer cell lines significantly inhibits cell proliferation and migration, establishing a functional role in breast cancer cell growth and motility.","method":"siRNA transfection into breast cancer cell lines; CCK-8 cell viability assay; wound healing migration assay","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean loss-of-function with two orthogonal cellular phenotype readouts (proliferation and migration), single lab","pmids":["38245717"],"is_preprint":false},{"year":2024,"finding":"PTGES3-PROTAC (a liposomal peptide-PROTAC using a PTGES3-binding peptide and the E3 ligase ligand pomalidomide) effectively degrades PTGES3 protein via ubiquitin-proteasome pathway and suppresses HCC malignant phenotype in vitro and in vivo.","method":"Peptide-PROTAC design; PTGES3 protein degradation assay; HCC cell proliferation and xenograft in vivo assays","journal":"Biology direct","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — targeted degradation validated in vitro and in vivo with phenotypic readouts; single lab, mechanistic inference from PROTAC approach","pmids":["39726032"],"is_preprint":false}],"current_model":"PTGES3 (cPGES/p23) is a multifunctional protein that acts as an Hsp90-associated co-chaperone (p23): it stabilizes the glucocorticoid receptor (GR) complex and is required for GR-dependent gene induction in vivo; it binds directly to the androgen receptor (AR) in the nucleus, regulating AR protein stability and transcriptional activity at AR target genes; it possesses cytosolic PGH2-to-PGE2 isomerase activity coupled to COX-1 in some cellular contexts and positively regulates expression of the PGE2-inactivating enzyme 15-PGDH; and it forms a complex with Hsp90 that can be disrupted by covalent modification at Cys58, suppressing NF-κB signaling—making PTGES3 a chaperone co-factor at the intersection of steroid receptor signaling, prostaglandin metabolism, and inflammatory pathways."},"narrative":{"mechanistic_narrative":"PTGES3 (cPGES/p23) is an Hsp90-associated co-chaperone that operates at the intersection of steroid receptor signaling, prostaglandin metabolism, and inflammatory pathways [PMID:17438133, PMID:17719010]. As a stabilizer of the Hsp90 chaperone complex, it is required for glucocorticoid receptor function in vivo: PTGES3-knockout mice fail to induce GR-sensitive gluconeogenic enzymes prenatally and phenocopy GR-deficient neonates, with retarded lung development [PMID:17438133]. In prostate cancer cells PTGES3 binds the androgen receptor directly, forms a nuclear AR complex, and is required for AR protein stability and transcription at AR target genes; its loss collapses AR protein levels and triggers cell-cycle arrest and death in AR-driven models [PMID:41193657]. PTGES3 also contributes to prostaglandin homeostasis, with knockout pups showing reduced lung PGE2 content [PMID:17719010] and PTGES3 positively regulating the PGE2-inactivating enzyme 15-PGDH [PMID:21334450], although metabolite profiling in embryonic tissues and fibroblasts argued against a general role in PGE2 biosynthesis [PMID:17438133]. Covalent modification of Cys58 at an allosteric site disrupts the PTGES3-Hsp90 complex and inhibits its PGE2 synthase activity, suppressing NF-κB signaling [PMID:42144059]. Across multiple cancer contexts—breast, hepatocellular, and prostate—PTGES3 depletion impairs proliferation, migration, and viability, marking it as a candidate dependency amenable to degrader approaches [PMID:41193657, PMID:38245717, PMID:39726032].","teleology":[{"year":2007,"claim":"Establishing whether PTGES3 has an essential physiological function clarified its role as a stabilizer of the glucocorticoid receptor complex rather than solely a prostaglandin synthase.","evidence":"Knockout mouse with GR-sensitive gluconeogenic enzyme induction analysis and arachidonic acid metabolite profiling","pmids":["17438133"],"confidence":"High","gaps":["Did not resolve the direct biochemical mechanism of GR complex stabilization","Metabolite data conflicted with a PGE2 biosynthesis role"]},{"year":2007,"claim":"The same knockout revealed a proliferation requirement, indicating PTGES3 function extends beyond GR stabilization.","evidence":"Body weight measurements and primary fibroblast proliferation assays in null mice","pmids":["17438133"],"confidence":"Medium","gaps":["Molecular driver of the proliferation defect not identified","Single lab"]},{"year":2007,"claim":"An independent knockout addressed the contested PGE2 question, providing evidence that PTGES3 contributes to lung PGE2 in vivo.","evidence":"Knockout targeting catalytic Tyr9 exons with lung PGE2 quantification","pmids":["17719010"],"confidence":"Medium","gaps":["Partially contradicts the metabolite findings of the parallel knockout study","Tissue-specific basis of the discrepancy unresolved"]},{"year":2011,"claim":"Linking PTGES3 to 15-PGDH expression extended its influence over prostaglandin homeostasis to PGE2 degradation, not just synthesis.","evidence":"Null fibroblast analysis, siRNA knockdown, and overexpression with 15-PGDH promoter luciferase reporter","pmids":["21334450"],"confidence":"Medium","gaps":["Direct vs indirect transcriptional mechanism not established","Single lab; rat 3Y1 cell context"]},{"year":2024,"claim":"Loss-of-function in breast cancer cells positioned PTGES3 as a tumor cell growth and motility factor.","evidence":"siRNA knockdown with CCK-8 viability and wound-healing migration assays","pmids":["38245717"],"confidence":"Medium","gaps":["Molecular pathway mediating proliferation/migration not defined","Single lab"]},{"year":2024,"claim":"A peptide-PROTAC demonstrated PTGES3 is druggable by targeted degradation and that its depletion suppresses HCC malignancy.","evidence":"Liposomal peptide-PROTAC with proteasomal degradation assays and HCC xenograft models","pmids":["39726032"],"confidence":"Medium","gaps":["Specificity of the binding peptide for PTGES3 not fully delineated","Downstream effector pathway in HCC not identified"]},{"year":2025,"claim":"An unbiased screen identified PTGES3 as a direct AR-binding regulator of AR stability, defining a chaperone role specific to prostate cancer dependency.","evidence":"Genome-scale CRISPRi screen with live-cell AR reporter, direct binding/co-IP, AR stability assays, and chromatin AR target gene analysis","pmids":["41193657"],"confidence":"High","gaps":["Structural basis of the direct PTGES3-AR interaction not resolved","Whether AR regulation requires Hsp90 co-chaperone activity not tested"]},{"year":2026,"claim":"Covalent targeting of Cys58 mapped an allosteric site whose modification couples PTGES3 enzymatic and chaperone functions to NF-κB suppression.","evidence":"Activity-based protein profiling, Cys58 mutagenesis, PGE2 synthase assay, and Ptges3 knockdown in bleomycin/LPS mouse models","pmids":["42144059"],"confidence":"High","gaps":["How Cys58 modification mechanistically disrupts Hsp90 binding not structurally defined","Link between PGE2 synthase activity loss and NF-κB suppression not dissected"]},{"year":null,"claim":"It remains unresolved how PTGES3's distinct activities—Hsp90 co-chaperone, steroid receptor stabilizer, and PGE2 synthase—are mechanistically integrated within a single protein and which is operative in each disease context.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified structural model linking the catalytic, Hsp90-binding, and AR-binding functions","Context-dependence of PGE2 synthase activity in vivo unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[4]},{"term_id":"GO:0044183","term_label":"protein folding chaperone","supporting_discovery_ids":[0,6]},{"term_id":"GO:0016853","term_label":"isomerase activity","supporting_discovery_ids":[2,5]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,4]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[4]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,4]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[4,6]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[2,3,5]}],"complexes":["Hsp90 chaperone complex"],"partners":["HSP90","AR","CK2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q15185","full_name":"Prostaglandin E synthase 3","aliases":["Cytosolic prostaglandin E2 synthase","cPGES","Hsp90 co-chaperone","Progesterone receptor complex p23","Telomerase-binding protein p23"],"length_aa":160,"mass_kda":18.7,"function":"Cytosolic prostaglandin synthase that catalyzes the oxidoreduction of prostaglandin endoperoxide H2 (PGH2) to prostaglandin E2 (PGE2) (PubMed:10922363). Molecular chaperone that localizes to genomic response elements in a hormone-dependent manner and disrupts receptor-mediated transcriptional activation, by promoting disassembly of transcriptional regulatory complexes (PubMed:11274138, PubMed:12077419). Facilitates HIF alpha proteins hydroxylation via interaction with EGLN1/PHD2, leading to recruit EGLN1/PHD2 to the HSP90 pathway (PubMed:24711448)","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q15185/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PTGES3","classification":"Not Classified","n_dependent_lines":139,"n_total_lines":1208,"dependency_fraction":0.11506622516556292},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000110958","cell_line_id":"CID000073","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"nucleoplasm","grade":3}],"interactors":[{"gene":"HSP90AA1","stoichiometry":10.0},{"gene":"HSP90AB1","stoichiometry":10.0},{"gene":"PFDN6","stoichiometry":4.0},{"gene":"HSP90B1","stoichiometry":4.0},{"gene":"RUVBL1","stoichiometry":4.0},{"gene":"RUVBL2","stoichiometry":4.0},{"gene":"CACYBP","stoichiometry":4.0},{"gene":"FKBP4","stoichiometry":4.0},{"gene":"FKBP5","stoichiometry":0.2},{"gene":"FKBP8","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000073","total_profiled":1310},"omim":[{"mim_id":"615940","title":"PROTEIN TYROSINE PHOSPHATASE-LIKE A DOMAIN-CONTAINING PROTEIN 1; PTPLAD1","url":"https://www.omim.org/entry/615940"},{"mim_id":"610346","title":"CELL DIVISION CYCLE 37-LIKE 1; CDC37L1","url":"https://www.omim.org/entry/610346"},{"mim_id":"610325","title":"NUCLEAR DISTRIBUTION C, DYNEIN COMPLEX REGULATOR; NUDC","url":"https://www.omim.org/entry/610325"},{"mim_id":"610296","title":"NUDC DOMAIN-CONTAINING PROTEIN 3; NUDCD3","url":"https://www.omim.org/entry/610296"},{"mim_id":"607061","title":"PROSTAGLANDIN E SYNTHASE 3; PTGES3","url":"https://www.omim.org/entry/607061"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PTGES3"},"hgnc":{"alias_symbol":["p23","TEBP","cPGES"],"prev_symbol":[]},"alphafold":{"accession":"Q15185","domains":[{"cath_id":"2.60.40.790","chopping":"1-84","consensus_level":"medium","plddt":97.2832,"start":1,"end":84}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15185","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q15185-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q15185-F1-predicted_aligned_error_v6.png","plddt_mean":85.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PTGES3","jax_strain_url":"https://www.jax.org/strain/search?query=PTGES3"},"sequence":{"accession":"Q15185","fasta_url":"https://rest.uniprot.org/uniprotkb/Q15185.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q15185/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15185"}},"corpus_meta":[{"pmid":"8557195","id":"PMC_8557195","title":"The T/ebp null mouse: thyroid-specific enhancer-binding protein is essential for the organogenesis of the thyroid, lung, ventral forebrain, and pituitary.","date":"1996","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/8557195","citation_count":958,"is_preprint":false},{"pmid":"17237767","id":"PMC_17237767","title":"TPP1 is a homologue of ciliate TEBP-beta and interacts with POT1 to recruit telomerase.","date":"2007","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/17237767","citation_count":390,"is_preprint":false},{"pmid":"1922026","id":"PMC_1922026","title":"Thyroid-specific enhancer-binding protein (T/EBP): cDNA cloning, functional characterization, and structural identity with thyroid transcription factor TTF-1.","date":"1991","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/1922026","citation_count":111,"is_preprint":false},{"pmid":"24345775","id":"PMC_24345775","title":"Dysregulation of glucocorticoid receptor co-factors FKBP5, BAG1 and PTGES3 in prefrontal cortex in psychotic illness.","date":"2013","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/24345775","citation_count":88,"is_preprint":false},{"pmid":"17438133","id":"PMC_17438133","title":"cPGES/p23 is required for glucocorticoid receptor function and embryonic growth but not prostaglandin E2 synthesis.","date":"2007","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/17438133","citation_count":66,"is_preprint":false},{"pmid":"19347995","id":"PMC_19347995","title":"The terminal prostaglandin synthases mPGES-1, mPGES-2, and cPGES are all overexpressed in human gliomas.","date":"2009","source":"Neuropathology : official journal of the Japanese Society of Neuropathology","url":"https://pubmed.ncbi.nlm.nih.gov/19347995","citation_count":44,"is_preprint":false},{"pmid":"17719010","id":"PMC_17719010","title":"Knockout mice lacking cPGES/p23, a constitutively expressed PGE2 synthetic enzyme, are peri-natally lethal.","date":"2007","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/17719010","citation_count":43,"is_preprint":false},{"pmid":"25912394","id":"PMC_25912394","title":"Altered mRNA Levels of Glucocorticoid Receptor, Mineralocorticoid Receptor, and Co-Chaperones (FKBP5 and PTGES3) in the Middle Frontal Gyrus of Autism Spectrum Disorder Subjects.","date":"2015","source":"Molecular neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/25912394","citation_count":38,"is_preprint":false},{"pmid":"16806120","id":"PMC_16806120","title":"Cytosolic prostaglandin E2 synthase (cPGES) expression is decreased in discrete cortical regions in psychiatric disease.","date":"2006","source":"Brain research","url":"https://pubmed.ncbi.nlm.nih.gov/16806120","citation_count":33,"is_preprint":false},{"pmid":"33976151","id":"PMC_33976151","title":"The double-stranded DNA-binding proteins TEBP-1 and TEBP-2 form a telomeric complex with POT-1.","date":"2021","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/33976151","citation_count":17,"is_preprint":false},{"pmid":"7711079","id":"PMC_7711079","title":"The complete nucleotide sequence of the mouse thyroid-specific enhancer-binding protein (T/EBP) gene: extensive identity of the deduced amino acid sequence with the human protein.","date":"1995","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/7711079","citation_count":16,"is_preprint":false},{"pmid":"38245717","id":"PMC_38245717","title":"The integration of multidisciplinary approaches revealed PTGES3 as a novel drug target for breast cancer treatment.","date":"2024","source":"Journal of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/38245717","citation_count":13,"is_preprint":false},{"pmid":"32222548","id":"PMC_32222548","title":"A multi-approach analysis highlights the relevance of RPA-1 as a telomere end-binding protein (TEBP) in Leishmania amazonensis.","date":"2020","source":"Biochimica et biophysica acta. General subjects","url":"https://pubmed.ncbi.nlm.nih.gov/32222548","citation_count":11,"is_preprint":false},{"pmid":"21334450","id":"PMC_21334450","title":"Involvement of the constitutive prostaglandin E synthase cPGES/p23 in expression of an initial prostaglandin E2 inactivating enzyme, 15-PGDH.","date":"2011","source":"Prostaglandins & other lipid mediators","url":"https://pubmed.ncbi.nlm.nih.gov/21334450","citation_count":9,"is_preprint":false},{"pmid":"16314111","id":"PMC_16314111","title":"Thermodynamic and electrostatic properties of ternary Oxytricha nova TEBP-DNA complex.","date":"2005","source":"Journal of structural biology","url":"https://pubmed.ncbi.nlm.nih.gov/16314111","citation_count":6,"is_preprint":false},{"pmid":"38588418","id":"PMC_38588418","title":"Caenorhabditis elegans telomere-binding proteins TEBP-1 and TEBP-2 adapt the Myb module to dimerize and bind telomeric DNA.","date":"2024","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/38588418","citation_count":5,"is_preprint":false},{"pmid":"39726032","id":"PMC_39726032","title":"PTGES3 proteolysis using the liposomal peptide-PROTAC approach.","date":"2024","source":"Biology direct","url":"https://pubmed.ncbi.nlm.nih.gov/39726032","citation_count":5,"is_preprint":false},{"pmid":"41193657","id":"PMC_41193657","title":"Genome-scale CRISPR screens identify PTGES3 as a direct modulator of androgen receptor function in advanced prostate cancer.","date":"2025","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/41193657","citation_count":3,"is_preprint":false},{"pmid":"40237054","id":"PMC_40237054","title":"Integrated Metabolomics and Proteomics to Decipher Simiao Pill Improving Lipid Homeostasis through PTGES3-mediated Arachidonic Acid Metabolism in AIA Model.","date":"2025","source":"Current pharmaceutical design","url":"https://pubmed.ncbi.nlm.nih.gov/40237054","citation_count":2,"is_preprint":false},{"pmid":"40501535","id":"PMC_40501535","title":"Genome-wide CRISPR screens identify PTGES3 as a novel AR modulator.","date":"2025","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/40501535","citation_count":0,"is_preprint":false},{"pmid":"42144059","id":"PMC_42144059","title":"Andrographolide attenuates pulmonary fibrosis by covalently targeting Ptges3 and disrupting the Ptges3-Hsp90-NF-κB axis.","date":"2026","source":"Journal of advanced research","url":"https://pubmed.ncbi.nlm.nih.gov/42144059","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.07.15.664547","title":"Programmable translational inhibition by a molecular glue-oligonucleotide conjugate","date":"2025-07-16","source":"bioRxiv","url":"https://doi.org/10.1101/2025.07.15.664547","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":13207,"output_tokens":2433,"usd":0.038058,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9548,"output_tokens":2850,"usd":0.059495,"stage2_stop_reason":"end_turn"},"total_usd":0.097553,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2007,\n      \"finding\": \"cPGES/p23 (PTGES3) is required for glucocorticoid receptor (GR) function in vivo: cPGES/p23-knockout mice display retarded lung development and failure to induce GR-sensitive gluconeogenic enzymes prenatally, phenocopying GR-deficient neonates, establishing PTGES3 as a stabilizer of the GR complex. However, analysis of arachidonic acid metabolites in embryonic tissues and primary fibroblasts failed to support a role for this protein in PGE2 biosynthesis in vivo.\",\n      \"method\": \"Knockout mouse generation; analysis of GR-sensitive gluconeogenic enzyme induction; arachidonic acid metabolite profiling in embryonic tissues and primary fibroblasts\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO with defined cellular and developmental phenotypes, multiple orthogonal readouts (lung morphology, enzyme induction, metabolite profiling), replicated by independent lab (PMID:17719010)\",\n      \"pmids\": [\"17438133\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"cPGES/p23-null embryos are smaller and primary fibroblasts show a proliferation defect, revealing a role for PTGES3 in cell proliferation beyond GR stabilization.\",\n      \"method\": \"Knockout mouse generation; body weight measurements; primary fibroblast proliferation assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with defined phenotypic readout (proliferation), single lab, two orthogonal measurements\",\n      \"pmids\": [\"17438133\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"cPGES/p23-null pups die perinatally with abnormal skin and lung morphology and lower lung PGE2 content, indicating that cPGES (PTGES3) contributes to PGE2 biosynthesis in lung development in vivo.\",\n      \"method\": \"Knockout mouse generation targeting catalytic Tyr9-containing exons; PGE2 measurement in lung tissue by ELISA/mass spectrometry\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with defined phenotype and biochemical readout (PGE2 levels), single lab; partially contradicts PMID:17438133 on PGE2 synthesis role\",\n      \"pmids\": [\"17719010\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"PTGES3 (cPGES/p23) positively regulates expression of the PGE2-inactivating enzyme 15-PGDH: cPGES/p23-null fibroblasts show decreased 15-PGDH expression; siRNA knockdown of cPGES/p23 in 3Y1 cells reduces 15-PGDH expression; and forced overexpression of cPGES/p23 in 3Y1 cells increases 15-PGDH promoter activity.\",\n      \"method\": \"Knockout fibroblast analysis; siRNA knockdown; forced overexpression with luciferase promoter reporter assay\",\n      \"journal\": \"Prostaglandins & other lipid mediators\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function and gain-of-function with reporter assay, single lab, multiple orthogonal approaches\",\n      \"pmids\": [\"21334450\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PTGES3 binds directly to the androgen receptor (AR), forms a protein complex with AR in the nucleus, regulates AR protein stability, and is necessary for AR function at AR target genes in prostate cancer cells; PTGES3 repression causes loss of AR protein, cell-cycle arrest, and cell death in AR-driven prostate cancer models.\",\n      \"method\": \"Genome-scale CRISPRi screen with live-cell AR fluorescent reporter; co-immunoprecipitation/direct binding assays; AR protein stability assays in vitro and in vivo; chromatin-associated AR target gene analysis; cell-cycle and viability assays after PTGES3 knockdown\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-scale functional screen validated with direct binding, protein stability, nuclear function, and cell phenotype assays; peer-reviewed, multiple orthogonal methods\",\n      \"pmids\": [\"41193657\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Andrographolide covalently binds Cys58 of PTGES3 at an allosteric site distinct from both its catalytic and Hsp90-binding regions; this inhibits PTGES3 enzymatic (PGE2 synthase) activity and disrupts the PTGES3-Hsp90 chaperone complex, leading to suppressed NF-κB signaling; genetic knockdown of Ptges3 attenuates the anti-inflammatory/antifibrotic effects of andrographolide in vitro and in vivo.\",\n      \"method\": \"Activity-based protein profiling (ABPP) for covalent target identification; site-specific mutagenesis (Cys58); enzymatic PGE2 synthase assay; molecular docking; biophysical analyses; siRNA knockdown in vitro and lung-specific Ptges3 knockdown in bleomycin/LPS mouse models\",\n      \"journal\": \"Journal of advanced research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — ABPP-based covalent site identification with mutagenesis validation, enzymatic assay, and in vivo knockdown with functional consequence; multiple orthogonal methods in single study\",\n      \"pmids\": [\"42144059\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Hsp90 regulates both cPGES/p23 (PTGES3) and its client protein kinase CK2, identifying PTGES3 as an Hsp90-associated co-chaperone (p23) that participates in Hsp90 client regulation.\",\n      \"method\": \"Cited as prior finding within the cPGES/p23 knockout study; biochemical characterization of Hsp90 complex\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — referenced as prior finding within abstract without detailed methods described; single lab\",\n      \"pmids\": [\"17719010\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PTGES3 knockdown by siRNA in breast cancer cell lines significantly inhibits cell proliferation and migration, establishing a functional role in breast cancer cell growth and motility.\",\n      \"method\": \"siRNA transfection into breast cancer cell lines; CCK-8 cell viability assay; wound healing migration assay\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean loss-of-function with two orthogonal cellular phenotype readouts (proliferation and migration), single lab\",\n      \"pmids\": [\"38245717\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PTGES3-PROTAC (a liposomal peptide-PROTAC using a PTGES3-binding peptide and the E3 ligase ligand pomalidomide) effectively degrades PTGES3 protein via ubiquitin-proteasome pathway and suppresses HCC malignant phenotype in vitro and in vivo.\",\n      \"method\": \"Peptide-PROTAC design; PTGES3 protein degradation assay; HCC cell proliferation and xenograft in vivo assays\",\n      \"journal\": \"Biology direct\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — targeted degradation validated in vitro and in vivo with phenotypic readouts; single lab, mechanistic inference from PROTAC approach\",\n      \"pmids\": [\"39726032\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PTGES3 (cPGES/p23) is a multifunctional protein that acts as an Hsp90-associated co-chaperone (p23): it stabilizes the glucocorticoid receptor (GR) complex and is required for GR-dependent gene induction in vivo; it binds directly to the androgen receptor (AR) in the nucleus, regulating AR protein stability and transcriptional activity at AR target genes; it possesses cytosolic PGH2-to-PGE2 isomerase activity coupled to COX-1 in some cellular contexts and positively regulates expression of the PGE2-inactivating enzyme 15-PGDH; and it forms a complex with Hsp90 that can be disrupted by covalent modification at Cys58, suppressing NF-κB signaling—making PTGES3 a chaperone co-factor at the intersection of steroid receptor signaling, prostaglandin metabolism, and inflammatory pathways.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PTGES3 (cPGES/p23) is an Hsp90-associated co-chaperone that operates at the intersection of steroid receptor signaling, prostaglandin metabolism, and inflammatory pathways [#0, #6]. As a stabilizer of the Hsp90 chaperone complex, it is required for glucocorticoid receptor function in vivo: PTGES3-knockout mice fail to induce GR-sensitive gluconeogenic enzymes prenatally and phenocopy GR-deficient neonates, with retarded lung development [#0]. In prostate cancer cells PTGES3 binds the androgen receptor directly, forms a nuclear AR complex, and is required for AR protein stability and transcription at AR target genes; its loss collapses AR protein levels and triggers cell-cycle arrest and death in AR-driven models [#4]. PTGES3 also contributes to prostaglandin homeostasis, with knockout pups showing reduced lung PGE2 content [#2] and PTGES3 positively regulating the PGE2-inactivating enzyme 15-PGDH [#3], although metabolite profiling in embryonic tissues and fibroblasts argued against a general role in PGE2 biosynthesis [#0]. Covalent modification of Cys58 at an allosteric site disrupts the PTGES3-Hsp90 complex and inhibits its PGE2 synthase activity, suppressing NF-\\u03baB signaling [#5]. Across multiple cancer contexts\\u2014breast, hepatocellular, and prostate\\u2014PTGES3 depletion impairs proliferation, migration, and viability, marking it as a candidate dependency amenable to degrader approaches [#4, #7, #8].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Establishing whether PTGES3 has an essential physiological function clarified its role as a stabilizer of the glucocorticoid receptor complex rather than solely a prostaglandin synthase.\",\n      \"evidence\": \"Knockout mouse with GR-sensitive gluconeogenic enzyme induction analysis and arachidonic acid metabolite profiling\",\n      \"pmids\": [\"17438133\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the direct biochemical mechanism of GR complex stabilization\", \"Metabolite data conflicted with a PGE2 biosynthesis role\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"The same knockout revealed a proliferation requirement, indicating PTGES3 function extends beyond GR stabilization.\",\n      \"evidence\": \"Body weight measurements and primary fibroblast proliferation assays in null mice\",\n      \"pmids\": [\"17438133\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular driver of the proliferation defect not identified\", \"Single lab\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"An independent knockout addressed the contested PGE2 question, providing evidence that PTGES3 contributes to lung PGE2 in vivo.\",\n      \"evidence\": \"Knockout targeting catalytic Tyr9 exons with lung PGE2 quantification\",\n      \"pmids\": [\"17719010\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Partially contradicts the metabolite findings of the parallel knockout study\", \"Tissue-specific basis of the discrepancy unresolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Linking PTGES3 to 15-PGDH expression extended its influence over prostaglandin homeostasis to PGE2 degradation, not just synthesis.\",\n      \"evidence\": \"Null fibroblast analysis, siRNA knockdown, and overexpression with 15-PGDH promoter luciferase reporter\",\n      \"pmids\": [\"21334450\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect transcriptional mechanism not established\", \"Single lab; rat 3Y1 cell context\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Loss-of-function in breast cancer cells positioned PTGES3 as a tumor cell growth and motility factor.\",\n      \"evidence\": \"siRNA knockdown with CCK-8 viability and wound-healing migration assays\",\n      \"pmids\": [\"38245717\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular pathway mediating proliferation/migration not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"A peptide-PROTAC demonstrated PTGES3 is druggable by targeted degradation and that its depletion suppresses HCC malignancy.\",\n      \"evidence\": \"Liposomal peptide-PROTAC with proteasomal degradation assays and HCC xenograft models\",\n      \"pmids\": [\"39726032\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specificity of the binding peptide for PTGES3 not fully delineated\", \"Downstream effector pathway in HCC not identified\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"An unbiased screen identified PTGES3 as a direct AR-binding regulator of AR stability, defining a chaperone role specific to prostate cancer dependency.\",\n      \"evidence\": \"Genome-scale CRISPRi screen with live-cell AR reporter, direct binding/co-IP, AR stability assays, and chromatin AR target gene analysis\",\n      \"pmids\": [\"41193657\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the direct PTGES3-AR interaction not resolved\", \"Whether AR regulation requires Hsp90 co-chaperone activity not tested\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Covalent targeting of Cys58 mapped an allosteric site whose modification couples PTGES3 enzymatic and chaperone functions to NF-\\u03baB suppression.\",\n      \"evidence\": \"Activity-based protein profiling, Cys58 mutagenesis, PGE2 synthase assay, and Ptges3 knockdown in bleomycin/LPS mouse models\",\n      \"pmids\": [\"42144059\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How Cys58 modification mechanistically disrupts Hsp90 binding not structurally defined\", \"Link between PGE2 synthase activity loss and NF-\\u03baB suppression not dissected\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how PTGES3's distinct activities\\u2014Hsp90 co-chaperone, steroid receptor stabilizer, and PGE2 synthase\\u2014are mechanistically integrated within a single protein and which is operative in each disease context.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified structural model linking the catalytic, Hsp90-binding, and AR-binding functions\", \"Context-dependence of PGE2 synthase activity in vivo unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0044183\", \"supporting_discovery_ids\": [0, 6]},\n      {\"term_id\": \"GO:0016853\", \"supporting_discovery_ids\": [2, 5]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 4]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [4, 6]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [2, 3, 5]}\n    ],\n    \"complexes\": [\"Hsp90 chaperone complex\"],\n    \"partners\": [\"HSP90\", \"AR\", \"CK2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}