{"gene":"ESRRA","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":2004,"finding":"Crystal structure of ERRα ligand-binding domain (LBD) complexed with a PGC-1α coactivator peptide reveals a transcriptionally active conformation in the absence of a ligand. The putative ligand-binding pocket is almost completely occupied by bulky side chains (particularly Phe328), providing structural evidence for ligand-independent transcriptional activation. The structure also reveals how a PGC-1α LLXYL (inverted LXXLL) motif binds the LBD.","method":"X-ray crystallography at 2.5 Å resolution; binding affinity assays with PGC-1α peptides","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with direct functional validation of ligand-independent activation and coactivator binding mode","pmids":["15337744"],"is_preprint":false},{"year":2004,"finding":"ERRα is a downstream effector of PGC-1α in mitochondrial biogenesis: inhibition of ERRα compromises PGC-1α-induced expression of mitochondrial protein-encoding genes and mitochondrial DNA content. A constitutively active ERRα is sufficient to induce both responses. ERRα binding sites in promoters of target genes contribute to the PGC-1α transcriptional response.","method":"Dominant-negative and constitutively active ERRα overexpression; mitochondrial DNA quantification; reporter/promoter assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal functional methods (loss-of-function, gain-of-function, promoter assays, mtDNA quantification), widely replicated","pmids":["15087503"],"is_preprint":false},{"year":2004,"finding":"ERRα autoregulates its own expression via a polymorphic 23-bp hormone response element (ESRRA23) in the human ESRRA promoter that binds ERRα. PGC-1α induces ESRRA promoter activity in an ESRRA23- and ERRα-dependent manner, and co-expression of ERRα and PGC-1α synergistically activates the promoter. Chromatin immunoprecipitation confirmed endogenous ERRα occupies its own promoter in vivo.","method":"ChIP; luciferase reporter assays; ERRα null fibroblasts; transient transfection","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP confirmed in vivo occupancy, multiple orthogonal methods (reporter assay, null cells, co-expression), replicated concept across labs","pmids":["14978033"],"is_preprint":false},{"year":2004,"finding":"ERRα directly regulates the apolipoprotein A-IV (apoA-IV) promoter via interaction with the apoC-III enhancer element; ERRα cooperates with PGC-1α to activate apoA-IV transcription. ERRα knockout mice display lipid malabsorption and reduced enterocyte β-oxidation capacity, establishing ERRα as a direct transcriptional regulator of intestinal lipid handling.","method":"Microarray; promoter luciferase assays; ERRα knockout mice; isolated enterocyte β-oxidation assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct promoter binding established, in vivo knockout phenotype with defined molecular target","pmids":["15466464"],"is_preprint":false},{"year":2005,"finding":"PGC-1α drives mitofusin 2 (Mfn2) gene expression through ERRα in an ERRα-dependent transcriptional programme, linking the PGC-1α/ERRα axis to mitochondrial fusion and architecture in skeletal muscle.","method":"In vitro cellular reporter assays; mRNA expression analysis in human exercise cohort","journal":"The Journal of physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro mechanistic assay plus human exercise data, single lab","pmids":["15961417"],"is_preprint":false},{"year":2005,"finding":"ERRα controls morphogenetic movements (epiboly and convergent-extension) during zebrafish gastrulation. Loss-of-function via morpholinos or dominant-negative ERRα disrupts these movements; gain-of-function by mRNA injection also perturbs them, establishing a role in early embryonic development independent of cell fate determination.","method":"Zebrafish morpholino knockdown; dominant-negative overexpression; mRNA injection gain-of-function","journal":"Developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal loss- and gain-of-function in zebrafish, single lab","pmids":["15848392"],"is_preprint":false},{"year":2007,"finding":"ERRα is required for the bioenergetic adaptation to cardiac pressure overload: ERRα−/− mice develop heart failure with abnormal phosphocreatine depletion and reduced maximal mitochondrial ATP synthesis rates. ERRα target genes involved in energy substrate oxidation, ATP synthesis, and phosphate transfer are downregulated at baseline or with pressure overload.","method":"ERRα knockout mice; left ventricular pressure overload model; 31P-NMR; mitochondrial respiration assays; gene expression analysis","journal":"Cell metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal in vivo methods (NMR, respiration, gene expression) in knockout model with clear bioenergetic phenotype","pmids":["17618854"],"is_preprint":false},{"year":2010,"finding":"ERRα and PGC-1β co-occupy the ERBB2 amplicon on chromosome 17q12-21 in human breast cancer cells, directing co-recruitment of PGC-1β and RNA polymerase II to ERBB2 and co-amplified gene promoters. ERRα ablation delays ERBB2-induced mammary tumor development and lowers amplicon transcript levels. ERRα also competitively displaces ERα from the ERBB2 locus to de-repress expression.","method":"Chromosome 17q-wide ChIP; ERRα knockout mouse mammary tumor model; RNA polymerase II ChIP; tamoxifen sensitivity assays","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide ChIP location analysis plus in vivo mouse tumor model with reciprocal competitive binding mechanism established","pmids":["20961995"],"is_preprint":false},{"year":2011,"finding":"ERRα directly regulates all major molecular clock components and is an output gene of the circadian oscillator (shown by Clock/Clock mutant mice). Genome-wide ChIP-seq identified extensive overlap between ERRα, its corepressor PROX1, and the core clock factor BMAL1 binding sites in liver, establishing transcriptional regulatory loops between these factors controlling daily metabolic rhythms. ERRα-null mice display deregulated locomotor activity rhythms and time-dependent hypoglycemia/hypoinsulinemia.","method":"ChIP-seq; ERRα-null mouse phenotyping; Clock mutant mice; circadian locomotor activity analysis; metabolic profiling","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide ChIP-seq plus multiple in vivo genetic models with defined metabolic phenotypes","pmids":["21731503"],"is_preprint":false},{"year":2011,"finding":"A recurrent ESRRA-C11orf20 fusion transcript, joining 5′ exons of ESRRA to 3′ exons of C11orf20, was identified in ~15% of serous ovarian carcinomas by deep paired-end mRNA sequencing, with a corresponding genomic rearrangement confirmed in tumor samples.","method":"Deep paired-end RNA sequencing; RT-PCR validation; targeted genomic resequencing","journal":"PLoS biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — identified by sequencing and confirmed by RT-PCR in 10/67 tumors with genomic evidence; functional consequence of the fusion not established","pmids":["21949640"],"is_preprint":false},{"year":2012,"finding":"ERRα directly binds an evolutionarily conserved response element in the PGC-1α promoter and is required for PGC-1α expression in primary cardiomyocytes. Overexpression of ERRα overcomes HDAC5-mediated repression of PGC-1α. Hypoxia reduces ERRα mRNA, preceding loss of PGC-1α mRNA, though ChIP shows ERRα loss is not responsible for PGC-1α loss during hypoxia.","method":"Luciferase reporter assays; ERRα overexpression/knockdown in primary cardiomyocytes; ChIP; HDAC5 co-expression","journal":"Biochemistry and cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and reporter assays in primary cells, single lab","pmids":["23668787"],"is_preprint":false},{"year":2013,"finding":"mTOR occupies regulatory regions of ERRα target genes (TCA cycle, lipid biosynthesis) genome-wide in mouse liver. mTOR regulates ERRα activity through ubiquitin-mediated proteasomal degradation via transcriptional control of the ubiquitin-proteasome pathway. Combined genetic/pharmacological inhibition of ERRα and rapamycin exacerbates hepatic hyperlipidemia, placing ERRα downstream of mTOR in hepatic lipid metabolism.","method":"ChIP-seq in mouse liver; genetic ERRα ablation; rapamycin treatment; TCA metabolite quantification; hepatic lipid measurement","journal":"Cell metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide ChIP-seq, genetic ablation, pharmacological inhibition, and metabolite analyses providing mechanistic placement of ERRα downstream of mTOR","pmids":["23562079"],"is_preprint":false},{"year":2013,"finding":"ERRα regulates colon cancer cell proliferation, colony formation, and tumorigenic capacity. ERRα depletion causes G1-to-S cell cycle arrest with reduced CDK2 activity and altered retinoblastoma phosphorylation. ERRα-depleted cells show reduced expression of glycolysis, TCA cycle, and lipid synthesis genes, and reduced glucose incorporation and glucose-mediated lipogenesis measured by 14C isotope tracing.","method":"shRNA knockdown; colony formation assays; xenograft; cell cycle analysis; 14C isotope tracer analysis","journal":"Carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional assays including isotope tracing, single lab","pmids":["23720198"],"is_preprint":false},{"year":2013,"finding":"ESRRA and HDAC4 interact both in vitro (HeLa cells) and in vivo (mouse cortex). HDAC4 potently represses ESRRA-induced target gene expression. A missense mutation in ESRRA decreases its transcriptional activity, while an HDAC4 mutation increases repression of ESRRA target genes, establishing a functional ESRRA-HDAC4 transcriptional regulatory axis.","method":"Co-immunoprecipitation in HeLa cells and mouse cortex; transcriptional activity assays; whole-genome/exome sequencing of human families","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP in two systems plus transcriptional functional assay, single lab","pmids":["24216484"],"is_preprint":false},{"year":2015,"finding":"ERRα and ERRγ together are required for cardiomyocyte metabolism and cardiac function: mice lacking both ERRα and cardiac ERRγ develop severe bradycardia, lethal cardiomyopathy, and heart failure. ERRα and ERRγ directly control genes for mitochondrial function/dynamics and genes for contraction, calcium homeostasis, and conduction.","method":"ERRα/ERRγ double-knockout mice; cardiac phenotyping; transcriptional target gene analysis","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — double-knockout in vivo model with defined lethal phenotype and direct transcriptional target identification","pmids":["25624346"],"is_preprint":false},{"year":2015,"finding":"ERRα negatively regulates TLR-induced inflammation in macrophages by directly binding the Tnfaip3 (A20 deubiquitinase) promoter to promote its transcription. ERRα also regulates NF-κB signaling by controlling p65 acetylation via maintenance of NAD+ levels and sirtuin 1 activation. ERRα-deficient macrophages display increased glycolysis and impaired mitochondrial respiratory function.","method":"ERRα knockout mice; ChIP; promoter assays; NF-κB p65 acetylation measurement; NAD+ quantification; Seahorse metabolic flux analysis","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct promoter ChIP, in vivo knockout model with septic shock phenotype, multiple orthogonal mechanistic assays","pmids":["26200012"],"is_preprint":false},{"year":2015,"finding":"ERRα directly binds the Sirt3 promoter as its transcription factor (in a PGC-1α/ERRα complex) to regulate Sirt3 expression and dopaminergic neuronal survival. PGC-1α interacts with ERRα for this function. Loss of the PGC-1α/ERRα-Sirt3 pathway leads to elevated acetylation of SOD2 (K130) and ATP synthase β (K485) and dopaminergic neuronal death.","method":"ChIP; co-immunoprecipitation; promoter reporter assays; MPTP mouse model; Sirt3 knockout mice","journal":"Antioxidants & redox signaling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and Co-IP establish direct binding, supported by in vivo models, single lab","pmids":["26421366"],"is_preprint":false},{"year":2016,"finding":"Cholesterol was identified as an endogenous ERRα agonist by affinity chromatography of tissue lipidomes with the ERRα LBD followed by transcriptional assays. In bone, cholesterol effects, statin effects, and bisphosphonate osteoprotection on osteoclastogenesis all require ERRα; these effects are lost in ERRα knockout mice.","method":"Affinity chromatography; transcriptional activation assays; ERRα knockout mice; osteoclastogenesis assays; in vivo bone loss models","journal":"Cell metabolism","confidence":"High","confidence_rationale":"Tier 1 / Strong — biochemical LBD binding assay plus in vivo genetic validation in knockout mice across multiple pharmacological contexts","pmids":["26777690"],"is_preprint":false},{"year":2016,"finding":"Lapatinib induces degradation of ERRα protein. In lapatinib-resistant breast cancer cells, mTOR reactivation restores ERRα expression, which triggers metabolic adaptations including increased glutamine metabolism and ROS detoxification. An ERRα inverse agonist counteracts these metabolic adaptations and overcomes lapatinib resistance in a HER2-induced mouse mammary tumor model.","method":"Protein stability assays; mTOR inhibition; metabolic flux analysis (glutamine); ROS measurement; ERRα inverse agonist treatment; HER2 mouse tumor model","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal metabolic and genetic methods plus in vivo mouse model validation","pmids":["27402251"],"is_preprint":false},{"year":2016,"finding":"The PGC-1α/ERRα axis negatively regulates one-carbon metabolism genes, reducing purine biosynthesis in breast cancer cells. Activation of AMPK increases PGC-1α/ERRα expression and ERRα binding to target sites. This repression of the folate cycle by ERRα promotes sensitivity to the anti-folate drug methotrexate in vitro and in vivo.","method":"ChIP-seq; gene-expression datasets; AMPK activation; ERRα binding site analysis; methotrexate sensitivity assays in mice","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq binding data plus functional drug sensitivity assay in vivo, single lab","pmids":["26804918"],"is_preprint":false},{"year":2016,"finding":"MYC drives metabolic reprogramming to an oxidative state during osteoclast differentiation and transcriptionally induces ERRα. ERRα then cooperates with NFATc1 to drive osteoclastogenesis. Pharmacological inhibition of ERRα attenuated ovariectomy-induced bone loss in mice. Osteoclast-specific Myc deletion increased bone mass and protected against OVX-induced osteoporosis.","method":"Osteoclast-specific Myc knockout mice; transcriptomic analysis; pharmacological ERRα inhibition; OVX mouse model","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic knockout plus pharmacological validation with defined transcriptional pathway","pmids":["28530645"],"is_preprint":false},{"year":2016,"finding":"ERRα induces LSD1 to demethylate H3K9 (rather than its default H3K4 substrate) at the transcriptional start site of commonly activated target genes including MMP1. ERRα is sufficient to switch LSD1 substrate specificity to H3K9 demethylation in vitro. This ERRα-LSD1 axis promotes cell invasion, which is rescued by MMP1 re-expression after LSD1 or ERRα depletion.","method":"In vitro H3K9 demethylation assay with purified ERRα and LSD1; ChIP for H3K9me marks; siRNA depletion; invasion assays; MMP1 rescue","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution of substrate switch plus ChIP and functional invasion assays","pmids":["28348226"],"is_preprint":false},{"year":2017,"finding":"ESRRA is required for autophagosome formation and autophagy-mediated antimicrobial defense against mycobacterial infection. AMPK pathway and SIRT1 activation induce ESRRA, which transcriptionally activates Atg genes via ERR response elements. Additionally, ESRRA operates in a feed-forward loop with SIRT1 to deacetylate ATG5, BECN1, and ATG7, activating autophagy post-translationally.","method":"ESRRA knockout macrophages; ChIP/promoter analysis of Atg genes; SIRT1 deacetylation assays; mycobacterial infection assays; autophagy flux measurement","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout combined with ChIP promoter binding and post-translational deacetylation mechanism, multiple orthogonal approaches","pmids":["28841353"],"is_preprint":false},{"year":2017,"finding":"ERRα negatively regulates type I interferon (IFN-I) production by associating with TBK1 and IRF3 to impede TBK1-IRF3 complex formation, IRF3 phosphorylation, IRF3 dimerization, and DNA binding. Viral infection induces TBK1-dependent ERRα stabilization. This anti-viral regulatory function is independent of ERRα transcriptional activity and PGC-1α.","method":"ERRα knockout mice; co-immunoprecipitation of TBK1-ERRα-IRF3 complex; IRF3 phosphorylation and dimerization assays; DNA binding assays; viral infection models","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP establishing ternary complex, in vivo knockout model, multiple functional assays for IRF3 inhibition","pmids":["28591144"],"is_preprint":false},{"year":2017,"finding":"LSD1 protects ERRα from ubiquitination and proteasomal degradation independently of LSD1's demethylase activities, resulting in elevated ERRα protein levels in breast cancer cells.","method":"Ubiquitination assays; LSD1 demethylase-inactive mutants; co-immunoprecipitation; ERRα protein stability measurement","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ubiquitination assay with demethylase-dead mutants, single lab","pmids":["29190800"],"is_preprint":false},{"year":2017,"finding":"ERRα directly transactivates the TMPRSS2:ERG fusion gene in prostate cancer cells via both ERR-binding element- and AR-binding element-dependent mechanisms. ERG expressed by the T:E fusion in turn transactivates the ESRRA gene, forming a reciprocal ERRα-ERG regulatory loop that promotes advanced prostate cancer growth.","method":"Luciferase reporter assays; ChIP; ERRα inverse agonist treatment; ERRα/ERG overexpression; in vivo metastasis assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and reporter assays establish direct binding and reciprocal regulation, supported by in vivo data, single lab","pmids":["30042415"],"is_preprint":false},{"year":2018,"finding":"Thyroid hormone (TH) increases ESRRA expression and activity through THRB1-dependent induction of PGC1α. ESRRA mediates TH-induced mitochondrial biogenesis, fission, and mitophagy. Mechanistically, ESRRA induces ULK1 expression, which then promotes DRP1-mediated fission and activates FUNDC1-MAP1LC3B-II interaction to induce mitophagy. siRNA knockdown of ESRRA, ULK1, DRP1, or FUNDC1 inhibits TH-induced mitophagy and decreases OXPHOS.","method":"Transcriptome analysis; ChIP-seq; siRNA knockdown; mitochondrial biogenesis/fission/mitophagy functional assays; co-immunoprecipitation (FUNDC1-LC3)","journal":"Science signaling","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP-seq, transcriptomics, and multiple siRNA knockdowns with defined pathway placement, multiple orthogonal approaches","pmids":["29945885"],"is_preprint":false},{"year":2018,"finding":"ERRα promotes breast cancer cell dissemination to bone by directly transactivating the RANK gene. ChIP and bioinformatics confirmed RANK as an ERRα target. ERRα overexpression promotes spontaneous bone micro-metastases in vivo; pharmacological ERRα inhibition reduces bone metastases and RANK expression.","method":"ChIP; transactivation assays; in vivo orthotopic breast cancer model; pharmacological ERRα inhibition; meta-analysis of human cohorts","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and transactivation assays plus in vivo model, single lab","pmids":["30478447"],"is_preprint":false},{"year":2018,"finding":"PERM1 physically interacts with ERRα in cardiomyocytes and the mouse heart (co-immunoprecipitation). PERM1 is recruited to ERR target gene promoters and activates their transcription partially through ERRα. Mammalian one-hybrid assay showed PERM1 activates transcription when recruited to a promoter, blunted by silencing PGC-1α, BAG6, or KANK2. PERM1 knockout mice show reduced cardiac function and energy reserves.","method":"Co-immunoprecipitation; DNA binding assays; reporter gene assays; Perm1 knockout mice; echocardiography; proteomics/metabolomics","journal":"Frontiers in cardiovascular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP plus reporter assays and in vivo knockout, single lab","pmids":["36419485"],"is_preprint":false},{"year":2018,"finding":"ERRα directly activates androgen response element (ARE)-containing promoters such as the PSA promoter in prostate cells, independent of androgen receptor expression or activity. All ERR subfamily members can activate steroid response element-containing promoters even in the presence of antisteroid compounds.","method":"ERRα inverse agonist treatment; ARE-containing promoter reporter assays; androgen receptor expression analysis","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — reporter assays establish functional activation, replicated across ERR family members, single lab","pmids":["18697814"],"is_preprint":false},{"year":2020,"finding":"In kidney proximal tubule cells, ESRRA directly controls both metabolic (fatty acid oxidation, oxidative phosphorylation) and proximal tubule cell-specific differentiation genes. ERRα knockout in mouse models of kidney disease worsens PT cell differentiation defects and disease, establishing that ERRα couples metabolism and differentiation in PT cells.","method":"scRNA-seq; cell trajectory analyses; ERRα knockout mouse models; ChIP/transcriptional target analysis in mouse and patient samples","journal":"Cell metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — scRNA-seq plus in vivo knockout with patient validation and direct transcriptional target evidence","pmids":["33301705"],"is_preprint":false},{"year":2020,"finding":"ESRRA activates autophagic flux and controls gut microbiota composition to maintain intestinal homeostasis. esrra-null mice show depressed AMPK phosphorylation, lower TFEB levels, and accumulation of p62 with defective mitochondria. Fecal microbiota transplantation from WT mice ameliorated colitis severity in Esrra-deficient mice.","method":"Esrra knockout mice; DSS colitis model; autophagy flux assays; gut microbiota analysis; fecal microbiota transplantation","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout with FMT rescue and defined molecular phenotypes, single lab","pmids":["33172329"],"is_preprint":false},{"year":2020,"finding":"DNMT1 promotes ERRα protein stability; ERRα in turn couples DNMT1 transcription with that of the methionine cycle and S-adenosylmethionine synthesis, driving DNA methylation. Combined inhibition of ERRα and DNMT1 (5-azadC) reverses IRF4 promoter hypermethylation and de-represses this tumor suppressor gene to suppress breast cancer in vivo.","method":"Genetic/pharmacological manipulation; bisulfite genomic sequencing; pre-clinical mouse model of breast cancer; protein stability assays; methylation analysis","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — large-scale bisulfite sequencing plus in vivo model, feedforward mechanism established, single lab","pmids":["32855526"],"is_preprint":false},{"year":2020,"finding":"ERRα directly transactivates two key steroidogenic enzyme genes, CYP11A1 and AKR1C3, to promote intratumoral androgen (DHT) biosynthesis in castration-resistant prostate cancer. ERRα inverse agonist reduces DHT production and suppresses AR signaling in prostate cancer cells.","method":"ERRα overexpression/knockdown; UPLC-MS/MS intratumoral androgen measurement; ERRα inverse agonist treatment; ChIP/promoter transactivation assays","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP/reporter assays with direct androgen measurement by UPLC-MS/MS, single lab","pmids":["32226548"],"is_preprint":false},{"year":2020,"finding":"ESRRA acts as a key regulator of intestinal homeostasis; ERRα-deficient mice were more susceptible to DSS-induced colitis, with impaired intestinal epithelial cell compensatory proliferation, enhanced apoptosis, and reduced goblet cell counts. ERRα exerts protective effects within the radio-resistant compartment via transcriptional control of intestinal homeostasis genes.","method":"ERRα knockout mice; DSS colitis model; microbiota analysis; epithelial proliferation/apoptosis assays; bone marrow transplantation","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout with defined cellular phenotypes, single lab","pmids":["34302001"],"is_preprint":false},{"year":2022,"finding":"Insulin enhances ERRα activity via a GSK3β/FBXW7 signaling axis: insulin inhibits GSK3β, preventing FBXW7-mediated ubiquitination and proteasomal degradation of ERRα, thus stabilizing ERRα. Liver-specific deletion of GSK3β or FBXW7 and ERRα phosphosite mutant (ERRα3SA) mice accumulate ERRα protein that no longer responds to fluctuating insulin levels, resulting in compromised energy homeostasis and reduced insulin sensitivity.","method":"Liver-specific conditional knockout mice (GSK3β, FBXW7); ERRα phosphosite knock-in mice (ERRα3SA); transcriptome analysis; insulin sensitivity assays; protein stability/ubiquitination assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple in vivo genetic models with biochemical ubiquitination mechanism and defined metabolic phenotypes","pmids":["35440636"],"is_preprint":false},{"year":2022,"finding":"RBBP6 E3 ubiquitin ligase promotes ERRα degradation through K48-linked polyubiquitination at the K100 residue of ERRα. This RBBP6-mediated ERRα degradation contributes to mitochondrial injury in proximal tubule cells in diabetic kidney disease. Conditional ERRα overexpression or RBBP6 inhibition reduced mitochondrial damage in diabetic mice.","method":"Biochemical ubiquitination assays; site-directed mutagenesis (K100); co-immunoprecipitation; conditional ERRα overexpression in DKD mouse models; human DKD specimens","journal":"Advanced science","confidence":"High","confidence_rationale":"Tier 1 / Moderate — biochemical identification of ubiquitin site plus E3 ligase with mutagenesis validation and in vivo rescue, single lab","pmids":["39441040"],"is_preprint":false},{"year":2020,"finding":"Carnosic acid directly binds the ligand-binding domain of ERRα and promotes ERRα ubiquitination and proteasomal degradation. STUB1 was identified as the E3 ligase of ERRα. Lysine residues K51 and K68 are essential for ERRα ubiquitination and degradation. Carnosic acid also decreases the interaction between ERRα and PGC1β.","method":"Direct LBD binding assay; ubiquitination assay with STUB1; site-directed mutagenesis (K51, K68); co-immunoprecipitation ERRα-PGC1β; osteoclastogenesis and OVX mouse model","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — direct LBD binding and ubiquitination with mutagenesis, but single lab and primarily pharmacological study","pmids":["31907393"],"is_preprint":false},{"year":2021,"finding":"ERRα directly binds the DSN1 promoter (confirmed by ChIP and dual-luciferase assays) to transcriptionally activate DSN1, which then promotes cell cycle progression via the CDC25C/CDK1/CyclinB1 pathway. ERRα silencing causes G2M arrest in gastric cancer cells via this pathway.","method":"RNA-seq; dual-luciferase reporter assay; ChIP; flow cytometry; ERRα silencing","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and reporter assays establish direct promoter binding and pathway placement, single lab","pmids":["34131395"],"is_preprint":false},{"year":2021,"finding":"FBXL10 interacts with ERRα (identified by mass spectrometry), stabilizes ERRα protein by reducing poly-ubiquitylation and promoting mono-ubiquitylation, increases ERRα transcriptional activity and promoter occupancy, and facilitates ERRα/PGC1β-mediated breast cancer cell proliferation and tumorigenesis in vitro and in vivo.","method":"Mass spectrometry interaction screen; co-immunoprecipitation; ubiquitination assays; reporter gene assay; ChIP; xenograft mouse model","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS-identified interaction confirmed by co-IP and ubiquitination mechanism, supported by in vivo model, single lab","pmids":["33450359"],"is_preprint":false},{"year":2022,"finding":"Cholesterol accumulation in lipid rafts during EGFR-TKI resistance promotes EGFR-Src interaction and EGFR/Src/Erk signaling reactivation, leading to SP1 nuclear translocation and SP1-dependent transcriptional upregulation of ERRα. ERRα re-expression sustains ROS detoxification in resistant cells. SP1 binding to the ERRα promoter was confirmed by luciferase reporter and ChIP assays.","method":"Co-immunoprecipitation; luciferase reporter assay; ChIP; immunofluorescence; xenograft mouse model","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and co-IP establish signaling pathway leading to ERRα regulation, in vivo validation, single lab","pmids":["35303882"],"is_preprint":false},{"year":2022,"finding":"ERRα binds to the NLRP3 promoter (confirmed by CUT&Tag) and inhibits caspase-1/GSDMD signaling to reduce pyroptosis in endometrial cancer. ERRα also activates glycolytic rate-limiting enzymes and bridges glycolytic metabolism with pyroptosis resistance. ERRα-HIF-1α interaction was confirmed by co-immunoprecipitation.","method":"Co-immunoprecipitation (ERRα-HIF-1α); dual-luciferase reporter; CUT&Tag sequencing; flow cytometry; electron microscopy; organoid and xenograft models","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CUT&Tag confirms direct NLRP3 promoter binding, co-IP establishes protein interaction, in vivo validation, single lab","pmids":["37864196"],"is_preprint":false},{"year":2023,"finding":"SLU-PP-332, a synthetic pan-ERR agonist with highest potency for ERRα, increases mitochondrial function and cellular respiration in skeletal muscle cells, increases type IIa oxidative muscle fibers, and enhances exercise endurance in mice. SLU-PP-332 induces an ERRα-specific acute aerobic exercise genetic program; ERRα activation is critical for enhanced exercise endurance.","method":"ERR agonist pharmacological characterization; ERRα-specific genetic models; Seahorse metabolic flux; skeletal muscle fiber typing; mouse exercise endurance testing","journal":"ACS chemical biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological tool plus ERRα-specific genetic evidence for exercise capacity, single lab","pmids":["36988910"],"is_preprint":false},{"year":2024,"finding":"Adipocyte-specific ESRRA deficiency preserves osteogenesis and vascular formation in adipocyte-rich bone marrow under estrogen deficiency or obesity. Mechanistically, adipocyte ESRRA suppresses SPP1 transcription (by interfering with E2/ESR1 signaling) and positively drives leptin expression by directly binding the leptin promoter. ESRRA abrogation enhances SPP1 secretion and decreases leptin, coordinately dictating bone marrow stromal stem cell fate and restoring type H vessel formation.","method":"Adipocyte-specific ESRRA knockout mice; OVX and obesity models; ChIP (leptin promoter); pharmacological ERRα inhibition; SPP1 and leptin secretion assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional tissue-specific knockout with ChIP-confirmed direct promoter binding and mechanistic downstream signaling, in vivo pharmacological validation","pmids":["38704393"],"is_preprint":false},{"year":2024,"finding":"The cholesterol/mevalonate biosynthetic pathway promotes ERRα transcriptional activity, leading to dysfunctional mitochondria, ROS production, DNA damage, and p53-dependent cellular senescence. This mevalonate-induced senescence is abrogated in ERRα knockout mice on a high-fat diet in vivo.","method":"ERRα knockout mice; high-fat diet model; mevalonate pathway inhibition; ROS and mitochondrial function assays; p53 pathway analysis","journal":"npj aging","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo knockout confirms pathway dependence, multiple mechanistic assays, single lab","pmids":["38216569"],"is_preprint":false},{"year":2025,"finding":"IL-6 suppresses mitochondrial function via a JAK1/STAT1/3 axis that upregulates HIF1A and ERRα transcription. ERRα then stabilizes HIF1α protein, which in turn inhibits ERRα—establishing a negative feedback loop. This IL-6-mediated suppression operates when PGC1 expression is low; higher PGC1 rescues ERRα from HIF1α-mediated inhibition to restore mitochondrial respiration.","method":"JAK1 inhibitors; STAT1/3 pathway analysis; ERRα transcription/protein stability assays; HIF1α stabilization assays; PGC1 overexpression rescue; Seahorse metabolic flux","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple pathway inhibitor experiments and mechanistic rescue assays, single lab","pmids":["40056415"],"is_preprint":false},{"year":2016,"finding":"ERRα negatively regulates S6K1 expression by directly binding to the S6K1 promoter. Downregulation of ERRα sensitizes ERα-negative breast cancer cells to mTORC1/S6K1 inhibitors.","method":"ChIP (ERRα at S6K1 promoter); ERRα knockdown; mTORC1/S6K1 inhibitor sensitivity assays","journal":"Signal transduction and targeted therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP establishes direct promoter binding, functional drug sensitivity assay, single lab","pmids":["28890840"],"is_preprint":false},{"year":2019,"finding":"The PGC1α-ERRα transcriptional complex suppresses prostate cancer invasion by downregulating MYC and inhibiting integrin alpha1 and beta4 expression. CRISPR/Cas9 deletion of ERRα abolishes PGC1α regulation of cytoskeletal organization and invasiveness. PGC1α and ERRα associate at the MYC promoter (confirmed by ChIP), supporting their inhibitory activity on MYC transcription.","method":"CRISPR/Cas9 ERRα deletion; PGC1α overexpression; ChIP (PGC1α/ERRα at MYC promoter); invasion assays in vitro and in vivo; integrin expression analysis","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR knockout plus ChIP and in vivo functional assays, single lab","pmids":["31594836"],"is_preprint":false},{"year":2017,"finding":"Parkin overexpression promotes ERRα ubiquitination and degradation, reducing ERRα protein levels and consequently decreasing eNOS (total and phosphorylated) in endothelial cells. ERRα overexpression increases eNOS levels; this parkin-eNOS regulatory effect is independent of autophagy and apoptosis.","method":"Parkin plasmid overexpression; co-immunoprecipitation; ERRα ubiquitination assay; flow cytometry; ERRα inhibitor treatment; siRNA knockdown","journal":"Cellular physiology and biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP and ubiquitination assay with functional eNOS measurement, single lab","pmids":["30244249"],"is_preprint":false},{"year":2016,"finding":"PGC-1α and PGC-1β increase creatine transporter (CrT/Slc6a8) expression and creatine uptake in myotubes via ERRα. An ERR response element (ERRE) was identified in the CrT gene first intron and upstream promoter. ChIP assays confirmed that PGC-1α and ERRα directly interact with the CrT gene. shRNA knockdown of ERRα inhibited the PGC-1-mediated increase in CrT expression.","method":"ChIP (ERRα at CrT gene); adenoviral overexpression; shRNA knockdown; creatine uptake assay; constitutively active ERRα (VP16-ERRα)","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP confirms direct binding, functional creatine uptake assay, single lab","pmids":["25173818"],"is_preprint":false},{"year":1997,"finding":"The human ESRL1 (ERRα) gene is localized to chromosome 11q12 by FISH, consists of 7 exons spanning ~20 kb, and has a GC-rich promoter with 10 Sp1 sites and two E-boxes but no TATA or CAAT boxes. Multiple transcription initiation start sites were identified. ERRα modulates estrogen responsiveness of the lactoferrin gene promoter in endometrial carcinoma cells.","method":"FISH; gene cloning and sequencing; primer extension; RNase protection assay; transient transfection reporter assay","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct genomic characterization and functional promoter assay, single lab","pmids":["9286700"],"is_preprint":false}],"current_model":"ERRα (ESRRA) is a ligand-independent orphan nuclear receptor whose LBD adopts a constitutively active conformation stabilized by PGC-1α coactivator binding; it functions as a master transcriptional regulator of mitochondrial biogenesis, oxidative phosphorylation, fatty acid oxidation, and energy metabolism by co-occupying target gene promoters with PGC-1α/PGC-1β and autoregulating its own expression. Its activity is modulated by cholesterol (an endogenous agonist activating the LBD), post-translational stability control via the GSK3β/FBXW7 and RBBP6 ubiquitin-proteasome axes, and protein-level regulation by LSD1, FBXL10, and parkin. Beyond metabolism, ERRα directly drives transcriptional programs controlling autophagy (via Atg gene induction and SIRT1-mediated deacetylation of ATG5/BECN1/ATG7), innate immune responses (repressing TLR-induced inflammation via A20/Tnfaip3 and inhibiting antiviral IFN-I production by blocking TBK1-IRF3 complex formation), circadian clock outputs, osteoclastogenesis (downstream of MYC), and cell invasion (by switching LSD1 substrate specificity to H3K9 demethylation). In cancer contexts, ERRα regulates ERBB2 amplicon transcription, intratumoral androgen biosynthesis in prostate cancer, and metabolic reprogramming underlying drug resistance, placing it at the intersection of energy metabolism, epigenetics, and signal transduction."},"narrative":{"mechanistic_narrative":"ERRα (ESRRA) is a ligand-independent orphan nuclear receptor that serves as a master transcriptional regulator of mitochondrial biogenesis, oxidative metabolism, and energy homeostasis, functioning downstream of and in complex with the PGC-1α/PGC-1β coactivators [PMID:15337744, PMID:15087503]. Structurally, its ligand-binding domain adopts a transcriptionally active conformation in the absence of ligand because bulky side chains (notably Phe328) occupy the pocket, while an inverted LXXLL motif of PGC-1α docks onto the LBD surface to drive activation [PMID:15337744]. ERRα is itself a downstream effector required for PGC-1α-induced mitochondrial gene expression and mtDNA replication, and it autoregulates its own promoter through a dedicated response element while synergizing with PGC-1α [PMID:15087503, PMID:14978033]. Through co-occupancy of target promoters it directs broad metabolic programs — fatty acid oxidation, OXPHOS, TCA cycle, mitochondrial fusion/dynamics, and creatine handling — in cardiac, skeletal muscle, hepatic, renal, and intestinal tissues, with in vivo loss producing bioenergetic failure under stress [PMID:17618854, PMID:25624346, PMID:33301705, PMID:15961417]. ERRα also drives autophagy by transcriptionally inducing Atg genes and operating in a feed-forward loop with SIRT1 to deacetylate ATG5/BECN1/ATG7, supporting antimicrobial defense and intestinal homeostasis [PMID:28841353, PMID:33172329]. Its protein level is a central control node, stabilized or destabilized by an array of factors including the GSK3β/FBXW7 axis downstream of insulin, the E3 ligases RBBP6 and STUB1, FBXL10, LSD1, and parkin [PMID:35440636, PMID:39441040, PMID:31907393, PMID:33450359, PMID:29190800]. Cholesterol acts as an endogenous LBD agonist that couples sterol status to ERRα activity in bone and cellular senescence [PMID:26777690, PMID:38216569]. Beyond metabolism, ERRα represses TLR-induced inflammation via transcription of the A20 deubiquitinase Tnfaip3 [PMID:26200012] and inhibits type I interferon production by associating with TBK1 and IRF3 to block their complex formation in a transcription-independent manner [PMID:28591144]. In cancer, ERRα co-occupies the ERBB2 amplicon with PGC-1β, drives metabolic adaptations underlying lapatinib resistance, and reprograms epigenetic and steroidogenic programs, including switching LSD1 substrate specificity to H3K9 demethylation to promote invasion [PMID:20961995, PMID:27402251, PMID:28348226]. A coding ESRRA mutation that decreases its transcriptional activity, together with HDAC4, defines an ESRRA-HDAC4 transcriptional axis linked to a human familial phenotype [PMID:24216484].","teleology":[{"year":1997,"claim":"Establishing the genomic structure and a first functional readout addressed where ERRα resides and whether it modulates estrogen-responsive transcription.","evidence":"FISH mapping, gene cloning, and lactoferrin promoter reporter assays in endometrial carcinoma cells","pmids":["9286700"],"confidence":"Medium","gaps":["No endogenous physiological target genes defined","Coactivator dependence not yet established"]},{"year":2004,"claim":"Crystallography resolved how an orphan receptor activates transcription without a ligand, explaining its constitutive activity and coactivator recruitment mode.","evidence":"X-ray structure of the LBD bound to a PGC-1α peptide at 2.5 Å with binding affinity assays","pmids":["15337744"],"confidence":"High","gaps":["Did not exclude endogenous regulatory ligands later shown to exist","No genome-wide target context"]},{"year":2004,"claim":"Placing ERRα as the effector of PGC-1α-driven mitochondrial biogenesis and demonstrating promoter autoregulation defined the core transcriptional circuit of energy metabolism.","evidence":"Dominant-negative/constitutively active ERRα, mtDNA quantification, ChIP, and reporter assays in fibroblasts","pmids":["15087503","14978033"],"confidence":"High","gaps":["Tissue-specific target repertoires not resolved","Upstream signals controlling the axis unknown"]},{"year":2004,"claim":"Knockout phenotypes linked ERRα to specific metabolic targets, showing it directly regulates intestinal lipid handling.","evidence":"ERRα knockout mice, apoA-IV promoter assays, and enterocyte β-oxidation assays","pmids":["15466464"],"confidence":"High","gaps":["Whether the same target set operates in other tissues unaddressed"]},{"year":2007,"claim":"In vivo bioenergetic profiling established that ERRα is required for cardiac metabolic adaptation to stress, not just baseline metabolism.","evidence":"ERRα knockout mice with pressure overload, 31P-NMR, and mitochondrial respiration assays","pmids":["17618854"],"confidence":"High","gaps":["Redundancy with ERRγ not yet tested","Direct cardiac target genes only partially defined"]},{"year":2011,"claim":"Genome-wide mapping integrated ERRα into the circadian clock, revealing reciprocal regulatory loops governing daily metabolic rhythms.","evidence":"ChIP-seq for ERRα/PROX1/BMAL1 in liver plus ERRα-null and Clock mutant phenotyping","pmids":["21731503"],"confidence":"High","gaps":["Mechanism of PROX1 corepression not fully resolved"]},{"year":2013,"claim":"Connecting mTOR to ERRα through proteasomal control positioned ERRα as a degradation-regulated node in hepatic lipid metabolism.","evidence":"ChIP-seq in mouse liver, genetic ERRα ablation, rapamycin treatment, and metabolite analysis","pmids":["23562079"],"confidence":"High","gaps":["Specific E3 ligase not identified in this study","Direct mTOR-ERRα biochemical link inferred via UPS transcription"]},{"year":2013,"claim":"A reciprocal interaction with HDAC4 and a hypomorphic human ESRRA mutation defined a transcriptional regulatory axis with disease relevance.","evidence":"Reciprocal co-IP in HeLa cells and mouse cortex, transcriptional activity assays, and family exome sequencing","pmids":["24216484"],"confidence":"Medium","gaps":["Causal disease mechanism of the variant not fully established","Single-lab functional characterization"]},{"year":2015,"claim":"Double-knockout genetics revealed functional redundancy and the breadth of cardiac targets ERRs control, extending the program to contraction and conduction genes.","evidence":"ERRα/ERRγ double-knockout mice with cardiac phenotyping and target gene analysis","pmids":["25624346"],"confidence":"High","gaps":["Relative contribution of each receptor to individual targets not dissected"]},{"year":2015,"claim":"Identifying direct ERRα binding to inflammatory and sirtuin target promoters extended its role beyond metabolism into innate immune restraint.","evidence":"ERRα knockout macrophages, ChIP at Tnfaip3, NF-κB acetylation, NAD+ quantification, and metabolic flux analysis","pmids":["26200012","26421366"],"confidence":"High","gaps":["Whether immune effects are separable from metabolic effects not fully resolved"]},{"year":2016,"claim":"Discovery of cholesterol as an endogenous LBD agonist reframed ERRα from a strictly ligand-independent receptor to a sterol-responsive one with pharmacological relevance in bone.","evidence":"Affinity chromatography of tissue lipidomes with the LBD, transcriptional assays, and ERRα knockout osteoclastogenesis/bone models","pmids":["26777690"],"confidence":"High","gaps":["Structural mode of cholesterol binding within the occluded pocket not defined"]},{"year":2016,"claim":"Linking ERRα to cancer drug resistance and metabolic reprogramming established it as a therapeutic target through inverse agonism.","evidence":"Protein stability assays, glutamine/ROS metabolic profiling, and ERRα inverse agonist in HER2 mouse tumors; AMPK/one-carbon metabolism ChIP-seq with methotrexate sensitivity","pmids":["27402251","26804918"],"confidence":"High","gaps":["Generality across tumor types not established"]},{"year":2017,"claim":"Two transcription-independent mechanisms — substrate-switching of LSD1 and inhibition of TBK1-IRF3 — revealed non-canonical functions distinct from classic coactivator-driven transcription.","evidence":"In vitro reconstitution of LSD1 H3K9 demethylation with invasion assays; co-IP of TBK1-ERRα-IRF3 with IRF3 phosphorylation/dimerization assays in knockout mice","pmids":["28348226","28591144"],"confidence":"High","gaps":["How ERRα toggles between transcriptional and non-transcriptional modes unknown"]},{"year":2017,"claim":"Defining ERRα's role in autophagosome formation through both Atg gene transcription and SIRT1-mediated deacetylation established a dual transcriptional/post-translational control of autophagy.","evidence":"ESRRA knockout macrophages, Atg promoter ChIP, SIRT1 deacetylation assays, and mycobacterial infection/autophagy flux","pmids":["28841353"],"confidence":"High","gaps":["Relative weight of transcriptional versus post-translational arms not quantified"]},{"year":2017,"claim":"Identifying LSD1 as a demethylase-independent stabilizer of ERRα protein opened a series of studies on post-translational control of ERRα abundance.","evidence":"Ubiquitination assays with LSD1 demethylase-dead mutants and protein stability measurement in breast cancer cells","pmids":["29190800"],"confidence":"Medium","gaps":["E3 ligase opposing LSD1 not identified here","Single-lab study"]},{"year":2018,"claim":"ERRα was shown to mediate thyroid-hormone-induced mitochondrial biogenesis, fission, and mitophagy by inducing ULK1, integrating endocrine signaling with mitochondrial quality control.","evidence":"Transcriptomics, ChIP-seq, siRNA of ESRRA/ULK1/DRP1/FUNDC1, and mitophagy/OXPHOS assays","pmids":["29945885"],"confidence":"High","gaps":["Direct ERRα occupancy at all fission/mitophagy effector genes not fully mapped"]},{"year":2018,"claim":"Characterizing PERM1 as a physical ERRα partner that activates ERR target promoters identified a new cardiac coactivator working alongside PGC-1α.","evidence":"Reciprocal co-IP, one-hybrid and reporter assays, and Perm1 knockout cardiac phenotyping","pmids":["36419485"],"confidence":"Medium","gaps":["Structural basis of PERM1-ERRα interaction undefined","Single-lab study"]},{"year":2020,"claim":"Single-cell analysis revealed ERRα couples metabolism to cell-type differentiation in the kidney, broadening its role beyond pure bioenergetics.","evidence":"scRNA-seq, trajectory analysis, ERRα knockout kidney disease models, and patient sample validation","pmids":["33301705"],"confidence":"High","gaps":["Direct differentiation target genes only partially defined"]},{"year":2020,"claim":"A series of post-translational regulators (DNMT1 stabilization, parkin/STUB1 degradation) and a synthetic feedforward DNA-methylation loop expanded the network controlling ERRα abundance and activity.","evidence":"Protein stability and ubiquitination assays, bisulfite sequencing, and co-IP across breast cancer and endothelial models","pmids":["32855526","30244249","31907393"],"confidence":"Medium","gaps":["Hierarchy among competing E3 ligases and stabilizers unresolved","Mostly single-lab pharmacological studies"]},{"year":2022,"claim":"Genetic dissection of the insulin/GSK3β/FBXW7 axis and the RBBP6 ligase established degradation-controlled ERRα as a sensor coupling hormonal and disease states to metabolic output.","evidence":"Liver-specific GSK3β/FBXW7 knockouts, ERRα phosphosite knock-in mice, and K100 ubiquitination mutagenesis in diabetic kidney models","pmids":["35440636","39441040"],"confidence":"High","gaps":["Integration of multiple ligase inputs on a shared ERRα pool not modeled"]},{"year":2024,"claim":"Adipocyte-specific deletion and the mevalonate-senescence axis showed ERRα coordinates bone marrow stromal fate and sterol-driven cellular senescence in vivo.","evidence":"Adipocyte-specific ESRRA knockout, leptin promoter ChIP, OVX/obesity models, and high-fat-diet senescence assays in knockouts","pmids":["38704393","38216569"],"confidence":"High","gaps":["Cell-type specificity of cholesterol/mevalonate effects not fully separated"]},{"year":null,"claim":"It remains unresolved how ERRα's competing degradation/stabilization inputs, its sterol-ligand sensing, and its transcription-independent functions are integrated to set context-specific output in vivo.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model reconciling the multiple E3 ligases and stabilizers","Structural basis of cholesterol agonism in the occluded pocket undefined","Switch between transcriptional and non-transcriptional modes uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,1,2,3,15,22]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[2,3,15,38,41,43]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[17,44]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[23,21]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,2,7,8]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[23]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,1,2]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[1,3,6,11,12,30]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[1,4,26]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[22,26,31]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[15,23]},{"term_id":"R-HSA-9909396","term_label":"Circadian clock","supporting_discovery_ids":[8]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[35,36,37,39]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[7,18,33]}],"complexes":["PGC-1α/ERRα transcriptional complex"],"partners":["PPARGC1A","PPARGC1B","KDM1A","TBK1","IRF3","HDAC4","PERM1","SIRT1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P11474","full_name":"Steroid hormone receptor ERR1","aliases":["Estrogen receptor-like 1","Estrogen-related receptor alpha","ERR-alpha","Nuclear receptor subfamily 3 group B member 1"],"length_aa":423,"mass_kda":45.5,"function":"Binds to an ERR-alpha response element (ERRE) containing a single consensus half-site, 5'-TNAAGGTCA-3'. Can bind to the medium-chain acyl coenzyme A dehydrogenase (MCAD) response element NRRE-1 and may act as an important regulator of MCAD promoter. Binds to the C1 region of the lactoferrin gene promoter. Requires dimerization and the coactivator, PGC-1A, for full activity. The ERRalpha/PGC1alpha complex is a regulator of energy metabolism. Induces the expression of PERM1 in the skeletal muscle","subcellular_location":"Nucleus; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/P11474/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ESRRA","classification":"Not Classified","n_dependent_lines":207,"n_total_lines":1208,"dependency_fraction":0.17135761589403972},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ESRRA","total_profiled":1310},"omim":[{"mim_id":"615921","title":"PPARGC1- AND ESRR-INDUCED REGULATOR, MUSCLE, 1; PERM1","url":"https://www.omim.org/entry/615921"},{"mim_id":"611906","title":"FIBRONECTIN TYPE III DOMAIN-CONTAINING PROTEIN 5; FNDC5","url":"https://www.omim.org/entry/611906"},{"mim_id":"605166","title":"HISTONE DEACETYLASE 3; HDAC3","url":"https://www.omim.org/entry/605166"},{"mim_id":"604517","title":"PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-GAMMA, COACTIVATOR 1, ALPHA; PPARGC1A","url":"https://www.omim.org/entry/604517"},{"mim_id":"602969","title":"ESTROGEN-RELATED RECEPTOR, GAMMA; ESRRG","url":"https://www.omim.org/entry/602969"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Nucleoli fibrillar center","reliability":"Supported"},{"location":"Microtubules","reliability":"Additional"},{"location":"Cytokinetic bridge","reliability":"Additional"},{"location":"Mitotic spindle","reliability":"Additional"},{"location":"Primary cilium","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"skeletal muscle","ntpm":179.8}],"url":"https://www.proteinatlas.org/search/ESRRA"},"hgnc":{"alias_symbol":["ERR1","ERRalpha","NR3B1","ERRa"],"prev_symbol":["ESRL1"]},"alphafold":{"accession":"P11474","domains":[{"cath_id":"3.30.50.10","chopping":"87-147","consensus_level":"high","plddt":93.8252,"start":87,"end":147},{"cath_id":"1.10.565.10","chopping":"197-203_216-419","consensus_level":"high","plddt":92.7767,"start":197,"end":419}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P11474","model_url":"https://alphafold.ebi.ac.uk/files/AF-P11474-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P11474-F1-predicted_aligned_error_v6.png","plddt_mean":77.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ESRRA","jax_strain_url":"https://www.jax.org/strain/search?query=ESRRA"},"sequence":{"accession":"P11474","fasta_url":"https://rest.uniprot.org/uniprotkb/P11474.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P11474/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P11474"}},"corpus_meta":[{"pmid":"15087503","id":"PMC_15087503","title":"The estrogen-related receptor alpha (ERRalpha) functions in PPARgamma coactivator 1alpha (PGC-1alpha)-induced mitochondrial biogenesis.","date":"2004","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/15087503","citation_count":560,"is_preprint":false},{"pmid":"15961417","id":"PMC_15961417","title":"Mitofusins 1/2 and ERRalpha expression are increased in human skeletal muscle after physical exercise.","date":"2005","source":"The Journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/15961417","citation_count":334,"is_preprint":false},{"pmid":"17618854","id":"PMC_17618854","title":"The nuclear receptor ERRalpha is required for the bioenergetic and functional adaptation to cardiac pressure overload.","date":"2007","source":"Cell metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/17618854","citation_count":224,"is_preprint":false},{"pmid":"18778951","id":"PMC_18778951","title":"ERRalpha: a metabolic 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EGFR-TKIs resistance in NSCLC by inducing EGFR/Src/Erk/SP1 signaling-mediated ERRα re-expression.","date":"2022","source":"Molecular cancer","url":"https://pubmed.ncbi.nlm.nih.gov/35303882","citation_count":129,"is_preprint":false},{"pmid":"23562079","id":"PMC_23562079","title":"Molecular and genetic crosstalks between mTOR and ERRα are key determinants of rapamycin-induced nonalcoholic fatty liver.","date":"2013","source":"Cell metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/23562079","citation_count":128,"is_preprint":false},{"pmid":"29945885","id":"PMC_29945885","title":"Thyroid hormone receptor and ERRα coordinately regulate mitochondrial fission, mitophagy, biogenesis, and function.","date":"2018","source":"Science signaling","url":"https://pubmed.ncbi.nlm.nih.gov/29945885","citation_count":116,"is_preprint":false},{"pmid":"26200012","id":"PMC_26200012","title":"Orphan Nuclear Receptor ERRα Controls Macrophage Metabolic Signaling and A20 Expression to Negatively Regulate 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with a PGC-1α coactivator peptide reveals a transcriptionally active conformation in the absence of a ligand. The putative ligand-binding pocket is almost completely occupied by bulky side chains (particularly Phe328), providing structural evidence for ligand-independent transcriptional activation. The structure also reveals how a PGC-1α LLXYL (inverted LXXLL) motif binds the LBD.\",\n      \"method\": \"X-ray crystallography at 2.5 Å resolution; binding affinity assays with PGC-1α peptides\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with direct functional validation of ligand-independent activation and coactivator binding mode\",\n      \"pmids\": [\"15337744\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"ERRα is a downstream effector of PGC-1α in mitochondrial biogenesis: inhibition of ERRα compromises PGC-1α-induced expression of mitochondrial protein-encoding genes and mitochondrial DNA content. A constitutively active ERRα is sufficient to induce both responses. ERRα binding sites in promoters of target genes contribute to the PGC-1α transcriptional response.\",\n      \"method\": \"Dominant-negative and constitutively active ERRα overexpression; mitochondrial DNA quantification; reporter/promoter assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal functional methods (loss-of-function, gain-of-function, promoter assays, mtDNA quantification), widely replicated\",\n      \"pmids\": [\"15087503\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"ERRα autoregulates its own expression via a polymorphic 23-bp hormone response element (ESRRA23) in the human ESRRA promoter that binds ERRα. PGC-1α induces ESRRA promoter activity in an ESRRA23- and ERRα-dependent manner, and co-expression of ERRα and PGC-1α synergistically activates the promoter. Chromatin immunoprecipitation confirmed endogenous ERRα occupies its own promoter in vivo.\",\n      \"method\": \"ChIP; luciferase reporter assays; ERRα null fibroblasts; transient transfection\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP confirmed in vivo occupancy, multiple orthogonal methods (reporter assay, null cells, co-expression), replicated concept across labs\",\n      \"pmids\": [\"14978033\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"ERRα directly regulates the apolipoprotein A-IV (apoA-IV) promoter via interaction with the apoC-III enhancer element; ERRα cooperates with PGC-1α to activate apoA-IV transcription. ERRα knockout mice display lipid malabsorption and reduced enterocyte β-oxidation capacity, establishing ERRα as a direct transcriptional regulator of intestinal lipid handling.\",\n      \"method\": \"Microarray; promoter luciferase assays; ERRα knockout mice; isolated enterocyte β-oxidation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct promoter binding established, in vivo knockout phenotype with defined molecular target\",\n      \"pmids\": [\"15466464\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"PGC-1α drives mitofusin 2 (Mfn2) gene expression through ERRα in an ERRα-dependent transcriptional programme, linking the PGC-1α/ERRα axis to mitochondrial fusion and architecture in skeletal muscle.\",\n      \"method\": \"In vitro cellular reporter assays; mRNA expression analysis in human exercise cohort\",\n      \"journal\": \"The Journal of physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro mechanistic assay plus human exercise data, single lab\",\n      \"pmids\": [\"15961417\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"ERRα controls morphogenetic movements (epiboly and convergent-extension) during zebrafish gastrulation. Loss-of-function via morpholinos or dominant-negative ERRα disrupts these movements; gain-of-function by mRNA injection also perturbs them, establishing a role in early embryonic development independent of cell fate determination.\",\n      \"method\": \"Zebrafish morpholino knockdown; dominant-negative overexpression; mRNA injection gain-of-function\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal loss- and gain-of-function in zebrafish, single lab\",\n      \"pmids\": [\"15848392\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"ERRα is required for the bioenergetic adaptation to cardiac pressure overload: ERRα−/− mice develop heart failure with abnormal phosphocreatine depletion and reduced maximal mitochondrial ATP synthesis rates. ERRα target genes involved in energy substrate oxidation, ATP synthesis, and phosphate transfer are downregulated at baseline or with pressure overload.\",\n      \"method\": \"ERRα knockout mice; left ventricular pressure overload model; 31P-NMR; mitochondrial respiration assays; gene expression analysis\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal in vivo methods (NMR, respiration, gene expression) in knockout model with clear bioenergetic phenotype\",\n      \"pmids\": [\"17618854\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"ERRα and PGC-1β co-occupy the ERBB2 amplicon on chromosome 17q12-21 in human breast cancer cells, directing co-recruitment of PGC-1β and RNA polymerase II to ERBB2 and co-amplified gene promoters. ERRα ablation delays ERBB2-induced mammary tumor development and lowers amplicon transcript levels. ERRα also competitively displaces ERα from the ERBB2 locus to de-repress expression.\",\n      \"method\": \"Chromosome 17q-wide ChIP; ERRα knockout mouse mammary tumor model; RNA polymerase II ChIP; tamoxifen sensitivity assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide ChIP location analysis plus in vivo mouse tumor model with reciprocal competitive binding mechanism established\",\n      \"pmids\": [\"20961995\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"ERRα directly regulates all major molecular clock components and is an output gene of the circadian oscillator (shown by Clock/Clock mutant mice). Genome-wide ChIP-seq identified extensive overlap between ERRα, its corepressor PROX1, and the core clock factor BMAL1 binding sites in liver, establishing transcriptional regulatory loops between these factors controlling daily metabolic rhythms. ERRα-null mice display deregulated locomotor activity rhythms and time-dependent hypoglycemia/hypoinsulinemia.\",\n      \"method\": \"ChIP-seq; ERRα-null mouse phenotyping; Clock mutant mice; circadian locomotor activity analysis; metabolic profiling\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide ChIP-seq plus multiple in vivo genetic models with defined metabolic phenotypes\",\n      \"pmids\": [\"21731503\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"A recurrent ESRRA-C11orf20 fusion transcript, joining 5′ exons of ESRRA to 3′ exons of C11orf20, was identified in ~15% of serous ovarian carcinomas by deep paired-end mRNA sequencing, with a corresponding genomic rearrangement confirmed in tumor samples.\",\n      \"method\": \"Deep paired-end RNA sequencing; RT-PCR validation; targeted genomic resequencing\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — identified by sequencing and confirmed by RT-PCR in 10/67 tumors with genomic evidence; functional consequence of the fusion not established\",\n      \"pmids\": [\"21949640\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"ERRα directly binds an evolutionarily conserved response element in the PGC-1α promoter and is required for PGC-1α expression in primary cardiomyocytes. Overexpression of ERRα overcomes HDAC5-mediated repression of PGC-1α. Hypoxia reduces ERRα mRNA, preceding loss of PGC-1α mRNA, though ChIP shows ERRα loss is not responsible for PGC-1α loss during hypoxia.\",\n      \"method\": \"Luciferase reporter assays; ERRα overexpression/knockdown in primary cardiomyocytes; ChIP; HDAC5 co-expression\",\n      \"journal\": \"Biochemistry and cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and reporter assays in primary cells, single lab\",\n      \"pmids\": [\"23668787\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"mTOR occupies regulatory regions of ERRα target genes (TCA cycle, lipid biosynthesis) genome-wide in mouse liver. mTOR regulates ERRα activity through ubiquitin-mediated proteasomal degradation via transcriptional control of the ubiquitin-proteasome pathway. Combined genetic/pharmacological inhibition of ERRα and rapamycin exacerbates hepatic hyperlipidemia, placing ERRα downstream of mTOR in hepatic lipid metabolism.\",\n      \"method\": \"ChIP-seq in mouse liver; genetic ERRα ablation; rapamycin treatment; TCA metabolite quantification; hepatic lipid measurement\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide ChIP-seq, genetic ablation, pharmacological inhibition, and metabolite analyses providing mechanistic placement of ERRα downstream of mTOR\",\n      \"pmids\": [\"23562079\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"ERRα regulates colon cancer cell proliferation, colony formation, and tumorigenic capacity. ERRα depletion causes G1-to-S cell cycle arrest with reduced CDK2 activity and altered retinoblastoma phosphorylation. ERRα-depleted cells show reduced expression of glycolysis, TCA cycle, and lipid synthesis genes, and reduced glucose incorporation and glucose-mediated lipogenesis measured by 14C isotope tracing.\",\n      \"method\": \"shRNA knockdown; colony formation assays; xenograft; cell cycle analysis; 14C isotope tracer analysis\",\n      \"journal\": \"Carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional assays including isotope tracing, single lab\",\n      \"pmids\": [\"23720198\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"ESRRA and HDAC4 interact both in vitro (HeLa cells) and in vivo (mouse cortex). HDAC4 potently represses ESRRA-induced target gene expression. A missense mutation in ESRRA decreases its transcriptional activity, while an HDAC4 mutation increases repression of ESRRA target genes, establishing a functional ESRRA-HDAC4 transcriptional regulatory axis.\",\n      \"method\": \"Co-immunoprecipitation in HeLa cells and mouse cortex; transcriptional activity assays; whole-genome/exome sequencing of human families\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP in two systems plus transcriptional functional assay, single lab\",\n      \"pmids\": [\"24216484\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ERRα and ERRγ together are required for cardiomyocyte metabolism and cardiac function: mice lacking both ERRα and cardiac ERRγ develop severe bradycardia, lethal cardiomyopathy, and heart failure. ERRα and ERRγ directly control genes for mitochondrial function/dynamics and genes for contraction, calcium homeostasis, and conduction.\",\n      \"method\": \"ERRα/ERRγ double-knockout mice; cardiac phenotyping; transcriptional target gene analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — double-knockout in vivo model with defined lethal phenotype and direct transcriptional target identification\",\n      \"pmids\": [\"25624346\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ERRα negatively regulates TLR-induced inflammation in macrophages by directly binding the Tnfaip3 (A20 deubiquitinase) promoter to promote its transcription. ERRα also regulates NF-κB signaling by controlling p65 acetylation via maintenance of NAD+ levels and sirtuin 1 activation. ERRα-deficient macrophages display increased glycolysis and impaired mitochondrial respiratory function.\",\n      \"method\": \"ERRα knockout mice; ChIP; promoter assays; NF-κB p65 acetylation measurement; NAD+ quantification; Seahorse metabolic flux analysis\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct promoter ChIP, in vivo knockout model with septic shock phenotype, multiple orthogonal mechanistic assays\",\n      \"pmids\": [\"26200012\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ERRα directly binds the Sirt3 promoter as its transcription factor (in a PGC-1α/ERRα complex) to regulate Sirt3 expression and dopaminergic neuronal survival. PGC-1α interacts with ERRα for this function. Loss of the PGC-1α/ERRα-Sirt3 pathway leads to elevated acetylation of SOD2 (K130) and ATP synthase β (K485) and dopaminergic neuronal death.\",\n      \"method\": \"ChIP; co-immunoprecipitation; promoter reporter assays; MPTP mouse model; Sirt3 knockout mice\",\n      \"journal\": \"Antioxidants & redox signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and Co-IP establish direct binding, supported by in vivo models, single lab\",\n      \"pmids\": [\"26421366\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Cholesterol was identified as an endogenous ERRα agonist by affinity chromatography of tissue lipidomes with the ERRα LBD followed by transcriptional assays. In bone, cholesterol effects, statin effects, and bisphosphonate osteoprotection on osteoclastogenesis all require ERRα; these effects are lost in ERRα knockout mice.\",\n      \"method\": \"Affinity chromatography; transcriptional activation assays; ERRα knockout mice; osteoclastogenesis assays; in vivo bone loss models\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — biochemical LBD binding assay plus in vivo genetic validation in knockout mice across multiple pharmacological contexts\",\n      \"pmids\": [\"26777690\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Lapatinib induces degradation of ERRα protein. In lapatinib-resistant breast cancer cells, mTOR reactivation restores ERRα expression, which triggers metabolic adaptations including increased glutamine metabolism and ROS detoxification. An ERRα inverse agonist counteracts these metabolic adaptations and overcomes lapatinib resistance in a HER2-induced mouse mammary tumor model.\",\n      \"method\": \"Protein stability assays; mTOR inhibition; metabolic flux analysis (glutamine); ROS measurement; ERRα inverse agonist treatment; HER2 mouse tumor model\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal metabolic and genetic methods plus in vivo mouse model validation\",\n      \"pmids\": [\"27402251\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"The PGC-1α/ERRα axis negatively regulates one-carbon metabolism genes, reducing purine biosynthesis in breast cancer cells. Activation of AMPK increases PGC-1α/ERRα expression and ERRα binding to target sites. This repression of the folate cycle by ERRα promotes sensitivity to the anti-folate drug methotrexate in vitro and in vivo.\",\n      \"method\": \"ChIP-seq; gene-expression datasets; AMPK activation; ERRα binding site analysis; methotrexate sensitivity assays in mice\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq binding data plus functional drug sensitivity assay in vivo, single lab\",\n      \"pmids\": [\"26804918\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"MYC drives metabolic reprogramming to an oxidative state during osteoclast differentiation and transcriptionally induces ERRα. ERRα then cooperates with NFATc1 to drive osteoclastogenesis. Pharmacological inhibition of ERRα attenuated ovariectomy-induced bone loss in mice. Osteoclast-specific Myc deletion increased bone mass and protected against OVX-induced osteoporosis.\",\n      \"method\": \"Osteoclast-specific Myc knockout mice; transcriptomic analysis; pharmacological ERRα inhibition; OVX mouse model\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic knockout plus pharmacological validation with defined transcriptional pathway\",\n      \"pmids\": [\"28530645\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ERRα induces LSD1 to demethylate H3K9 (rather than its default H3K4 substrate) at the transcriptional start site of commonly activated target genes including MMP1. ERRα is sufficient to switch LSD1 substrate specificity to H3K9 demethylation in vitro. This ERRα-LSD1 axis promotes cell invasion, which is rescued by MMP1 re-expression after LSD1 or ERRα depletion.\",\n      \"method\": \"In vitro H3K9 demethylation assay with purified ERRα and LSD1; ChIP for H3K9me marks; siRNA depletion; invasion assays; MMP1 rescue\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution of substrate switch plus ChIP and functional invasion assays\",\n      \"pmids\": [\"28348226\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ESRRA is required for autophagosome formation and autophagy-mediated antimicrobial defense against mycobacterial infection. AMPK pathway and SIRT1 activation induce ESRRA, which transcriptionally activates Atg genes via ERR response elements. Additionally, ESRRA operates in a feed-forward loop with SIRT1 to deacetylate ATG5, BECN1, and ATG7, activating autophagy post-translationally.\",\n      \"method\": \"ESRRA knockout macrophages; ChIP/promoter analysis of Atg genes; SIRT1 deacetylation assays; mycobacterial infection assays; autophagy flux measurement\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout combined with ChIP promoter binding and post-translational deacetylation mechanism, multiple orthogonal approaches\",\n      \"pmids\": [\"28841353\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ERRα negatively regulates type I interferon (IFN-I) production by associating with TBK1 and IRF3 to impede TBK1-IRF3 complex formation, IRF3 phosphorylation, IRF3 dimerization, and DNA binding. Viral infection induces TBK1-dependent ERRα stabilization. This anti-viral regulatory function is independent of ERRα transcriptional activity and PGC-1α.\",\n      \"method\": \"ERRα knockout mice; co-immunoprecipitation of TBK1-ERRα-IRF3 complex; IRF3 phosphorylation and dimerization assays; DNA binding assays; viral infection models\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP establishing ternary complex, in vivo knockout model, multiple functional assays for IRF3 inhibition\",\n      \"pmids\": [\"28591144\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"LSD1 protects ERRα from ubiquitination and proteasomal degradation independently of LSD1's demethylase activities, resulting in elevated ERRα protein levels in breast cancer cells.\",\n      \"method\": \"Ubiquitination assays; LSD1 demethylase-inactive mutants; co-immunoprecipitation; ERRα protein stability measurement\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ubiquitination assay with demethylase-dead mutants, single lab\",\n      \"pmids\": [\"29190800\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ERRα directly transactivates the TMPRSS2:ERG fusion gene in prostate cancer cells via both ERR-binding element- and AR-binding element-dependent mechanisms. ERG expressed by the T:E fusion in turn transactivates the ESRRA gene, forming a reciprocal ERRα-ERG regulatory loop that promotes advanced prostate cancer growth.\",\n      \"method\": \"Luciferase reporter assays; ChIP; ERRα inverse agonist treatment; ERRα/ERG overexpression; in vivo metastasis assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and reporter assays establish direct binding and reciprocal regulation, supported by in vivo data, single lab\",\n      \"pmids\": [\"30042415\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Thyroid hormone (TH) increases ESRRA expression and activity through THRB1-dependent induction of PGC1α. ESRRA mediates TH-induced mitochondrial biogenesis, fission, and mitophagy. Mechanistically, ESRRA induces ULK1 expression, which then promotes DRP1-mediated fission and activates FUNDC1-MAP1LC3B-II interaction to induce mitophagy. siRNA knockdown of ESRRA, ULK1, DRP1, or FUNDC1 inhibits TH-induced mitophagy and decreases OXPHOS.\",\n      \"method\": \"Transcriptome analysis; ChIP-seq; siRNA knockdown; mitochondrial biogenesis/fission/mitophagy functional assays; co-immunoprecipitation (FUNDC1-LC3)\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP-seq, transcriptomics, and multiple siRNA knockdowns with defined pathway placement, multiple orthogonal approaches\",\n      \"pmids\": [\"29945885\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ERRα promotes breast cancer cell dissemination to bone by directly transactivating the RANK gene. ChIP and bioinformatics confirmed RANK as an ERRα target. ERRα overexpression promotes spontaneous bone micro-metastases in vivo; pharmacological ERRα inhibition reduces bone metastases and RANK expression.\",\n      \"method\": \"ChIP; transactivation assays; in vivo orthotopic breast cancer model; pharmacological ERRα inhibition; meta-analysis of human cohorts\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and transactivation assays plus in vivo model, single lab\",\n      \"pmids\": [\"30478447\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PERM1 physically interacts with ERRα in cardiomyocytes and the mouse heart (co-immunoprecipitation). PERM1 is recruited to ERR target gene promoters and activates their transcription partially through ERRα. Mammalian one-hybrid assay showed PERM1 activates transcription when recruited to a promoter, blunted by silencing PGC-1α, BAG6, or KANK2. PERM1 knockout mice show reduced cardiac function and energy reserves.\",\n      \"method\": \"Co-immunoprecipitation; DNA binding assays; reporter gene assays; Perm1 knockout mice; echocardiography; proteomics/metabolomics\",\n      \"journal\": \"Frontiers in cardiovascular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP plus reporter assays and in vivo knockout, single lab\",\n      \"pmids\": [\"36419485\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ERRα directly activates androgen response element (ARE)-containing promoters such as the PSA promoter in prostate cells, independent of androgen receptor expression or activity. All ERR subfamily members can activate steroid response element-containing promoters even in the presence of antisteroid compounds.\",\n      \"method\": \"ERRα inverse agonist treatment; ARE-containing promoter reporter assays; androgen receptor expression analysis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — reporter assays establish functional activation, replicated across ERR family members, single lab\",\n      \"pmids\": [\"18697814\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In kidney proximal tubule cells, ESRRA directly controls both metabolic (fatty acid oxidation, oxidative phosphorylation) and proximal tubule cell-specific differentiation genes. ERRα knockout in mouse models of kidney disease worsens PT cell differentiation defects and disease, establishing that ERRα couples metabolism and differentiation in PT cells.\",\n      \"method\": \"scRNA-seq; cell trajectory analyses; ERRα knockout mouse models; ChIP/transcriptional target analysis in mouse and patient samples\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — scRNA-seq plus in vivo knockout with patient validation and direct transcriptional target evidence\",\n      \"pmids\": [\"33301705\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ESRRA activates autophagic flux and controls gut microbiota composition to maintain intestinal homeostasis. esrra-null mice show depressed AMPK phosphorylation, lower TFEB levels, and accumulation of p62 with defective mitochondria. Fecal microbiota transplantation from WT mice ameliorated colitis severity in Esrra-deficient mice.\",\n      \"method\": \"Esrra knockout mice; DSS colitis model; autophagy flux assays; gut microbiota analysis; fecal microbiota transplantation\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout with FMT rescue and defined molecular phenotypes, single lab\",\n      \"pmids\": [\"33172329\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"DNMT1 promotes ERRα protein stability; ERRα in turn couples DNMT1 transcription with that of the methionine cycle and S-adenosylmethionine synthesis, driving DNA methylation. Combined inhibition of ERRα and DNMT1 (5-azadC) reverses IRF4 promoter hypermethylation and de-represses this tumor suppressor gene to suppress breast cancer in vivo.\",\n      \"method\": \"Genetic/pharmacological manipulation; bisulfite genomic sequencing; pre-clinical mouse model of breast cancer; protein stability assays; methylation analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — large-scale bisulfite sequencing plus in vivo model, feedforward mechanism established, single lab\",\n      \"pmids\": [\"32855526\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ERRα directly transactivates two key steroidogenic enzyme genes, CYP11A1 and AKR1C3, to promote intratumoral androgen (DHT) biosynthesis in castration-resistant prostate cancer. ERRα inverse agonist reduces DHT production and suppresses AR signaling in prostate cancer cells.\",\n      \"method\": \"ERRα overexpression/knockdown; UPLC-MS/MS intratumoral androgen measurement; ERRα inverse agonist treatment; ChIP/promoter transactivation assays\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP/reporter assays with direct androgen measurement by UPLC-MS/MS, single lab\",\n      \"pmids\": [\"32226548\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ESRRA acts as a key regulator of intestinal homeostasis; ERRα-deficient mice were more susceptible to DSS-induced colitis, with impaired intestinal epithelial cell compensatory proliferation, enhanced apoptosis, and reduced goblet cell counts. ERRα exerts protective effects within the radio-resistant compartment via transcriptional control of intestinal homeostasis genes.\",\n      \"method\": \"ERRα knockout mice; DSS colitis model; microbiota analysis; epithelial proliferation/apoptosis assays; bone marrow transplantation\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout with defined cellular phenotypes, single lab\",\n      \"pmids\": [\"34302001\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Insulin enhances ERRα activity via a GSK3β/FBXW7 signaling axis: insulin inhibits GSK3β, preventing FBXW7-mediated ubiquitination and proteasomal degradation of ERRα, thus stabilizing ERRα. Liver-specific deletion of GSK3β or FBXW7 and ERRα phosphosite mutant (ERRα3SA) mice accumulate ERRα protein that no longer responds to fluctuating insulin levels, resulting in compromised energy homeostasis and reduced insulin sensitivity.\",\n      \"method\": \"Liver-specific conditional knockout mice (GSK3β, FBXW7); ERRα phosphosite knock-in mice (ERRα3SA); transcriptome analysis; insulin sensitivity assays; protein stability/ubiquitination assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple in vivo genetic models with biochemical ubiquitination mechanism and defined metabolic phenotypes\",\n      \"pmids\": [\"35440636\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"RBBP6 E3 ubiquitin ligase promotes ERRα degradation through K48-linked polyubiquitination at the K100 residue of ERRα. This RBBP6-mediated ERRα degradation contributes to mitochondrial injury in proximal tubule cells in diabetic kidney disease. Conditional ERRα overexpression or RBBP6 inhibition reduced mitochondrial damage in diabetic mice.\",\n      \"method\": \"Biochemical ubiquitination assays; site-directed mutagenesis (K100); co-immunoprecipitation; conditional ERRα overexpression in DKD mouse models; human DKD specimens\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — biochemical identification of ubiquitin site plus E3 ligase with mutagenesis validation and in vivo rescue, single lab\",\n      \"pmids\": [\"39441040\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Carnosic acid directly binds the ligand-binding domain of ERRα and promotes ERRα ubiquitination and proteasomal degradation. STUB1 was identified as the E3 ligase of ERRα. Lysine residues K51 and K68 are essential for ERRα ubiquitination and degradation. Carnosic acid also decreases the interaction between ERRα and PGC1β.\",\n      \"method\": \"Direct LBD binding assay; ubiquitination assay with STUB1; site-directed mutagenesis (K51, K68); co-immunoprecipitation ERRα-PGC1β; osteoclastogenesis and OVX mouse model\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct LBD binding and ubiquitination with mutagenesis, but single lab and primarily pharmacological study\",\n      \"pmids\": [\"31907393\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ERRα directly binds the DSN1 promoter (confirmed by ChIP and dual-luciferase assays) to transcriptionally activate DSN1, which then promotes cell cycle progression via the CDC25C/CDK1/CyclinB1 pathway. ERRα silencing causes G2M arrest in gastric cancer cells via this pathway.\",\n      \"method\": \"RNA-seq; dual-luciferase reporter assay; ChIP; flow cytometry; ERRα silencing\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and reporter assays establish direct promoter binding and pathway placement, single lab\",\n      \"pmids\": [\"34131395\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FBXL10 interacts with ERRα (identified by mass spectrometry), stabilizes ERRα protein by reducing poly-ubiquitylation and promoting mono-ubiquitylation, increases ERRα transcriptional activity and promoter occupancy, and facilitates ERRα/PGC1β-mediated breast cancer cell proliferation and tumorigenesis in vitro and in vivo.\",\n      \"method\": \"Mass spectrometry interaction screen; co-immunoprecipitation; ubiquitination assays; reporter gene assay; ChIP; xenograft mouse model\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS-identified interaction confirmed by co-IP and ubiquitination mechanism, supported by in vivo model, single lab\",\n      \"pmids\": [\"33450359\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Cholesterol accumulation in lipid rafts during EGFR-TKI resistance promotes EGFR-Src interaction and EGFR/Src/Erk signaling reactivation, leading to SP1 nuclear translocation and SP1-dependent transcriptional upregulation of ERRα. ERRα re-expression sustains ROS detoxification in resistant cells. SP1 binding to the ERRα promoter was confirmed by luciferase reporter and ChIP assays.\",\n      \"method\": \"Co-immunoprecipitation; luciferase reporter assay; ChIP; immunofluorescence; xenograft mouse model\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and co-IP establish signaling pathway leading to ERRα regulation, in vivo validation, single lab\",\n      \"pmids\": [\"35303882\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ERRα binds to the NLRP3 promoter (confirmed by CUT&Tag) and inhibits caspase-1/GSDMD signaling to reduce pyroptosis in endometrial cancer. ERRα also activates glycolytic rate-limiting enzymes and bridges glycolytic metabolism with pyroptosis resistance. ERRα-HIF-1α interaction was confirmed by co-immunoprecipitation.\",\n      \"method\": \"Co-immunoprecipitation (ERRα-HIF-1α); dual-luciferase reporter; CUT&Tag sequencing; flow cytometry; electron microscopy; organoid and xenograft models\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CUT&Tag confirms direct NLRP3 promoter binding, co-IP establishes protein interaction, in vivo validation, single lab\",\n      \"pmids\": [\"37864196\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SLU-PP-332, a synthetic pan-ERR agonist with highest potency for ERRα, increases mitochondrial function and cellular respiration in skeletal muscle cells, increases type IIa oxidative muscle fibers, and enhances exercise endurance in mice. SLU-PP-332 induces an ERRα-specific acute aerobic exercise genetic program; ERRα activation is critical for enhanced exercise endurance.\",\n      \"method\": \"ERR agonist pharmacological characterization; ERRα-specific genetic models; Seahorse metabolic flux; skeletal muscle fiber typing; mouse exercise endurance testing\",\n      \"journal\": \"ACS chemical biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological tool plus ERRα-specific genetic evidence for exercise capacity, single lab\",\n      \"pmids\": [\"36988910\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Adipocyte-specific ESRRA deficiency preserves osteogenesis and vascular formation in adipocyte-rich bone marrow under estrogen deficiency or obesity. Mechanistically, adipocyte ESRRA suppresses SPP1 transcription (by interfering with E2/ESR1 signaling) and positively drives leptin expression by directly binding the leptin promoter. ESRRA abrogation enhances SPP1 secretion and decreases leptin, coordinately dictating bone marrow stromal stem cell fate and restoring type H vessel formation.\",\n      \"method\": \"Adipocyte-specific ESRRA knockout mice; OVX and obesity models; ChIP (leptin promoter); pharmacological ERRα inhibition; SPP1 and leptin secretion assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional tissue-specific knockout with ChIP-confirmed direct promoter binding and mechanistic downstream signaling, in vivo pharmacological validation\",\n      \"pmids\": [\"38704393\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The cholesterol/mevalonate biosynthetic pathway promotes ERRα transcriptional activity, leading to dysfunctional mitochondria, ROS production, DNA damage, and p53-dependent cellular senescence. This mevalonate-induced senescence is abrogated in ERRα knockout mice on a high-fat diet in vivo.\",\n      \"method\": \"ERRα knockout mice; high-fat diet model; mevalonate pathway inhibition; ROS and mitochondrial function assays; p53 pathway analysis\",\n      \"journal\": \"npj aging\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo knockout confirms pathway dependence, multiple mechanistic assays, single lab\",\n      \"pmids\": [\"38216569\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"IL-6 suppresses mitochondrial function via a JAK1/STAT1/3 axis that upregulates HIF1A and ERRα transcription. ERRα then stabilizes HIF1α protein, which in turn inhibits ERRα—establishing a negative feedback loop. This IL-6-mediated suppression operates when PGC1 expression is low; higher PGC1 rescues ERRα from HIF1α-mediated inhibition to restore mitochondrial respiration.\",\n      \"method\": \"JAK1 inhibitors; STAT1/3 pathway analysis; ERRα transcription/protein stability assays; HIF1α stabilization assays; PGC1 overexpression rescue; Seahorse metabolic flux\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple pathway inhibitor experiments and mechanistic rescue assays, single lab\",\n      \"pmids\": [\"40056415\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ERRα negatively regulates S6K1 expression by directly binding to the S6K1 promoter. Downregulation of ERRα sensitizes ERα-negative breast cancer cells to mTORC1/S6K1 inhibitors.\",\n      \"method\": \"ChIP (ERRα at S6K1 promoter); ERRα knockdown; mTORC1/S6K1 inhibitor sensitivity assays\",\n      \"journal\": \"Signal transduction and targeted therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP establishes direct promoter binding, functional drug sensitivity assay, single lab\",\n      \"pmids\": [\"28890840\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The PGC1α-ERRα transcriptional complex suppresses prostate cancer invasion by downregulating MYC and inhibiting integrin alpha1 and beta4 expression. CRISPR/Cas9 deletion of ERRα abolishes PGC1α regulation of cytoskeletal organization and invasiveness. PGC1α and ERRα associate at the MYC promoter (confirmed by ChIP), supporting their inhibitory activity on MYC transcription.\",\n      \"method\": \"CRISPR/Cas9 ERRα deletion; PGC1α overexpression; ChIP (PGC1α/ERRα at MYC promoter); invasion assays in vitro and in vivo; integrin expression analysis\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR knockout plus ChIP and in vivo functional assays, single lab\",\n      \"pmids\": [\"31594836\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Parkin overexpression promotes ERRα ubiquitination and degradation, reducing ERRα protein levels and consequently decreasing eNOS (total and phosphorylated) in endothelial cells. ERRα overexpression increases eNOS levels; this parkin-eNOS regulatory effect is independent of autophagy and apoptosis.\",\n      \"method\": \"Parkin plasmid overexpression; co-immunoprecipitation; ERRα ubiquitination assay; flow cytometry; ERRα inhibitor treatment; siRNA knockdown\",\n      \"journal\": \"Cellular physiology and biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP and ubiquitination assay with functional eNOS measurement, single lab\",\n      \"pmids\": [\"30244249\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"PGC-1α and PGC-1β increase creatine transporter (CrT/Slc6a8) expression and creatine uptake in myotubes via ERRα. An ERR response element (ERRE) was identified in the CrT gene first intron and upstream promoter. ChIP assays confirmed that PGC-1α and ERRα directly interact with the CrT gene. shRNA knockdown of ERRα inhibited the PGC-1-mediated increase in CrT expression.\",\n      \"method\": \"ChIP (ERRα at CrT gene); adenoviral overexpression; shRNA knockdown; creatine uptake assay; constitutively active ERRα (VP16-ERRα)\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP confirms direct binding, functional creatine uptake assay, single lab\",\n      \"pmids\": [\"25173818\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"The human ESRL1 (ERRα) gene is localized to chromosome 11q12 by FISH, consists of 7 exons spanning ~20 kb, and has a GC-rich promoter with 10 Sp1 sites and two E-boxes but no TATA or CAAT boxes. Multiple transcription initiation start sites were identified. ERRα modulates estrogen responsiveness of the lactoferrin gene promoter in endometrial carcinoma cells.\",\n      \"method\": \"FISH; gene cloning and sequencing; primer extension; RNase protection assay; transient transfection reporter assay\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct genomic characterization and functional promoter assay, single lab\",\n      \"pmids\": [\"9286700\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ERRα (ESRRA) is a ligand-independent orphan nuclear receptor whose LBD adopts a constitutively active conformation stabilized by PGC-1α coactivator binding; it functions as a master transcriptional regulator of mitochondrial biogenesis, oxidative phosphorylation, fatty acid oxidation, and energy metabolism by co-occupying target gene promoters with PGC-1α/PGC-1β and autoregulating its own expression. Its activity is modulated by cholesterol (an endogenous agonist activating the LBD), post-translational stability control via the GSK3β/FBXW7 and RBBP6 ubiquitin-proteasome axes, and protein-level regulation by LSD1, FBXL10, and parkin. Beyond metabolism, ERRα directly drives transcriptional programs controlling autophagy (via Atg gene induction and SIRT1-mediated deacetylation of ATG5/BECN1/ATG7), innate immune responses (repressing TLR-induced inflammation via A20/Tnfaip3 and inhibiting antiviral IFN-I production by blocking TBK1-IRF3 complex formation), circadian clock outputs, osteoclastogenesis (downstream of MYC), and cell invasion (by switching LSD1 substrate specificity to H3K9 demethylation). In cancer contexts, ERRα regulates ERBB2 amplicon transcription, intratumoral androgen biosynthesis in prostate cancer, and metabolic reprogramming underlying drug resistance, placing it at the intersection of energy metabolism, epigenetics, and signal transduction.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ERRα (ESRRA) is a ligand-independent orphan nuclear receptor that serves as a master transcriptional regulator of mitochondrial biogenesis, oxidative metabolism, and energy homeostasis, functioning downstream of and in complex with the PGC-1α/PGC-1β coactivators [#0, #1]. Structurally, its ligand-binding domain adopts a transcriptionally active conformation in the absence of ligand because bulky side chains (notably Phe328) occupy the pocket, while an inverted LXXLL motif of PGC-1α docks onto the LBD surface to drive activation [#0]. ERRα is itself a downstream effector required for PGC-1α-induced mitochondrial gene expression and mtDNA replication, and it autoregulates its own promoter through a dedicated response element while synergizing with PGC-1α [#1, #2]. Through co-occupancy of target promoters it directs broad metabolic programs — fatty acid oxidation, OXPHOS, TCA cycle, mitochondrial fusion/dynamics, and creatine handling — in cardiac, skeletal muscle, hepatic, renal, and intestinal tissues, with in vivo loss producing bioenergetic failure under stress [#6, #14, #30, #4]. ERRα also drives autophagy by transcriptionally inducing Atg genes and operating in a feed-forward loop with SIRT1 to deacetylate ATG5/BECN1/ATG7, supporting antimicrobial defense and intestinal homeostasis [#22, #31]. Its protein level is a central control node, stabilized or destabilized by an array of factors including the GSK3β/FBXW7 axis downstream of insulin, the E3 ligases RBBP6 and STUB1, FBXL10, LSD1, and parkin [#35, #36, #37, #39, #24]. Cholesterol acts as an endogenous LBD agonist that couples sterol status to ERRα activity in bone and cellular senescence [#17, #44]. Beyond metabolism, ERRα represses TLR-induced inflammation via transcription of the A20 deubiquitinase Tnfaip3 [#15] and inhibits type I interferon production by associating with TBK1 and IRF3 to block their complex formation in a transcription-independent manner [#23]. In cancer, ERRα co-occupies the ERBB2 amplicon with PGC-1β, drives metabolic adaptations underlying lapatinib resistance, and reprograms epigenetic and steroidogenic programs, including switching LSD1 substrate specificity to H3K9 demethylation to promote invasion [#7, #18, #21]. A coding ESRRA mutation that decreases its transcriptional activity, together with HDAC4, defines an ESRRA-HDAC4 transcriptional axis linked to a human familial phenotype [#13].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Establishing the genomic structure and a first functional readout addressed where ERRα resides and whether it modulates estrogen-responsive transcription.\",\n      \"evidence\": \"FISH mapping, gene cloning, and lactoferrin promoter reporter assays in endometrial carcinoma cells\",\n      \"pmids\": [\"9286700\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No endogenous physiological target genes defined\", \"Coactivator dependence not yet established\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Crystallography resolved how an orphan receptor activates transcription without a ligand, explaining its constitutive activity and coactivator recruitment mode.\",\n      \"evidence\": \"X-ray structure of the LBD bound to a PGC-1α peptide at 2.5 Å with binding affinity assays\",\n      \"pmids\": [\"15337744\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not exclude endogenous regulatory ligands later shown to exist\", \"No genome-wide target context\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Placing ERRα as the effector of PGC-1α-driven mitochondrial biogenesis and demonstrating promoter autoregulation defined the core transcriptional circuit of energy metabolism.\",\n      \"evidence\": \"Dominant-negative/constitutively active ERRα, mtDNA quantification, ChIP, and reporter assays in fibroblasts\",\n      \"pmids\": [\"15087503\", \"14978033\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tissue-specific target repertoires not resolved\", \"Upstream signals controlling the axis unknown\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Knockout phenotypes linked ERRα to specific metabolic targets, showing it directly regulates intestinal lipid handling.\",\n      \"evidence\": \"ERRα knockout mice, apoA-IV promoter assays, and enterocyte β-oxidation assays\",\n      \"pmids\": [\"15466464\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the same target set operates in other tissues unaddressed\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"In vivo bioenergetic profiling established that ERRα is required for cardiac metabolic adaptation to stress, not just baseline metabolism.\",\n      \"evidence\": \"ERRα knockout mice with pressure overload, 31P-NMR, and mitochondrial respiration assays\",\n      \"pmids\": [\"17618854\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Redundancy with ERRγ not yet tested\", \"Direct cardiac target genes only partially defined\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Genome-wide mapping integrated ERRα into the circadian clock, revealing reciprocal regulatory loops governing daily metabolic rhythms.\",\n      \"evidence\": \"ChIP-seq for ERRα/PROX1/BMAL1 in liver plus ERRα-null and Clock mutant phenotyping\",\n      \"pmids\": [\"21731503\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of PROX1 corepression not fully resolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Connecting mTOR to ERRα through proteasomal control positioned ERRα as a degradation-regulated node in hepatic lipid metabolism.\",\n      \"evidence\": \"ChIP-seq in mouse liver, genetic ERRα ablation, rapamycin treatment, and metabolite analysis\",\n      \"pmids\": [\"23562079\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific E3 ligase not identified in this study\", \"Direct mTOR-ERRα biochemical link inferred via UPS transcription\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"A reciprocal interaction with HDAC4 and a hypomorphic human ESRRA mutation defined a transcriptional regulatory axis with disease relevance.\",\n      \"evidence\": \"Reciprocal co-IP in HeLa cells and mouse cortex, transcriptional activity assays, and family exome sequencing\",\n      \"pmids\": [\"24216484\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal disease mechanism of the variant not fully established\", \"Single-lab functional characterization\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Double-knockout genetics revealed functional redundancy and the breadth of cardiac targets ERRs control, extending the program to contraction and conduction genes.\",\n      \"evidence\": \"ERRα/ERRγ double-knockout mice with cardiac phenotyping and target gene analysis\",\n      \"pmids\": [\"25624346\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of each receptor to individual targets not dissected\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identifying direct ERRα binding to inflammatory and sirtuin target promoters extended its role beyond metabolism into innate immune restraint.\",\n      \"evidence\": \"ERRα knockout macrophages, ChIP at Tnfaip3, NF-κB acetylation, NAD+ quantification, and metabolic flux analysis\",\n      \"pmids\": [\"26200012\", \"26421366\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether immune effects are separable from metabolic effects not fully resolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Discovery of cholesterol as an endogenous LBD agonist reframed ERRα from a strictly ligand-independent receptor to a sterol-responsive one with pharmacological relevance in bone.\",\n      \"evidence\": \"Affinity chromatography of tissue lipidomes with the LBD, transcriptional assays, and ERRα knockout osteoclastogenesis/bone models\",\n      \"pmids\": [\"26777690\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural mode of cholesterol binding within the occluded pocket not defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Linking ERRα to cancer drug resistance and metabolic reprogramming established it as a therapeutic target through inverse agonism.\",\n      \"evidence\": \"Protein stability assays, glutamine/ROS metabolic profiling, and ERRα inverse agonist in HER2 mouse tumors; AMPK/one-carbon metabolism ChIP-seq with methotrexate sensitivity\",\n      \"pmids\": [\"27402251\", \"26804918\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generality across tumor types not established\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Two transcription-independent mechanisms — substrate-switching of LSD1 and inhibition of TBK1-IRF3 — revealed non-canonical functions distinct from classic coactivator-driven transcription.\",\n      \"evidence\": \"In vitro reconstitution of LSD1 H3K9 demethylation with invasion assays; co-IP of TBK1-ERRα-IRF3 with IRF3 phosphorylation/dimerization assays in knockout mice\",\n      \"pmids\": [\"28348226\", \"28591144\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How ERRα toggles between transcriptional and non-transcriptional modes unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defining ERRα's role in autophagosome formation through both Atg gene transcription and SIRT1-mediated deacetylation established a dual transcriptional/post-translational control of autophagy.\",\n      \"evidence\": \"ESRRA knockout macrophages, Atg promoter ChIP, SIRT1 deacetylation assays, and mycobacterial infection/autophagy flux\",\n      \"pmids\": [\"28841353\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative weight of transcriptional versus post-translational arms not quantified\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identifying LSD1 as a demethylase-independent stabilizer of ERRα protein opened a series of studies on post-translational control of ERRα abundance.\",\n      \"evidence\": \"Ubiquitination assays with LSD1 demethylase-dead mutants and protein stability measurement in breast cancer cells\",\n      \"pmids\": [\"29190800\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"E3 ligase opposing LSD1 not identified here\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"ERRα was shown to mediate thyroid-hormone-induced mitochondrial biogenesis, fission, and mitophagy by inducing ULK1, integrating endocrine signaling with mitochondrial quality control.\",\n      \"evidence\": \"Transcriptomics, ChIP-seq, siRNA of ESRRA/ULK1/DRP1/FUNDC1, and mitophagy/OXPHOS assays\",\n      \"pmids\": [\"29945885\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct ERRα occupancy at all fission/mitophagy effector genes not fully mapped\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Characterizing PERM1 as a physical ERRα partner that activates ERR target promoters identified a new cardiac coactivator working alongside PGC-1α.\",\n      \"evidence\": \"Reciprocal co-IP, one-hybrid and reporter assays, and Perm1 knockout cardiac phenotyping\",\n      \"pmids\": [\"36419485\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of PERM1-ERRα interaction undefined\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Single-cell analysis revealed ERRα couples metabolism to cell-type differentiation in the kidney, broadening its role beyond pure bioenergetics.\",\n      \"evidence\": \"scRNA-seq, trajectory analysis, ERRα knockout kidney disease models, and patient sample validation\",\n      \"pmids\": [\"33301705\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct differentiation target genes only partially defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"A series of post-translational regulators (DNMT1 stabilization, parkin/STUB1 degradation) and a synthetic feedforward DNA-methylation loop expanded the network controlling ERRα abundance and activity.\",\n      \"evidence\": \"Protein stability and ubiquitination assays, bisulfite sequencing, and co-IP across breast cancer and endothelial models\",\n      \"pmids\": [\"32855526\", \"30244249\", \"31907393\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Hierarchy among competing E3 ligases and stabilizers unresolved\", \"Mostly single-lab pharmacological studies\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Genetic dissection of the insulin/GSK3β/FBXW7 axis and the RBBP6 ligase established degradation-controlled ERRα as a sensor coupling hormonal and disease states to metabolic output.\",\n      \"evidence\": \"Liver-specific GSK3β/FBXW7 knockouts, ERRα phosphosite knock-in mice, and K100 ubiquitination mutagenesis in diabetic kidney models\",\n      \"pmids\": [\"35440636\", \"39441040\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Integration of multiple ligase inputs on a shared ERRα pool not modeled\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Adipocyte-specific deletion and the mevalonate-senescence axis showed ERRα coordinates bone marrow stromal fate and sterol-driven cellular senescence in vivo.\",\n      \"evidence\": \"Adipocyte-specific ESRRA knockout, leptin promoter ChIP, OVX/obesity models, and high-fat-diet senescence assays in knockouts\",\n      \"pmids\": [\"38704393\", \"38216569\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cell-type specificity of cholesterol/mevalonate effects not fully separated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how ERRα's competing degradation/stabilization inputs, its sterol-ligand sensing, and its transcription-independent functions are integrated to set context-specific output in vivo.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model reconciling the multiple E3 ligases and stabilizers\", \"Structural basis of cholesterol agonism in the occluded pocket undefined\", \"Switch between transcriptional and non-transcriptional modes uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 1, 2, 3, 15, 22]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [2, 3, 15, 38, 41, 43]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [17, 44]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [23, 21]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 2, 7, 8]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [23]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [1, 3, 6, 11, 12, 30]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [1, 4, 26]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [22, 26, 31]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [15, 23]},\n      {\"term_id\": \"R-HSA-9909396\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [35, 36, 37, 39]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [7, 18, 33]}\n    ],\n    \"complexes\": [\n      \"PGC-1α/ERRα transcriptional complex\"\n    ],\n    \"partners\": [\n      \"PPARGC1A\",\n      \"PPARGC1B\",\n      \"KDM1A\",\n      \"TBK1\",\n      \"IRF3\",\n      \"HDAC4\",\n      \"PERM1\",\n      \"SIRT1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":10,"faith_total":10,"faith_pct":100.0}}