{"gene":"PPARD","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":1995,"finding":"hNUC1 (PPARD) acts as a repressor of hPPARα and human thyroid hormone receptor transcriptional activation. It cooperatively binds a PPAR-responsive element with hRXRα, and in the presence of hRXRα its affinity for the peroxisome proliferator ligand is comparable to hPPARα. Repression of hPPARα can be overcome by transfecting excess hPPARα, suggesting hNUC1 titrates out a factor required for activation.","method":"Transient transfection reporter assays, cooperative DNA binding assays, ligand binding assays in the presence of hRXRα","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional assays (reporter, binding, competition) in single lab; establishes repressor mechanism and RXRα co-binding","pmids":["7876127"],"is_preprint":false},{"year":2007,"finding":"A selective small-molecule PPARβ/δ (PPARD) antagonist ligand was identified and characterized, demonstrating that the receptor's biological activity can be blocked by a specific ligand — the first antagonist described for this receptor subtype.","method":"Cellular and biochemical characterization of small molecule antagonist ligand binding and functional activity","journal":"Molecular endocrinology (Baltimore, Md.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ligand characterization with functional cellular assays, single lab but multiple methods","pmids":["17975020"],"is_preprint":false},{"year":2011,"finding":"A missense mutation (G32E) in the A/B domain of porcine PPARD is the causal variant underlying a major QTL for ear size; the mutation mediates downregulation of β-catenin and its target gene expression crucial for fat deposition in skin.","method":"QTL mapping, identical-by-descent analysis, selective sweep analysis, luciferase reporter assays for β-catenin target gene expression, association studies in experimental cross and outbred populations","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic fine-mapping plus functional reporter assay; single lab but multiple orthogonal approaches","pmids":["21573137"],"is_preprint":false},{"year":2013,"finding":"The G32E substitution in porcine PPARD (A/B domain) reduces transcription activity in a ligand-dependent manner, promotes CRM1-mediated nuclear export of PPARD, and greatly reduces ubiquitination of the A/B domain, consequently decreasing transcriptional activity. Surface plasmon resonance showed the mutation has negligible effect on ligand binding affinity.","method":"Luciferase reporter assays, subcellular localization imaging in PK-15 cells and primary chondrocytes, co-immunoprecipitation for ubiquitination, surface plasmon resonance for ligand binding","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (reporter assay, live-cell localization, CoIP, SPR) in single study establishing mechanism of A/B domain mutation","pmids":["24058710"],"is_preprint":false},{"year":2015,"finding":"PPARD modulates spermatogenesis by regulating Sertoli cell function via temporal inhibition of ERK activation. Ligand activation of PPARD inhibited Sertoli cell (TM4) proliferation; PPARD-dependent ERK signaling altered expression of claudin-11, p27, cyclin D1, and cyclin D2, causing inhibition of proliferation, maturation, and tight junction formation in Sertoli cells.","method":"Ppard knockout mouse phenotyping, immunofluorescence, western blotting, Sertoli cell line (TM4) treatment with PPARD ligand and inverse agonist (DG172), ERK pathway analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo KO phenotype plus in vitro mechanistic rescue with ligand/inverse agonist; multiple pathway readouts across two orthogonal systems","pmids":["26242735"],"is_preprint":false},{"year":2015,"finding":"In porcine PPARD, functional SNPs (g.1015 A>G and g.1018 T>C) in the 5' regulatory region affect transcriptional activity; TCF7L2 (transcription factor 7-like 2) enhances PPARD promoter transcription in C2C12 and 3T3-L1 cells and binds differentially to the haplotypes, with haplotype AC showing the lowest TCF7L2 binding capacity and transcriptional activity.","method":"Luciferase reporter assays, electrophoretic mobility shift assay (nuclear extract binding), western blot of PPARD protein expression, qPCR, association analysis in pig populations","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reporter assay plus EMSA plus protein expression; single lab, multiple orthogonal methods","pmids":["26599230"],"is_preprint":false},{"year":2017,"finding":"PPARD promotes tumor metastasis by promoting angiogenesis via interleukin-8 (IL-8) in vivo and in vitro. Genetic deletion of PPARD in cancer cells identified pro-metastatic target genes (GJA1, VIM, SPARC, STC1, SNCG) and demonstrated PPARD's necessity for epithelial-mesenchymal transition, migration, and invasion.","method":"Genetic deletion (CRISPR) of PPARD in cancer cells, in vivo metastasis models, transcriptome profiling, TCGA database analysis, migration/invasion assays, angiogenesis assay with IL-8 quantification","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic deletion in multiple cancer models in vivo plus mechanistic pathway (IL-8/angiogenesis) identified in vitro; multiple orthogonal methods","pmids":["28097239"],"is_preprint":false},{"year":2017,"finding":"PPARD retards auricular cartilage development by accelerating apoptosis of cartilage stem/progenitor cells (CSPCs), promoting terminal differentiation, and degrading cartilage extracellular matrix. ChIP-seq identified direct PPARD target genes including PPARG, and the G32E mutant upregulates PPARG expression, leading to downregulation of genes that inhibit cartilage growth.","method":"ChIP-seq, gene expression analysis, apoptosis assays, histological analysis of cartilage, comparison of wild-type vs. G32E mutant PPARD","journal":"International journal of biological sciences","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — ChIP-seq for direct target identification plus functional cellular phenotype assays; multiple methods supporting mechanistic model","pmids":["28539839"],"is_preprint":false},{"year":2018,"finding":"An insulator element (CTCF binding confirmed) and a repressor/silencer element were identified and functionally validated in intron 2 of the human PPARD gene; the two cis-regulatory elements interact with each other.","method":"Bioinformatic prediction, transient transfection reporter assays, CTCF binding assay, ENCODE 5C data","journal":"Epigenomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reporter assay plus CTCF binding confirmation; single lab, two orthogonal methods","pmids":["29583017"],"is_preprint":false},{"year":2019,"finding":"PPARD overexpression or deletion in intestinal epithelial cells augments or suppresses β-catenin activation via up- or downregulation of BMP7/TAK1 signaling, strongly promoting or suppressing colorectal cancer. Depletion of PPARD in human colorectal cancer organoid cells inhibited BMP7/β-catenin signaling and suppressed organoid self-renewal. PPARD agonist GW501516 enhanced tumorigenesis in Apc mice while antagonist GSK3787 suppressed it. Reverse-phase protein microarray identified additional PPARD-regulated proinvasive pathways: connexin 43, PDGFRβ, AKT1, EIF4G1, and CDK1.","method":"Mouse models of PPARD overexpression/deletion combined with Apc mutation, human CRC organoids with PPARD depletion, pharmacological agonist/antagonist treatment in Apc mice, reverse-phase protein microarray","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic gain- and loss-of-function in multiple in vivo and in vitro models; BMP7/TAK1/β-catenin pathway placement established by multiple orthogonal approaches","pmids":["30679176"],"is_preprint":false},{"year":2019,"finding":"PPARD overexpression in villin-positive gastric progenitor cells (VGPCs) causes spontaneous invasive gastric adenocarcinoma in mice. Mechanistically, PPARD upregulates CCL20 and CXCL1 chemokines, increasing immune cell infiltration; a positive-feedback loop between PPARD and interferon gamma (IFNγ) signaling sustains gastric inflammation and drives VGPC transformation and tumorigenesis.","method":"Villin-PPARD transgenic mouse model, lineage-tracing experiments, cytokine/chemokine profiling, immunohistochemistry, transcriptome analysis, PPARD/IFNγ feedback loop characterization","journal":"Gastroenterology","confidence":"High","confidence_rationale":"Tier 2 / Strong — transgenic mouse model with lineage tracing, cytokine profiling, and mechanistic feedback loop identification; multiple orthogonal methods","pmids":["30885780"],"is_preprint":false},{"year":2020,"finding":"Conditional deletion of Ppard in CD11c+ cells attenuated atherosclerotic plaque formation and reduced activation and migration of myeloid-derived dendritic cells and T lymphocyte polarization to Th1. In bone marrow-derived DCs, Ppard deficiency reduced palmitic acid-induced upregulation of co-stimulatory molecules and pro-inflammatory cytokines IL-12 and TNFα, demonstrating that PPARδ activation by fatty acids mediates DC activation.","method":"Cre-loxP conditional knockout in ApoE-/- mice on high cholesterol diet, bone marrow-derived DC culture with palmitic acid, flow cytometry, cytokine measurements","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO in vivo atherosclerosis model plus in vitro mechanistic validation in primary DCs; multiple orthogonal methods","pmids":["31919912"],"is_preprint":false},{"year":2025,"finding":"Dietary lipid accumulation (oleic acid) in macrophages via CD36 leads to PPARδ (PPARD) release of the transcriptional repressor BCL6, which suppresses Il23a transcription in LPS-exposed macrophages. Deleting CD36 on macrophages restored IL-23 and IL-22 responses and reduced intestinal damage in HFD-fed DSS-treated mice.","method":"Conditional CD36 knockout in macrophages, DSS colitis model, oleic acid treatment of macrophages, LPS stimulation, IL-23/IL-22 measurements, PPARδ/BCL6 co-repressor complex characterization","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo conditional KO rescue plus in vitro mechanistic dissection of PPARD/BCL6 repressor complex; multiple orthogonal methods","pmids":["40717126"],"is_preprint":false},{"year":2025,"finding":"H3K18 lactylation (H3K18la) promotes PPARD expression in breast cancer cells; PPARD in turn promotes transcription and phosphorylation of AKT (but not ILK), supporting cell survival under anaerobic glycolysis conditions. HDAC2 and HDAC3 act as erasers for H3 lysine lactylation upstream of PPARD.","method":"ChIP-seq with H3K18la antibodies, transcriptomics, proteomics, ATAC-seq, qPCR, western blot; HDAC2/3 identified as H3K18la erasers","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq plus multiple omics approaches in single study; HDAC2/3 as erasers identified but not experimentally reconstituted","pmids":["39922804"],"is_preprint":false},{"year":2025,"finding":"PPARD mediates transcriptional inhibition of MECP2 (methyl-CpG-binding protein 2), which in turn blocks STAT3 activation and alleviates Th17/Treg imbalance. PPARD knockdown-induced Th17/Treg imbalance was rescued by MECP2 deletion or STAT3 inhibition.","method":"PPARD siRNA knockdown, MECP2 deletion, STAT3 inhibition in vitro; rat CARAS model; Th17 differentiation assays","journal":"Phytomedicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function knockdown with epistatic rescue experiments (MECP2 deletion, STAT3 inhibition) confirming pathway placement; single lab","pmids":["40031093"],"is_preprint":false},{"year":2025,"finding":"PPARD activates PDK4 and ANGPTL4 expression in gastric smooth muscle cells (SMCs), leading to SMC dedifferentiation (phenotypic switching) under obese/lipid-excess conditions. Inhibition of PDK4 or ANGPTL4 upregulation prevented lipid-induced SMC modifications.","method":"High-fat diet mouse model, lipid-treated differentiated human gastric SMCs, siRNA-peptide nanoparticles for knockdown, pharmaceutical PPARD activation, global lipidomics and RNA sequencing, immunofluorescence, western blotting, validation in human obesity gastric samples","journal":"Journal of biomedical science","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo HFD model plus in vitro mechanistic dissection with PPARD activation and downstream target inhibition; multiple orthogonal methods validated in human tissue","pmids":["40652248"],"is_preprint":false},{"year":2025,"finding":"ACSS2 promotes acetylation at the H3K27 site in the PPARD promoter region, increasing PPARD transcription, which in turn transcriptionally activates BCAT1 to alter branched-chain amino acid catabolism and promote pancreatic cancer proliferation and invasion.","method":"ACSS2 knockout, ChIP assays for H3K27 acetylation at PPARD promoter, qPCR/western blot for PPARD and BCAT1 expression, functional assays for proliferation and invasion","journal":"Acta biochimica et biophysica Sinica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP evidence for histone acetylation at PPARD promoter plus genetic KO with functional readout; single lab","pmids":["40908872"],"is_preprint":false},{"year":2025,"finding":"PPARD transcriptionally represses CDC20 by binding to its promoter; CDC20 downregulation inhibits proliferation of cisplatin-resistant cervical cancer cells, reduces Wnt/β-catenin pathway activity, and increases apoptosis. APS (Astragalus polysaccharide) promotes PPARD expression to suppress CDC20.","method":"Bioinformatics target prediction, ChIP for PPARD binding at CDC20 promoter, PPARD/CDC20 knockdown, Wnt/β-catenin pathway agonist rescue experiments, xenograft tumor model","journal":"Cytotechnology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP for direct binding plus genetic knockdown with pathway rescue; single lab","pmids":["40538591"],"is_preprint":false}],"current_model":"PPARD (PPARβ/δ) is a ligand-activated nuclear receptor that heterodimerizes with RXRα to bind PPAR-responsive elements and can act as either a transcriptional activator or repressor depending on context; it directly represses hPPARα and thyroid hormone receptors, modulates β-catenin/BMP7/TAK1 signaling in colorectal tumorigenesis, promotes metastasis via IL-8-driven angiogenesis and EMT, drives gastric carcinogenesis through a PPARD/IFNγ positive-feedback loop and CCL20/CXCL1 chemokine upregulation, regulates Sertoli cell function and spermatogenesis via ERK signaling, mediates macrophage inflammatory responses to dietary fatty acids through a PPARδ/BCL6 transcriptional repressor complex suppressing IL-23, transcriptionally represses MECP2 to modulate Th17/Treg balance, and promotes SMC dedifferentiation via a PPARD/PDK4/ANGPTL4 axis; its activity is regulated by ubiquitination and CRM1-mediated nuclear export (modulated by the G32E variant), H3K18 lactylation (with HDAC2/3 as erasers), and upstream H3K27 acetylation at its promoter by ACSS2."},"narrative":{"mechanistic_narrative":"PPARD (PPARβ/δ) is a ligand-activated nuclear receptor that cooperatively binds PPAR-responsive elements with RXRα and acts as a context-dependent transcriptional activator or repressor, originally characterized as a repressor of PPARα and thyroid hormone receptor activation that titrates a factor required for their activity [PMID:7876127]. Its activity is gated at the protein level: a G32E substitution in the A/B domain reduces ligand-dependent transcription by promoting CRM1-mediated nuclear export and reducing A/B-domain ubiquitination without affecting ligand binding [PMID:24058710], and its expression is shaped by cis-regulatory architecture, including an intron-2 insulator/silencer module and TCF7L2-responsive promoter elements [PMID:26599230, PMID:29583017]. As a transcription factor, PPARD directly binds target gene promoters identified by ChIP-seq, including PPARG [PMID:28539839], and represses CDC20 and MECP2 [PMID:40031093, PMID:40538591]. A dominant theme in the corpus is PPARD's role in carcinogenesis and tissue remodeling: it drives colorectal tumorigenesis by augmenting β-catenin activation through BMP7/TAK1 signaling [PMID:30679176], promotes metastasis via IL-8–driven angiogenesis and epithelial–mesenchymal transition [PMID:28097239], and induces invasive gastric adenocarcinoma through CCL20/CXCL1 chemokine induction and a self-sustaining PPARD/IFNγ feedback loop [PMID:30885780]. PPARD also senses dietary fatty acids to control immune and stromal cell states, mediating dendritic cell activation in atherosclerosis [PMID:31919912], restraining macrophage IL-23 via a PPARδ/BCL6 repressor complex downstream of CD36 lipid uptake [PMID:40717126], and driving smooth muscle cell dedifferentiation through a PDK4/ANGPTL4 axis [PMID:40652248]. It additionally regulates Sertoli cell proliferation and spermatogenesis through temporal control of ERK signaling [PMID:26242735].","teleology":[{"year":1995,"claim":"Established the founding biochemical identity of PPARD as an RXRα-partnered nuclear receptor that can repress rather than activate transcription, distinguishing it from PPARα.","evidence":"Transient transfection reporter, cooperative DNA-binding, and ligand-binding assays in the presence of hRXRα","pmids":["7876127"],"confidence":"Medium","gaps":["The titrated 'factor' required for activation was not identified","Endogenous target genes not defined"]},{"year":2007,"claim":"Demonstrated PPARD activity is pharmacologically tractable by identifying the first selective small-molecule antagonist, enabling loss-of-function dissection.","evidence":"Cellular and biochemical characterization of an antagonist ligand","pmids":["17975020"],"confidence":"Medium","gaps":["In vivo efficacy and selectivity not established in this work","Target gene consequences of antagonism not mapped"]},{"year":2011,"claim":"Linked a specific PPARD coding variant to a phenotype, showing the G32E A/B-domain mutation causally drives β-catenin target downregulation in tissue patterning.","evidence":"QTL mapping, IBD/selective sweep analysis, and luciferase reporter assays in porcine populations","pmids":["21573137"],"confidence":"Medium","gaps":["Molecular mechanism of the A/B-domain effect not resolved here","Restricted to porcine ear-size QTL"]},{"year":2013,"claim":"Resolved the molecular mechanism of the G32E variant, showing it impairs transcription by promoting CRM1-mediated nuclear export and reducing ubiquitination rather than altering ligand affinity.","evidence":"Reporter assays, live-cell localization, co-IP for ubiquitination, and SPR for ligand binding","pmids":["24058710"],"confidence":"High","gaps":["E3 ligase and CRM1-binding determinants not identified","Connection to physiological regulation of wild-type PPARD unclear"]},{"year":2015,"claim":"Defined a developmental role in male reproduction, showing PPARD controls Sertoli cell proliferation and tight-junction formation through temporal ERK inhibition.","evidence":"Ppard knockout mouse phenotyping plus TM4 Sertoli cell ligand/inverse-agonist treatment and ERK pathway readouts","pmids":["26242735"],"confidence":"High","gaps":["Direct transcriptional targets linking PPARD to ERK not identified","Ligand identity in vivo unknown"]},{"year":2015,"claim":"Mapped upstream transcriptional control of PPARD, showing TCF7L2 binds the promoter and functional 5' SNPs modulate its expression.","evidence":"Reporter assays, EMSA, western blot, and population association in pig models","pmids":["26599230"],"confidence":"Medium","gaps":["TCF7L2 regulation not confirmed in human cells","Crosstalk with Wnt signaling at PPARD promoter unexplored"]},{"year":2017,"claim":"Established PPARD as a driver of metastasis, showing it is required for EMT, migration, invasion, and IL-8–driven angiogenesis.","evidence":"CRISPR deletion in cancer cells, in vivo metastasis models, transcriptome profiling, and angiogenesis assays","pmids":["28097239"],"confidence":"High","gaps":["Direct vs indirect regulation of target genes (GJA1, VIM, SPARC) not distinguished","Ligand driving metastatic activity not defined"]},{"year":2017,"claim":"Identified direct genomic targets of PPARD including PPARG by ChIP-seq, linking the G32E variant to cartilage developmental phenotypes.","evidence":"ChIP-seq, apoptosis and differentiation assays, and wild-type vs G32E comparison in cartilage progenitors","pmids":["28539839"],"confidence":"High","gaps":["Whether PPARG activation is the sole effector unclear","Generalizability beyond auricular cartilage untested"]},{"year":2018,"claim":"Characterized the cis-regulatory architecture of the human PPARD locus, identifying an intron-2 CTCF insulator and an interacting silencer element.","evidence":"Bioinformatic prediction, reporter assays, CTCF binding assay, and ENCODE 5C data","pmids":["29583017"],"confidence":"Medium","gaps":["Physiological contexts engaging these elements not defined","Effect on endogenous PPARD expression not measured"]},{"year":2019,"claim":"Placed PPARD upstream of β-catenin in colorectal tumorigenesis via BMP7/TAK1 signaling, with bidirectional genetic and pharmacological control of tumor outcome.","evidence":"PPARD gain/loss mouse models with Apc mutation, human CRC organoids, agonist/antagonist treatment, and reverse-phase protein microarray","pmids":["30679176"],"confidence":"High","gaps":["Direct transcriptional targets within the BMP7/TAK1 axis not pinpointed","Mechanism of additional proinvasive pathways (PDGFRβ, AKT1) not detailed"]},{"year":2019,"claim":"Demonstrated PPARD drives gastric carcinogenesis through chemokine-mediated inflammation and a self-amplifying PPARD/IFNγ feedback loop.","evidence":"Villin-PPARD transgenic mice, lineage tracing, cytokine profiling, and transcriptome analysis","pmids":["30885780"],"confidence":"High","gaps":["Whether CCL20/CXCL1 are direct PPARD targets not shown","Molecular basis of the IFNγ feedback link unresolved"]},{"year":2020,"claim":"Showed PPARD acts as a fatty-acid sensor in dendritic cells, mediating palmitic acid–induced activation and Th1 polarization in atherosclerosis.","evidence":"CD11c-conditional Ppard knockout in ApoE-/- mice plus bone marrow-derived DC culture with palmitic acid","pmids":["31919912"],"confidence":"High","gaps":["Transcriptional targets controlling co-stimulatory molecule expression not identified","Direct fatty-acid binding to PPARD in DCs not demonstrated"]},{"year":2025,"claim":"Defined a PPARδ/BCL6 repressor mechanism by which dietary lipid uptake through CD36 suppresses macrophage IL-23, linking lipid sensing to intestinal immune tolerance.","evidence":"Macrophage CD36 conditional knockout, DSS colitis model, oleic acid/LPS treatment, and PPARδ/BCL6 complex characterization","pmids":["40717126"],"confidence":"High","gaps":["Direct binding stoichiometry of the PPARδ/BCL6 complex at Il23a not fully resolved","Generalizability to human macrophages untested"]},{"year":2025,"claim":"Identified PPARD as both a target and effector of metabolic epigenetic signaling, induced by H3K18 lactylation and driving AKT-dependent survival under glycolytic conditions.","evidence":"H3K18la ChIP-seq, multi-omics, ATAC-seq, and HDAC2/3 eraser identification in breast cancer cells","pmids":["39922804"],"confidence":"Medium","gaps":["HDAC2/3 eraser activity at the PPARD locus not reconstituted","Direct vs indirect AKT regulation by PPARD unresolved"]},{"year":2025,"claim":"Placed PPARD upstream of MECP2/STAT3 in immune balance, showing it represses MECP2 to alleviate Th17/Treg imbalance.","evidence":"PPARD siRNA knockdown with MECP2 deletion and STAT3 inhibition epistasis in a rat CARAS model","pmids":["40031093"],"confidence":"Medium","gaps":["Direct binding of PPARD to the MECP2 promoter not demonstrated","Single model system"]},{"year":2025,"claim":"Linked PPARD to smooth muscle phenotypic switching, showing it activates a PDK4/ANGPTL4 axis driving SMC dedifferentiation under lipid excess.","evidence":"High-fat diet mice, lipid-treated human gastric SMCs with siRNA knockdown and PPARD activation, lipidomics/RNA-seq, validated in human tissue","pmids":["40652248"],"confidence":"High","gaps":["Whether PDK4/ANGPTL4 are direct transcriptional targets not established","Reversibility of the dedifferentiated phenotype untested"]},{"year":2025,"claim":"Showed ACSS2-driven H3K27 acetylation at the PPARD promoter elevates PPARD, which transcriptionally activates BCAT1 to reprogram BCAA catabolism in pancreatic cancer.","evidence":"ACSS2 knockout, ChIP for H3K27ac at the PPARD promoter, and functional proliferation/invasion assays","pmids":["40908872"],"confidence":"Medium","gaps":["Direct PPARD binding at the BCAT1 promoter not confirmed","Single lab; mechanistic generality unknown"]},{"year":null,"claim":"The endogenous physiological ligands engaging PPARD across its diverse contexts and the rules governing its switch between activator and repressor modes remain undefined.","evidence":"No timeline study resolves a unified ligand-to-transcriptional-output model","pmids":[],"confidence":"Medium","gaps":["No structural model of context-dependent activator/repressor switching","Direct genome-wide target set unifying cancer, immune, and developmental roles not consolidated","Cofactor exchange mechanisms underlying repression not defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,7,9,10,12,14,15,17]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0,7,17]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[11,12]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[3]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[3]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,7,9,17]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[6,9,10,13,16,17]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[11,12,14]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,9,15]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[12,15,16]}],"complexes":["PPARD/RXRα heterodimer","PPARδ/BCL6 repressor complex"],"partners":["RXRA","BCL6","TCF7L2","CRM1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q03181","full_name":"Peroxisome proliferator-activated receptor delta","aliases":["NUCI","Nuclear hormone receptor 1","NUC1","Nuclear receptor subfamily 1 group C member 2","Peroxisome proliferator-activated receptor beta","PPAR-beta"],"length_aa":441,"mass_kda":49.9,"function":"Ligand-activated transcription factor key mediator of energy metabolism in adipose tissues (PubMed:35675826). Receptor that binds peroxisome proliferators such as hypolipidemic drugs and fatty acids. Has a preference for poly-unsaturated fatty acids, such as gamma-linoleic acid and eicosapentanoic acid. Once activated by a ligand, the receptor binds to promoter elements of target genes. Regulates the peroxisomal beta-oxidation pathway of fatty acids. Functions as transcription activator for the acyl-CoA oxidase gene. Decreases expression of NPC1L1 once activated by a ligand","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q03181/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PPARD","classification":"Not Classified","n_dependent_lines":4,"n_total_lines":1208,"dependency_fraction":0.0033112582781456954},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PPARD","total_profiled":1310},"omim":[{"mim_id":"617870","title":"CENTROSOMAL PROTEIN 350; CEP350","url":"https://www.omim.org/entry/617870"},{"mim_id":"611265","title":"PEROXISOMAL PROLIFERATOR-ACTIVATED RECEPTOR ALPHA-INTERACTING COFACTOR COMPLEX, 285-KD SUBUNIT","url":"https://www.omim.org/entry/611265"},{"mim_id":"609059","title":"PATATIN-LIKE PHOSPHOLIPASE DOMAIN-CONTAINING PROTEIN 2; PNPLA2","url":"https://www.omim.org/entry/609059"},{"mim_id":"606220","title":"INTELLECTUAL DEVELOPMENTAL DISORDER WITH SHORT STATURE, FACIAL ANOMALIES, AND SPEECH DEFECTS; IDDSFAS","url":"https://www.omim.org/entry/606220"},{"mim_id":"605653","title":"F-BOX AND LEUCINE-RICH REPEAT PROTEIN 3; FBXL3","url":"https://www.omim.org/entry/605653"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PPARD"},"hgnc":{"alias_symbol":["NUC1","NUCII","FAAR","NR1C2","PPARB"],"prev_symbol":[]},"alphafold":{"accession":"Q03181","domains":[{"cath_id":"3.30.50.10","chopping":"82-152","consensus_level":"high","plddt":89.8683,"start":82,"end":152},{"cath_id":"1.10.565.10","chopping":"170-436","consensus_level":"high","plddt":94.2716,"start":170,"end":436}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q03181","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q03181-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q03181-F1-predicted_aligned_error_v6.png","plddt_mean":82.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PPARD","jax_strain_url":"https://www.jax.org/strain/search?query=PPARD"},"sequence":{"accession":"Q03181","fasta_url":"https://rest.uniprot.org/uniprotkb/Q03181.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q03181/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q03181"}},"corpus_meta":[{"pmid":"10716942","id":"PMC_10716942","title":"NUC-1, 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(PPARD) acts as a repressor of hPPARα and human thyroid hormone receptor transcriptional activation. It cooperatively binds a PPAR-responsive element with hRXRα, and in the presence of hRXRα its affinity for the peroxisome proliferator ligand is comparable to hPPARα. Repression of hPPARα can be overcome by transfecting excess hPPARα, suggesting hNUC1 titrates out a factor required for activation.\",\n      \"method\": \"Transient transfection reporter assays, cooperative DNA binding assays, ligand binding assays in the presence of hRXRα\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional assays (reporter, binding, competition) in single lab; establishes repressor mechanism and RXRα co-binding\",\n      \"pmids\": [\"7876127\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"A selective small-molecule PPARβ/δ (PPARD) antagonist ligand was identified and characterized, demonstrating that the receptor's biological activity can be blocked by a specific ligand — the first antagonist described for this receptor subtype.\",\n      \"method\": \"Cellular and biochemical characterization of small molecule antagonist ligand binding and functional activity\",\n      \"journal\": \"Molecular endocrinology (Baltimore, Md.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ligand characterization with functional cellular assays, single lab but multiple methods\",\n      \"pmids\": [\"17975020\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"A missense mutation (G32E) in the A/B domain of porcine PPARD is the causal variant underlying a major QTL for ear size; the mutation mediates downregulation of β-catenin and its target gene expression crucial for fat deposition in skin.\",\n      \"method\": \"QTL mapping, identical-by-descent analysis, selective sweep analysis, luciferase reporter assays for β-catenin target gene expression, association studies in experimental cross and outbred populations\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic fine-mapping plus functional reporter assay; single lab but multiple orthogonal approaches\",\n      \"pmids\": [\"21573137\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The G32E substitution in porcine PPARD (A/B domain) reduces transcription activity in a ligand-dependent manner, promotes CRM1-mediated nuclear export of PPARD, and greatly reduces ubiquitination of the A/B domain, consequently decreasing transcriptional activity. Surface plasmon resonance showed the mutation has negligible effect on ligand binding affinity.\",\n      \"method\": \"Luciferase reporter assays, subcellular localization imaging in PK-15 cells and primary chondrocytes, co-immunoprecipitation for ubiquitination, surface plasmon resonance for ligand binding\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (reporter assay, live-cell localization, CoIP, SPR) in single study establishing mechanism of A/B domain mutation\",\n      \"pmids\": [\"24058710\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PPARD modulates spermatogenesis by regulating Sertoli cell function via temporal inhibition of ERK activation. Ligand activation of PPARD inhibited Sertoli cell (TM4) proliferation; PPARD-dependent ERK signaling altered expression of claudin-11, p27, cyclin D1, and cyclin D2, causing inhibition of proliferation, maturation, and tight junction formation in Sertoli cells.\",\n      \"method\": \"Ppard knockout mouse phenotyping, immunofluorescence, western blotting, Sertoli cell line (TM4) treatment with PPARD ligand and inverse agonist (DG172), ERK pathway analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo KO phenotype plus in vitro mechanistic rescue with ligand/inverse agonist; multiple pathway readouts across two orthogonal systems\",\n      \"pmids\": [\"26242735\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"In porcine PPARD, functional SNPs (g.1015 A>G and g.1018 T>C) in the 5' regulatory region affect transcriptional activity; TCF7L2 (transcription factor 7-like 2) enhances PPARD promoter transcription in C2C12 and 3T3-L1 cells and binds differentially to the haplotypes, with haplotype AC showing the lowest TCF7L2 binding capacity and transcriptional activity.\",\n      \"method\": \"Luciferase reporter assays, electrophoretic mobility shift assay (nuclear extract binding), western blot of PPARD protein expression, qPCR, association analysis in pig populations\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reporter assay plus EMSA plus protein expression; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"26599230\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"PPARD promotes tumor metastasis by promoting angiogenesis via interleukin-8 (IL-8) in vivo and in vitro. Genetic deletion of PPARD in cancer cells identified pro-metastatic target genes (GJA1, VIM, SPARC, STC1, SNCG) and demonstrated PPARD's necessity for epithelial-mesenchymal transition, migration, and invasion.\",\n      \"method\": \"Genetic deletion (CRISPR) of PPARD in cancer cells, in vivo metastasis models, transcriptome profiling, TCGA database analysis, migration/invasion assays, angiogenesis assay with IL-8 quantification\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic deletion in multiple cancer models in vivo plus mechanistic pathway (IL-8/angiogenesis) identified in vitro; multiple orthogonal methods\",\n      \"pmids\": [\"28097239\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"PPARD retards auricular cartilage development by accelerating apoptosis of cartilage stem/progenitor cells (CSPCs), promoting terminal differentiation, and degrading cartilage extracellular matrix. ChIP-seq identified direct PPARD target genes including PPARG, and the G32E mutant upregulates PPARG expression, leading to downregulation of genes that inhibit cartilage growth.\",\n      \"method\": \"ChIP-seq, gene expression analysis, apoptosis assays, histological analysis of cartilage, comparison of wild-type vs. G32E mutant PPARD\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — ChIP-seq for direct target identification plus functional cellular phenotype assays; multiple methods supporting mechanistic model\",\n      \"pmids\": [\"28539839\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"An insulator element (CTCF binding confirmed) and a repressor/silencer element were identified and functionally validated in intron 2 of the human PPARD gene; the two cis-regulatory elements interact with each other.\",\n      \"method\": \"Bioinformatic prediction, transient transfection reporter assays, CTCF binding assay, ENCODE 5C data\",\n      \"journal\": \"Epigenomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reporter assay plus CTCF binding confirmation; single lab, two orthogonal methods\",\n      \"pmids\": [\"29583017\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PPARD overexpression or deletion in intestinal epithelial cells augments or suppresses β-catenin activation via up- or downregulation of BMP7/TAK1 signaling, strongly promoting or suppressing colorectal cancer. Depletion of PPARD in human colorectal cancer organoid cells inhibited BMP7/β-catenin signaling and suppressed organoid self-renewal. PPARD agonist GW501516 enhanced tumorigenesis in Apc mice while antagonist GSK3787 suppressed it. Reverse-phase protein microarray identified additional PPARD-regulated proinvasive pathways: connexin 43, PDGFRβ, AKT1, EIF4G1, and CDK1.\",\n      \"method\": \"Mouse models of PPARD overexpression/deletion combined with Apc mutation, human CRC organoids with PPARD depletion, pharmacological agonist/antagonist treatment in Apc mice, reverse-phase protein microarray\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic gain- and loss-of-function in multiple in vivo and in vitro models; BMP7/TAK1/β-catenin pathway placement established by multiple orthogonal approaches\",\n      \"pmids\": [\"30679176\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PPARD overexpression in villin-positive gastric progenitor cells (VGPCs) causes spontaneous invasive gastric adenocarcinoma in mice. Mechanistically, PPARD upregulates CCL20 and CXCL1 chemokines, increasing immune cell infiltration; a positive-feedback loop between PPARD and interferon gamma (IFNγ) signaling sustains gastric inflammation and drives VGPC transformation and tumorigenesis.\",\n      \"method\": \"Villin-PPARD transgenic mouse model, lineage-tracing experiments, cytokine/chemokine profiling, immunohistochemistry, transcriptome analysis, PPARD/IFNγ feedback loop characterization\",\n      \"journal\": \"Gastroenterology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — transgenic mouse model with lineage tracing, cytokine profiling, and mechanistic feedback loop identification; multiple orthogonal methods\",\n      \"pmids\": [\"30885780\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Conditional deletion of Ppard in CD11c+ cells attenuated atherosclerotic plaque formation and reduced activation and migration of myeloid-derived dendritic cells and T lymphocyte polarization to Th1. In bone marrow-derived DCs, Ppard deficiency reduced palmitic acid-induced upregulation of co-stimulatory molecules and pro-inflammatory cytokines IL-12 and TNFα, demonstrating that PPARδ activation by fatty acids mediates DC activation.\",\n      \"method\": \"Cre-loxP conditional knockout in ApoE-/- mice on high cholesterol diet, bone marrow-derived DC culture with palmitic acid, flow cytometry, cytokine measurements\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO in vivo atherosclerosis model plus in vitro mechanistic validation in primary DCs; multiple orthogonal methods\",\n      \"pmids\": [\"31919912\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Dietary lipid accumulation (oleic acid) in macrophages via CD36 leads to PPARδ (PPARD) release of the transcriptional repressor BCL6, which suppresses Il23a transcription in LPS-exposed macrophages. Deleting CD36 on macrophages restored IL-23 and IL-22 responses and reduced intestinal damage in HFD-fed DSS-treated mice.\",\n      \"method\": \"Conditional CD36 knockout in macrophages, DSS colitis model, oleic acid treatment of macrophages, LPS stimulation, IL-23/IL-22 measurements, PPARδ/BCL6 co-repressor complex characterization\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo conditional KO rescue plus in vitro mechanistic dissection of PPARD/BCL6 repressor complex; multiple orthogonal methods\",\n      \"pmids\": [\"40717126\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"H3K18 lactylation (H3K18la) promotes PPARD expression in breast cancer cells; PPARD in turn promotes transcription and phosphorylation of AKT (but not ILK), supporting cell survival under anaerobic glycolysis conditions. HDAC2 and HDAC3 act as erasers for H3 lysine lactylation upstream of PPARD.\",\n      \"method\": \"ChIP-seq with H3K18la antibodies, transcriptomics, proteomics, ATAC-seq, qPCR, western blot; HDAC2/3 identified as H3K18la erasers\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq plus multiple omics approaches in single study; HDAC2/3 as erasers identified but not experimentally reconstituted\",\n      \"pmids\": [\"39922804\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PPARD mediates transcriptional inhibition of MECP2 (methyl-CpG-binding protein 2), which in turn blocks STAT3 activation and alleviates Th17/Treg imbalance. PPARD knockdown-induced Th17/Treg imbalance was rescued by MECP2 deletion or STAT3 inhibition.\",\n      \"method\": \"PPARD siRNA knockdown, MECP2 deletion, STAT3 inhibition in vitro; rat CARAS model; Th17 differentiation assays\",\n      \"journal\": \"Phytomedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function knockdown with epistatic rescue experiments (MECP2 deletion, STAT3 inhibition) confirming pathway placement; single lab\",\n      \"pmids\": [\"40031093\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PPARD activates PDK4 and ANGPTL4 expression in gastric smooth muscle cells (SMCs), leading to SMC dedifferentiation (phenotypic switching) under obese/lipid-excess conditions. Inhibition of PDK4 or ANGPTL4 upregulation prevented lipid-induced SMC modifications.\",\n      \"method\": \"High-fat diet mouse model, lipid-treated differentiated human gastric SMCs, siRNA-peptide nanoparticles for knockdown, pharmaceutical PPARD activation, global lipidomics and RNA sequencing, immunofluorescence, western blotting, validation in human obesity gastric samples\",\n      \"journal\": \"Journal of biomedical science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo HFD model plus in vitro mechanistic dissection with PPARD activation and downstream target inhibition; multiple orthogonal methods validated in human tissue\",\n      \"pmids\": [\"40652248\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ACSS2 promotes acetylation at the H3K27 site in the PPARD promoter region, increasing PPARD transcription, which in turn transcriptionally activates BCAT1 to alter branched-chain amino acid catabolism and promote pancreatic cancer proliferation and invasion.\",\n      \"method\": \"ACSS2 knockout, ChIP assays for H3K27 acetylation at PPARD promoter, qPCR/western blot for PPARD and BCAT1 expression, functional assays for proliferation and invasion\",\n      \"journal\": \"Acta biochimica et biophysica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP evidence for histone acetylation at PPARD promoter plus genetic KO with functional readout; single lab\",\n      \"pmids\": [\"40908872\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PPARD transcriptionally represses CDC20 by binding to its promoter; CDC20 downregulation inhibits proliferation of cisplatin-resistant cervical cancer cells, reduces Wnt/β-catenin pathway activity, and increases apoptosis. APS (Astragalus polysaccharide) promotes PPARD expression to suppress CDC20.\",\n      \"method\": \"Bioinformatics target prediction, ChIP for PPARD binding at CDC20 promoter, PPARD/CDC20 knockdown, Wnt/β-catenin pathway agonist rescue experiments, xenograft tumor model\",\n      \"journal\": \"Cytotechnology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP for direct binding plus genetic knockdown with pathway rescue; single lab\",\n      \"pmids\": [\"40538591\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PPARD (PPARβ/δ) is a ligand-activated nuclear receptor that heterodimerizes with RXRα to bind PPAR-responsive elements and can act as either a transcriptional activator or repressor depending on context; it directly represses hPPARα and thyroid hormone receptors, modulates β-catenin/BMP7/TAK1 signaling in colorectal tumorigenesis, promotes metastasis via IL-8-driven angiogenesis and EMT, drives gastric carcinogenesis through a PPARD/IFNγ positive-feedback loop and CCL20/CXCL1 chemokine upregulation, regulates Sertoli cell function and spermatogenesis via ERK signaling, mediates macrophage inflammatory responses to dietary fatty acids through a PPARδ/BCL6 transcriptional repressor complex suppressing IL-23, transcriptionally represses MECP2 to modulate Th17/Treg balance, and promotes SMC dedifferentiation via a PPARD/PDK4/ANGPTL4 axis; its activity is regulated by ubiquitination and CRM1-mediated nuclear export (modulated by the G32E variant), H3K18 lactylation (with HDAC2/3 as erasers), and upstream H3K27 acetylation at its promoter by ACSS2.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PPARD (PPARβ/δ) is a ligand-activated nuclear receptor that cooperatively binds PPAR-responsive elements with RXRα and acts as a context-dependent transcriptional activator or repressor, originally characterized as a repressor of PPARα and thyroid hormone receptor activation that titrates a factor required for their activity [#0]. Its activity is gated at the protein level: a G32E substitution in the A/B domain reduces ligand-dependent transcription by promoting CRM1-mediated nuclear export and reducing A/B-domain ubiquitination without affecting ligand binding [#3], and its expression is shaped by cis-regulatory architecture, including an intron-2 insulator/silencer module and TCF7L2-responsive promoter elements [#5, #8]. As a transcription factor, PPARD directly binds target gene promoters identified by ChIP-seq, including PPARG [#7], and represses CDC20 and MECP2 [#14, #17]. A dominant theme in the corpus is PPARD's role in carcinogenesis and tissue remodeling: it drives colorectal tumorigenesis by augmenting β-catenin activation through BMP7/TAK1 signaling [#9], promotes metastasis via IL-8–driven angiogenesis and epithelial–mesenchymal transition [#6], and induces invasive gastric adenocarcinoma through CCL20/CXCL1 chemokine induction and a self-sustaining PPARD/IFNγ feedback loop [#10]. PPARD also senses dietary fatty acids to control immune and stromal cell states, mediating dendritic cell activation in atherosclerosis [#11], restraining macrophage IL-23 via a PPARδ/BCL6 repressor complex downstream of CD36 lipid uptake [#12], and driving smooth muscle cell dedifferentiation through a PDK4/ANGPTL4 axis [#15]. It additionally regulates Sertoli cell proliferation and spermatogenesis through temporal control of ERK signaling [#4].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Established the founding biochemical identity of PPARD as an RXRα-partnered nuclear receptor that can repress rather than activate transcription, distinguishing it from PPARα.\",\n      \"evidence\": \"Transient transfection reporter, cooperative DNA-binding, and ligand-binding assays in the presence of hRXRα\",\n      \"pmids\": [\"7876127\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The titrated 'factor' required for activation was not identified\", \"Endogenous target genes not defined\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Demonstrated PPARD activity is pharmacologically tractable by identifying the first selective small-molecule antagonist, enabling loss-of-function dissection.\",\n      \"evidence\": \"Cellular and biochemical characterization of an antagonist ligand\",\n      \"pmids\": [\"17975020\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo efficacy and selectivity not established in this work\", \"Target gene consequences of antagonism not mapped\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Linked a specific PPARD coding variant to a phenotype, showing the G32E A/B-domain mutation causally drives β-catenin target downregulation in tissue patterning.\",\n      \"evidence\": \"QTL mapping, IBD/selective sweep analysis, and luciferase reporter assays in porcine populations\",\n      \"pmids\": [\"21573137\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism of the A/B-domain effect not resolved here\", \"Restricted to porcine ear-size QTL\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Resolved the molecular mechanism of the G32E variant, showing it impairs transcription by promoting CRM1-mediated nuclear export and reducing ubiquitination rather than altering ligand affinity.\",\n      \"evidence\": \"Reporter assays, live-cell localization, co-IP for ubiquitination, and SPR for ligand binding\",\n      \"pmids\": [\"24058710\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"E3 ligase and CRM1-binding determinants not identified\", \"Connection to physiological regulation of wild-type PPARD unclear\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined a developmental role in male reproduction, showing PPARD controls Sertoli cell proliferation and tight-junction formation through temporal ERK inhibition.\",\n      \"evidence\": \"Ppard knockout mouse phenotyping plus TM4 Sertoli cell ligand/inverse-agonist treatment and ERK pathway readouts\",\n      \"pmids\": [\"26242735\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct transcriptional targets linking PPARD to ERK not identified\", \"Ligand identity in vivo unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Mapped upstream transcriptional control of PPARD, showing TCF7L2 binds the promoter and functional 5' SNPs modulate its expression.\",\n      \"evidence\": \"Reporter assays, EMSA, western blot, and population association in pig models\",\n      \"pmids\": [\"26599230\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"TCF7L2 regulation not confirmed in human cells\", \"Crosstalk with Wnt signaling at PPARD promoter unexplored\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Established PPARD as a driver of metastasis, showing it is required for EMT, migration, invasion, and IL-8–driven angiogenesis.\",\n      \"evidence\": \"CRISPR deletion in cancer cells, in vivo metastasis models, transcriptome profiling, and angiogenesis assays\",\n      \"pmids\": [\"28097239\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs indirect regulation of target genes (GJA1, VIM, SPARC) not distinguished\", \"Ligand driving metastatic activity not defined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified direct genomic targets of PPARD including PPARG by ChIP-seq, linking the G32E variant to cartilage developmental phenotypes.\",\n      \"evidence\": \"ChIP-seq, apoptosis and differentiation assays, and wild-type vs G32E comparison in cartilage progenitors\",\n      \"pmids\": [\"28539839\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether PPARG activation is the sole effector unclear\", \"Generalizability beyond auricular cartilage untested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Characterized the cis-regulatory architecture of the human PPARD locus, identifying an intron-2 CTCF insulator and an interacting silencer element.\",\n      \"evidence\": \"Bioinformatic prediction, reporter assays, CTCF binding assay, and ENCODE 5C data\",\n      \"pmids\": [\"29583017\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological contexts engaging these elements not defined\", \"Effect on endogenous PPARD expression not measured\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Placed PPARD upstream of β-catenin in colorectal tumorigenesis via BMP7/TAK1 signaling, with bidirectional genetic and pharmacological control of tumor outcome.\",\n      \"evidence\": \"PPARD gain/loss mouse models with Apc mutation, human CRC organoids, agonist/antagonist treatment, and reverse-phase protein microarray\",\n      \"pmids\": [\"30679176\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct transcriptional targets within the BMP7/TAK1 axis not pinpointed\", \"Mechanism of additional proinvasive pathways (PDGFRβ, AKT1) not detailed\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrated PPARD drives gastric carcinogenesis through chemokine-mediated inflammation and a self-amplifying PPARD/IFNγ feedback loop.\",\n      \"evidence\": \"Villin-PPARD transgenic mice, lineage tracing, cytokine profiling, and transcriptome analysis\",\n      \"pmids\": [\"30885780\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CCL20/CXCL1 are direct PPARD targets not shown\", \"Molecular basis of the IFNγ feedback link unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showed PPARD acts as a fatty-acid sensor in dendritic cells, mediating palmitic acid–induced activation and Th1 polarization in atherosclerosis.\",\n      \"evidence\": \"CD11c-conditional Ppard knockout in ApoE-/- mice plus bone marrow-derived DC culture with palmitic acid\",\n      \"pmids\": [\"31919912\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Transcriptional targets controlling co-stimulatory molecule expression not identified\", \"Direct fatty-acid binding to PPARD in DCs not demonstrated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined a PPARδ/BCL6 repressor mechanism by which dietary lipid uptake through CD36 suppresses macrophage IL-23, linking lipid sensing to intestinal immune tolerance.\",\n      \"evidence\": \"Macrophage CD36 conditional knockout, DSS colitis model, oleic acid/LPS treatment, and PPARδ/BCL6 complex characterization\",\n      \"pmids\": [\"40717126\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct binding stoichiometry of the PPARδ/BCL6 complex at Il23a not fully resolved\", \"Generalizability to human macrophages untested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified PPARD as both a target and effector of metabolic epigenetic signaling, induced by H3K18 lactylation and driving AKT-dependent survival under glycolytic conditions.\",\n      \"evidence\": \"H3K18la ChIP-seq, multi-omics, ATAC-seq, and HDAC2/3 eraser identification in breast cancer cells\",\n      \"pmids\": [\"39922804\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"HDAC2/3 eraser activity at the PPARD locus not reconstituted\", \"Direct vs indirect AKT regulation by PPARD unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Placed PPARD upstream of MECP2/STAT3 in immune balance, showing it represses MECP2 to alleviate Th17/Treg imbalance.\",\n      \"evidence\": \"PPARD siRNA knockdown with MECP2 deletion and STAT3 inhibition epistasis in a rat CARAS model\",\n      \"pmids\": [\"40031093\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding of PPARD to the MECP2 promoter not demonstrated\", \"Single model system\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Linked PPARD to smooth muscle phenotypic switching, showing it activates a PDK4/ANGPTL4 axis driving SMC dedifferentiation under lipid excess.\",\n      \"evidence\": \"High-fat diet mice, lipid-treated human gastric SMCs with siRNA knockdown and PPARD activation, lipidomics/RNA-seq, validated in human tissue\",\n      \"pmids\": [\"40652248\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether PDK4/ANGPTL4 are direct transcriptional targets not established\", \"Reversibility of the dedifferentiated phenotype untested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed ACSS2-driven H3K27 acetylation at the PPARD promoter elevates PPARD, which transcriptionally activates BCAT1 to reprogram BCAA catabolism in pancreatic cancer.\",\n      \"evidence\": \"ACSS2 knockout, ChIP for H3K27ac at the PPARD promoter, and functional proliferation/invasion assays\",\n      \"pmids\": [\"40908872\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct PPARD binding at the BCAT1 promoter not confirmed\", \"Single lab; mechanistic generality unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The endogenous physiological ligands engaging PPARD across its diverse contexts and the rules governing its switch between activator and repressor modes remain undefined.\",\n      \"evidence\": \"No timeline study resolves a unified ligand-to-transcriptional-output model\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of context-dependent activator/repressor switching\", \"Direct genome-wide target set unifying cancer, immune, and developmental roles not consolidated\", \"Cofactor exchange mechanisms underlying repression not defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 7, 9, 10, 12, 14, 15, 17]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0, 7, 17]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [11, 12]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 7, 9, 17]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [6, 9, 10, 13, 16, 17]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [11, 12, 14]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 9, 15]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [12, 15, 16]}\n    ],\n    \"complexes\": [\"PPARD/RXRα heterodimer\", \"PPARδ/BCL6 repressor complex\"],\n    \"partners\": [\"RXRA\", \"BCL6\", \"TCF7L2\", \"CRM1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}