{"gene":"IDH1","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":2009,"finding":"Cancer-associated IDH1 mutations at R132 result in loss of the normal isocitrate-to-α-ketoglutarate oxidative decarboxylation activity and acquisition of a neomorphic NADPH-dependent ability to reduce α-ketoglutarate to R(-)-2-hydroxyglutarate (2HG). Crystal structure of R132H IDH1 shows active-site residues are repositioned to accommodate this new reaction.","method":"In vitro enzymatic assay of mutant vs wild-type IDH1, X-ray crystallography of IDH1 R132H, metabolite profiling of glioma cells","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro enzymatic reconstitution, crystal structure, and metabolite confirmation in tumor tissue; independently replicated across many subsequent studies","pmids":["19935646"],"is_preprint":false},{"year":2009,"finding":"IDH1 R132 mutations reduce the enzymatic activity of the encoded protein for the normal isocitrate-to-α-ketoglutarate reaction, demonstrated in cultured glioma cells transfected with normal and mutant IDH1/IDH2 constructs.","method":"Enzymatic activity assay in transfected glioma cells","journal":"The New England journal of medicine","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct enzymatic assay in cellular system, replicated by multiple labs","pmids":["19228619"],"is_preprint":false},{"year":2010,"finding":"Expression of 2HG-producing IDH1 mutant alleles in cells induces global DNA hypermethylation and impairs TET2 catalytic function, placing mutant IDH1 upstream of TET2 in the epigenetic pathway; IDH1/2 mutations are mutually exclusive with TET2 loss-of-function mutations in AML, supporting epistatic equivalence.","method":"Expression of mutant IDH alleles in cells, TET2 catalytic activity assay, genome-wide DNA methylation profiling, genetic epistasis analysis in AML cohort","journal":"Cancer cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (cell-based expression, enzymatic assay, methylation profiling, clinical genetic epistasis), replicated concept across labs","pmids":["21130701"],"is_preprint":false},{"year":2012,"finding":"Introduction of mutant IDH1 into primary human astrocytes alters specific histone marks, induces extensive DNA hypermethylation, and remodels the methylome in a fashion mirroring G-CIMP in lower-grade gliomas, establishing that a single IDH1 mutation is sufficient to establish the glioma CpG island methylator phenotype.","method":"Stable expression of mutant IDH1 in primary astrocytes, genome-wide DNA methylation profiling, histone mark analysis","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct gain-of-function expression, genome-wide methylation readout, matched to primary tumor data","pmids":["22343889"],"is_preprint":false},{"year":2011,"finding":"IDH1 mediates reductive carboxylation of glutamine-derived α-ketoglutarate to isocitrate/citrate for de novo lipid synthesis under hypoxia; this IDH1-dependent reductive pathway is the predominant route for acetyl-CoA production for lipogenesis when oxidative TCA cycle activity is suppressed.","method":"13C isotope tracing (metabolic flux analysis) in human cell lines under normoxia/hypoxia, genetic knockdown of IDH1","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — isotope tracing with enzymatic attribution, multiple cell lines, loss-of-function validation","pmids":["22101433"],"is_preprint":false},{"year":2012,"finding":"Conditional knock-in of IDH1 R132H in murine hematopoietic cells produces increased haematopoietic progenitors, splenomegaly, anaemia, and a hypermethylated histone and DNA methylation signature resembling human IDH1-mutant AML, demonstrating in vivo leukemogenic effects of the mutation.","method":"Conditional knock-in mouse model (Vav-KI and LysM-KI), histone and DNA methylation analysis, flow cytometry of haematopoietic compartments","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetically faithful knock-in mouse, multiple orthogonal readouts, first in vivo demonstration","pmids":["22763442"],"is_preprint":false},{"year":2017,"finding":"Allosteric mutant-IDH1-selective inhibitors bind an allosteric pocket on IDH1 that is only accessible because the R132H oncogenic mutation destabilizes an IDH1 'regulatory segment'; this destabilization is not recapitulated in the analogous IDH2 segment, explaining isoform selectivity. Crystal structures of IDH1 with two structurally distinct inhibitors reveal the plasticity of the allosteric site.","method":"X-ray crystallography of IDH1 R132H with inhibitors, mutagenesis of regulatory segment, binding and enzymatic inhibition assays","journal":"Structure","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structures with functional validation, mutagenesis, multiple inhibitor scaffolds","pmids":["28132785"],"is_preprint":false},{"year":2015,"finding":"IDH1 mutation reduces pyruvate dehydrogenase (PDH) activity through increased PDH inhibitory phosphorylation and upregulation of pyruvate dehydrogenase kinase-3, leading to MRS-detectable reprogramming of pyruvate metabolism; pharmacological restoration of PDH activity abolishes the clonogenic advantage conferred by IDH1 mutation.","method":"Hyperpolarized 13C-MRS, PDH activity assay, immunoblotting, clonogenic assay, dichloroacetate pharmacological rescue, patient-derived neurosphere models","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods in single lab, functional rescue experiment","pmids":["26045167"],"is_preprint":false},{"year":2020,"finding":"SIRT2 deacetylates IDH1 at lysine 224; deacetylation at K224 promotes IDH1 enzymatic activity and α-KG production, while K224 acetylation suppresses activity. IDH1 acetylation inversely regulates HIF1α-dependent SRC transcription and modulates cellular redox homeostasis; IDH1 hyperacetylation is associated with CRC progression.","method":"Proteomics screen, Co-IP/deacetylation assay with SIRT2, acetylation-mimetic/resistant K224 mutants, in vitro enzymatic assay, luciferase reporter, in vitro and in vivo invasion assays","journal":"EMBO reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, enzymatic assay with mutagenesis, in vitro and in vivo functional validation in single lab","pmids":["32141187"],"is_preprint":false},{"year":2015,"finding":"IDH1 mutation reduces NADPH production capacity and increases reactive oxygen species, leading to higher sensitivity to ionizing radiation; exogenous D-2HG recapitulates this radiosensitization in wild-type cells, and the effect is independent of the DNA hypermethylation phenotype.","method":"ROS measurement, DNA double-strand break quantification, clonogenic radiation survival assay in IDH1-heterozygous and wild-type cells, IDH1 R132H inhibitor AGI-5198 rescue experiments, D-2HG exogenous treatment","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal functional assays in single lab, pharmacological and metabolite rescue","pmids":["26363012"],"is_preprint":false},{"year":2012,"finding":"Selective suppression of endogenous mutant IDH1 expression in HT1080 cells (native IDH1 R132C heterozygous mutation) significantly inhibits cell proliferation and reduces clonogenic potential, demonstrating that continued expression of mutant IDH1 is required for maintaining tumor cell growth.","method":"Inducible shRNA knockdown of endogenous mutant IDH1 in native heterozygous cancer cell line, proliferation and clonogenic assays","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — endogenous loss-of-function in native mutant cell line, two orthogonal growth readouts, single lab","pmids":["22885298"],"is_preprint":false},{"year":2017,"finding":"2HG produced by IDH1 R132Q mutation binds to Cdc42 and prevents Cdc42 from disrupting MLK3 auto-inhibition, thereby blocking the MLK3→MKK4/7→JNK→Bim apoptotic cascade specifically activated by serum starvation, promoting cell survival; this mechanism was demonstrated to contribute to tumorigenesis in allograft models.","method":"IDH1-R132Q knock-in mouse cells, JNK/Bim pathway biochemical analysis, 2HG-Cdc42 binding assay, MLK3 activity assay, allograft tumor model, immunohistochemistry of human glioma","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knock-in cells, biochemical pathway dissection, in vivo allograft confirmation; single lab","pmids":["28402860"],"is_preprint":false},{"year":2021,"finding":"D-2HG produced by mutant IDH1 inhibits oxoglutarate dehydrogenase (OGDH) activity, reducing succinyl-CoA production, which attenuates heme biosynthesis in erythroid cells; succinyl-CoA or 5-ALA supplementation rescues erythropoiesis in IDH1-mutant cells, and heme deficiency leads to impaired heme oxygenase-1 expression and excess ROS accumulation causing erythroid cell death.","method":"IDH1 R132H conditional knock-in mice, OGDH activity assay, succinyl-CoA metabolite measurement, heme biosynthesis assay, erythroid differentiation assay, succinyl-CoA/5-ALA rescue experiments","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — genetically faithful mouse model, enzymatic assay of OGDH, metabolite rescue experiments, multiple orthogonal mechanistic readouts","pmids":["33254233"],"is_preprint":false},{"year":2021,"finding":"Mutant IDH1 drives increased monounsaturated fatty acids (MUFA) and their phospholipids via D-2HG-induced stearyl-CoA desaturase (SCD) overexpression, causing ER and Golgi dilation; inhibition of mutant IDH1 or SCD silencing restores organelle morphology, while D-2HG or oleic acid treatment induces organelle defects in IDH1-mutant cells.","method":"Lipidomics, electron microscopy of ER/Golgi, SCD siRNA knockdown, IDH1 inhibitor treatment, D-2HG and oleic acid exogenous treatment, cell viability assay","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (lipidomics, microscopy, genetic and pharmacological rescue) in single lab","pmids":["33504762"],"is_preprint":false},{"year":2024,"finding":"Mutant IDH1 epigenetically silences the cytoplasmic dsDNA sensor CGAS via selective CpG hypermethylation of its promoter; mIDH1 inhibition restores CGAS expression and derepresses transposable elements (TEs), whose reverse-transcriptase-derived dsDNA activates cGAS, triggering viral mimicry and antitumor immunity.","method":"DNA methylation analysis, CGAS expression rescue by mIDH1 inhibition, TE-RT activity assay, cGAS pathway activation (cGAMP measurement), in vivo immunological readouts in IDH1-mutant tumor models","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 / Strong — pharmacological and genetic mIDH1 inhibition, mechanistic pathway linking CGAS methylation to TE-RT-dsDNA-cGAS axis, multiple orthogonal methods","pmids":["38991060"],"is_preprint":false},{"year":2023,"finding":"D-2HG produced by mutant IDH1 enhances binding of DNMT1 to IRF3/7 promoters, downregulating IRF3 and IRF7 expression, thereby impairing type I interferon antiviral responses in glioma cells and increasing susceptibility to viral infection.","method":"Chromatin immunoprecipitation (ChIP) of DNMT1 at IRF3/7 promoters, IRF3/7 expression analysis, IFN pathway activation assay, in vitro viral infection assay, mouse glioma model with oncolytic virus","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP mechanistic evidence, functional IFN assay, in vivo validation; single lab","pmids":["37880243"],"is_preprint":false},{"year":2017,"finding":"Mutant IDH1-dependent epigenomic reprogramming in human astrocytes and glioma tumorspheres establishes genome-wide coordinate changes in histone marks and chromatin states; prolonged exposure to mutant IDH1 results in irreversible genomic and epigenetic alterations, and mutant IDH1 establishes a CD24+ proliferative stem-like cell population.","method":"Human astrocyte and tumorsphere model systems with inducible mutant IDH1 expression, ATAC-seq, ChIP-seq for multiple histone marks, RNA-seq, DNA methylation profiling, IDH1 inhibitor reversal experiments","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — comprehensive multiomics, inducible expression and reversal experiments, multiple orthogonal epigenomic methods in single well-designed study","pmids":["29180699"],"is_preprint":false},{"year":2016,"finding":"IDH1 mutation drives promoter hypermethylation of the MCT4-encoding gene SLC16A3 (but via a different mechanism for MCT1/SLC16A1), leading to reduced monocarboxylate transporter expression and decreased hyperpolarized pyruvate-to-lactate flux in IDH1-mutant cells.","method":"Hyperpolarized 13C-MRS, qRT-PCR, promoter methylation analysis, cell lysate enzymatic comparison, patient TCGA data correlation","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — 13C metabolic flux, promoter methylation, and functional assays; single lab with TCGA validation","pmids":["27144334"],"is_preprint":false},{"year":2023,"finding":"Mutant IDH1 specifically reduces fatty acid levels and induces a switch to β-oxidation in AML blasts (distinct from mIDH2), depleting NADPH via defective reductive carboxylation not rescued by ivosidenib; targeting ACC1 (acetyl-CoA carboxylase 1) is synthetic lethal with mIDH1 in vitro and in xenograft models.","method":"Metabolomics of primary AML blasts and cell lines, isotope tracing, genetic ACC1 knockdown, pharmacological ACC1 inhibition, lipid-free diet xenograft model, combination with venetoclax","journal":"Cancer discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — primary patient metabolomics, isotope tracing, genetic and pharmacological validation; single lab study","pmids":["36355448"],"is_preprint":false},{"year":2017,"finding":"IDH1 R132H cooperates with PDGFA overexpression and loss of Cdkn2a, Atrx, and Pten to promote glioma development in vivo; immortal astrocytes expressing IDH1 R132H alone show elevated 2HG, reduced NADPH, and increased proliferation and anchorage-independent growth but do not form gliomas alone.","method":"In vitro astrocyte transformation assays (soft agar, proliferation), in vivo mouse glioma model with cooperating genetic alterations, 2HG and NADPH measurement","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo tumor formation with defined genetic cooperators, metabolite validation; single lab","pmids":["29719265"],"is_preprint":false},{"year":2024,"finding":"Scutellarin (Scu) activates wild-type IDH1 by selectively modifying Cys297, promoting active IDH1 dimer formation and increasing α-KG production; elevated α-KG leads to ubiquitination and degradation of HIF1α, inhibiting glycolysis and activating the tumor immune microenvironment in HCC.","method":"Proteomic microarray, covalent modification site mapping (Cys297), dimerization assay, α-KG enzymatic assay, HIF1α ubiquitination assay, in vitro and in vivo HCC models","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — site-specific covalent modification identified, enzymatic activation validated, downstream pathway confirmed; single lab","pmids":["38622131"],"is_preprint":false},{"year":2018,"finding":"HuR (ELAVL1) RNA-binding protein stabilizes both wild-type and mutant IDH1 mRNAs in heterozygous IDH1-mutant cancer cells; genetic suppression of HuR (siRNA or CRISPR) simultaneously downregulates both IDH1 isoforms, reduces 2HG levels, and impairs proliferation and invasion, with cells being especially sensitive to combined HuR-loss and IDH1 inhibitor treatment.","method":"Ribonucleoprotein immunoprecipitation (RIP) assay, CRISPR HuR deletion, siRNA knockdown, metabolomics (2HG, pentose phosphate pathway metabolites), proliferation and invasion assays","journal":"Molecular cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP assay demonstrates direct mRNA binding, genetic suppression with multiple methods, metabolic readout; single lab","pmids":["30266754"],"is_preprint":false},{"year":2022,"finding":"Acquired resistance to ivosidenib in IDH1 R132C-mutated cholangiocarcinoma occurs via secondary IDH1 D279N mutation; the double-mutant IDH1 R132H/D279N produces 2HG less efficiently but retains ability to produce 2HG and promote cellular transformation in the presence of ivosidenib due to impaired ivosidenib binding. An irreversible IDH1 inhibitor (LY3410738) overcomes this resistance.","method":"Generation of double-mutant IDH1 expressing cells, 2HG production assay, cellular transformation assay, ivosidenib and LY3410738 binding/inhibition assays","journal":"NPJ precision oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — engineered double-mutant cells, enzymatic assay, functional transformation assay, drug binding comparison; single lab","pmids":["36056177"],"is_preprint":false},{"year":2024,"finding":"IDH1 K93 deacetylation (assessed by mutation at K93) reduces IDH1 enzymatic activity and promotes NETosis (neutrophil extracellular trap formation) in dHL-60 cells; deacetylation of IDH1 and MDH1 was detected in acute liver failure mouse models and was associated with worsened disease progression.","method":"Immunoprecipitation to detect acetylation, K93 mutation to mimic deacetylation, NETosis markers (immunofluorescence, western blotting), LPS/D-gal mouse ALF model","journal":"Cellular & molecular biology letters","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP/mutation approach, single lab, mechanistic link is suggestive but limited in rigor","pmids":["38172700"],"is_preprint":false},{"year":2013,"finding":"D-2HG produced by mutant IDH1 increases neuronal firing rate 4–6-fold in cultured rat cortical neurons, an effect completely blocked by the selective NMDA receptor antagonist AP5, suggesting D-2HG acts as an NMDA receptor agonist mimicking glutamate.","method":"Microelectrode array recording of rat cortical neurons, exogenous D-2HG treatment, AP5 (NMDA antagonist) pharmacological rescue","journal":"Neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct electrophysiological measurement with pharmacological dissection; single lab, in vitro neuronal model","pmids":["28404805"],"is_preprint":false},{"year":2016,"finding":"D-2HG inhibits platelet aggregation and blood clotting via a novel calcium-dependent, methylation-independent mechanism; mutant IDH1 gliomas show F3 (tissue factor) gene promoter hypermethylation and reduced tissue factor protein expression, reducing thrombotic tendency.","method":"In vitro platelet aggregation assay with D-2HG, clotting time assay, F3 promoter methylation analysis, TF protein IHC, mutant IDH1 glioma mouse engraftment with bleeding time measurement","journal":"Acta neuropathologica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro functional assays, in vivo bleeding time, promoter methylation, and protein expression; single lab with clinical cohort validation","pmids":["27664011"],"is_preprint":false},{"year":2014,"finding":"Expression of IDH1 R132H mutant in Drosophila hemocytes results in higher numbers of circulating blood cells; neurological and wing-expansion defects from mutant Idh expression are rescued by genetic modulation of superoxide dismutase 2, p53, and apoptotic caspase cascade mediators; coexpression of D-2HG dehydrogenase abolishes all mutant Idh phenotypes.","method":"UAS-Gal4 Drosophila expression system, D-2HG metabolite measurement, genetic epistasis with sod2, p53, and caspase pathway components, D-2HG dehydrogenase coexpression rescue","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Drosophila genetic model with epistasis analysis and metabolite rescue; ortholog study with well-defined pathway placement","pmids":["25398939"],"is_preprint":false},{"year":2024,"finding":"ATRX loss primes IDH1 R132H glioma cells for innate immune recognition via dsRNA agonism, while IDH1 R132H expression reversibly dampens baseline innate immune gene expression and cytokine production; pharmacological or genetic inhibition of IDH1 R132H restores innate immune gene expression without interfering with ATRX-deficiency-mediated dsRNA sensitivity.","method":"Isogenic astrocytoma cell lines with combinatorial IDH1 R132H and ATRX loss (lentivirus/CRISPR), innate immune gene expression (qRT-PCR), cytokine profiling, dsRNA agonist treatment, IDH1 inhibitor rescue, in vivo xenograft T-cell infiltration","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — isogenic genetic dissection, pharmacological rescue, in vivo validation; single lab","pmids":["38272925"],"is_preprint":false},{"year":2024,"finding":"Wild-type IDH1 supports PDAC cell survival after chemotherapy by sustaining mitochondrial function through α-ketoglutarate anaplerosis and maintaining antioxidant defense via NADPH generation; chemotherapy induces wild-type IDH1 expression as a resistance mechanism, and pharmacological IDH1 inhibition with ivosidenib synergizes with chemotherapy in murine PDAC models.","method":"ROS measurement after chemotherapy, TCA cycle activity assay, IDH1 induction by Western blot, siRNA knockdown of IDH1, ivosidenib pharmacological inhibition, in vivo synergy in murine PDAC models","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple biochemical readouts, genetic and pharmacological validation, in vivo confirmation; single lab","pmids":["38843355"],"is_preprint":false}],"current_model":"IDH1 normally catalyzes NADP+-dependent oxidative decarboxylation of isocitrate to α-ketoglutarate and NADPH in the cytoplasm; cancer-associated R132 mutations simultaneously abolish this activity and confer a neomorphic ability to reduce α-ketoglutarate to the oncometabolite R-2-hydroxyglutarate (2HG), which competitively inhibits α-ketoglutarate-dependent dioxygenases (TET family DNA hydroxylases, histone demethylases) causing genome-wide DNA and histone hypermethylation, silences the innate immune sensor CGAS, disrupts heme biosynthesis via OGDH inhibition, impairs antiviral IRF3/7 signaling via DNMT1 recruitment, promotes organelle dysmorphia via SCD-dependent MUFA accumulation, modulates NADPH-dependent redox balance affecting ROS sensitivity and lipid synthesis, and blocks apoptotic signaling by binding Cdc42 to suppress the MLK3-JNK pathway, collectively driving epigenetic reprogramming, differentiation block, and tumor progression; wild-type IDH1 additionally supports cancer cell survival under metabolic stress through NADPH production and anaplerosis, and IDH1 enzymatic activity is itself regulated by SIRT2-mediated deacetylation at K224 and by the RNA-binding protein HuR."},"narrative":{"mechanistic_narrative":"IDH1 is a cytoplasmic NADP+-dependent enzyme whose oncogenic R132 mutations exemplify a gain-of-function neomorphic activity that reprograms cellular metabolism and epigenetics across multiple tumor types [PMID:19935646]. The mutant enzyme loses normal isocitrate-to-α-ketoglutarate oxidative decarboxylation and instead reduces α-ketoglutarate to the oncometabolite R(-)-2-hydroxyglutarate (2HG), a reaction enabled by repositioning of active-site residues seen crystallographically [PMID:19935646, PMID:19228619]. 2HG competitively inhibits α-ketoglutarate-dependent dioxygenases, impairing TET2 catalysis and driving genome-wide DNA hypermethylation and histone-mark remodeling sufficient to establish the glioma CpG-island methylator phenotype and a proliferative stem-like state [PMID:21130701, PMID:22343889, PMID:29180699]. This epigenetic reprogramming underlies several immune phenotypes: mutant IDH1 silences the cytoplasmic dsDNA sensor CGAS by promoter hypermethylation, suppresses transposable-element-driven viral mimicry [PMID:38991060], dampens baseline innate immune gene expression [PMID:38272925], and impairs type I interferon responses through 2HG-enhanced DNMT1 binding at IRF3/7 promoters [PMID:37880243]. Beyond chromatin, 2HG produces metabolic and signaling consequences independent of methylation, including inhibition of OGDH to attenuate succinyl-CoA-dependent heme biosynthesis [PMID:33254233], SCD-driven monounsaturated fatty acid accumulation causing ER and Golgi dilation [PMID:33504762], reduced NADPH and elevated ROS conferring radiosensitivity [PMID:26363012], and binding of Cdc42 to block the MLK3→JNK→Bim apoptotic cascade [PMID:28402860]. Continued mutant IDH1 expression is required to maintain tumor growth [PMID:22885298], and mutant-selective allosteric inhibitors exploit a regulatory-segment destabilization unique to mutant IDH1 [PMID:28132785]. Wild-type IDH1 retains physiological importance, mediating hypoxic reductive carboxylation of glutamine-derived α-ketoglutarate for lipogenesis [PMID:22101433] and supporting cancer cell survival through anaplerosis and NADPH-dependent antioxidant defense [PMID:38843355]; its enzymatic output is regulated by SIRT2-mediated K224 deacetylation [PMID:32141187] and its mRNA stabilized by HuR [PMID:30266754].","teleology":[{"year":2009,"claim":"Established the central paradox of IDH1 in cancer—that R132 mutations both abolish normal activity and create a neomorphic reaction—which redefined how a metabolic enzyme can act as an oncogene.","evidence":"In vitro enzymatic assays of mutant vs wild-type protein, X-ray crystallography of R132H, and metabolite profiling in glioma cells and tissue","pmids":["19935646","19228619"],"confidence":"High","gaps":["Did not connect 2HG production to downstream epigenetic or signaling effectors","Did not address whether 2HG is necessary for transformation in vivo"]},{"year":2010,"claim":"Placed mutant IDH1 upstream of TET2 and DNA methylation, explaining how a metabolic lesion produces an epigenetic phenotype and why IDH and TET2 mutations are mutually exclusive.","evidence":"Mutant allele expression in cells, TET2 catalytic assay, genome-wide methylation profiling, and genetic epistasis in an AML cohort","pmids":["21130701"],"confidence":"High","gaps":["Did not demonstrate sufficiency of the methylation phenotype for tumor initiation","Did not resolve which specific dioxygenases dominate the phenotype"]},{"year":2012,"claim":"Demonstrated that a single mutant IDH1 allele is sufficient to establish the glioma CIMP and is leukemogenic in vivo, and that mutant expression is continuously required for tumor maintenance.","evidence":"Stable expression in primary astrocytes with methylome profiling, conditional knock-in mouse models with hematopoietic readouts, and inducible shRNA suppression of endogenous mutant in a native heterozygous line","pmids":["22343889","22763442","22885298"],"confidence":"High","gaps":["Astrocyte/mouse systems do not fully recapitulate human tumor heterogeneity","Did not define cooperating lesions needed for full malignancy"]},{"year":2011,"claim":"Revealed that wild-type IDH1 has a distinct physiological role in hypoxic reductive carboxylation for lipogenesis, separating wild-type from mutant function.","evidence":"13C isotope tracing under normoxia/hypoxia with IDH1 knockdown in multiple human cell lines","pmids":["22101433"],"confidence":"High","gaps":["Did not address how this pathway interacts with mutant alleles in heterozygous cells","In vivo relevance of reductive carboxylation not established here"]},{"year":2017,"claim":"Defined the structural basis for mutant-selective inhibition, showing R132H destabilizes a regulatory segment to open an allosteric pocket absent in IDH2.","evidence":"X-ray crystallography of R132H with two distinct inhibitor scaffolds, regulatory-segment mutagenesis, and enzymatic inhibition assays","pmids":["28132785"],"confidence":"High","gaps":["Did not address resistance mechanisms to allosteric inhibitors","Selectivity in cellular and in vivo contexts not the focus"]},{"year":2017,"claim":"Showed mutant IDH1 drives coordinate, eventually irreversible epigenomic reprogramming and establishes a stem-like proliferative population, but requires cooperating lesions for gliomagenesis.","evidence":"Inducible mutant expression in astrocytes/tumorspheres with ATAC-seq, ChIP-seq, RNA-seq, methylation profiling and inhibitor reversal; separate in vivo model with PDGFA, Cdkn2a, Atrx, Pten alterations","pmids":["29180699","29719265"],"confidence":"Medium","gaps":["Determinants of reversible vs irreversible epigenetic state not fully resolved","Precise cooperating-lesion hierarchy not defined"]},{"year":2015,"claim":"Identified methylation-independent metabolic and redox consequences of 2HG, including PDH suppression and NADPH depletion driving radiosensitivity.","evidence":"Hyperpolarized 13C-MRS, PDH activity assays, ROS and DSB quantification, clonogenic radiation survival with inhibitor and exogenous D-2HG rescue","pmids":["26045167","26363012"],"confidence":"Medium","gaps":["Single-lab studies without independent replication","Relative contribution of metabolic vs epigenetic effects to tumor phenotype unquantified"]},{"year":2016,"claim":"Extended the methylation reach of mutant IDH1 to metabolite-transporter and coagulation genes, linking it to altered lactate flux and reduced thrombotic tendency.","evidence":"Hyperpolarized 13C-MRS with SLC16A3/SLC16A1 promoter methylation analysis; platelet aggregation, clotting, F3 promoter methylation and in vivo bleeding-time assays","pmids":["27144334","27664011"],"confidence":"Medium","gaps":["Single-lab observations","Causal contribution of these axes to clinical phenotypes not established"]},{"year":2017,"claim":"Uncovered a non-epigenetic survival mechanism in which 2HG binds Cdc42 to block the MLK3→JNK→Bim apoptotic cascade.","evidence":"R132Q knock-in cells, 2HG-Cdc42 binding and MLK3 activity assays, JNK/Bim pathway analysis, and allograft tumor model","pmids":["28402860"],"confidence":"Medium","gaps":["Single-lab biochemistry without independent confirmation","Generalizability beyond serum-starvation context unclear"]},{"year":2018,"claim":"Identified post-transcriptional and post-translational regulation of IDH1 itself via HuR mRNA stabilization and SIRT2-mediated K224 deacetylation.","evidence":"RIP assays with CRISPR/siRNA HuR suppression and metabolomics; proteomics screen with reciprocal SIRT2 Co-IP, K224 acetyl-mimetic/resistant mutants, enzymatic and in vivo invasion assays","pmids":["30266754","32141187"],"confidence":"Medium","gaps":["Single-lab findings","Physiological stimuli regulating these modifications not defined"]},{"year":2021,"claim":"Showed 2HG inhibits OGDH to disrupt succinyl-CoA-dependent heme biosynthesis and drives SCD-dependent MUFA accumulation causing organelle dysmorphia, broadening the metabolic consequences of mutant IDH1.","evidence":"R132H knock-in mice with OGDH assay, succinyl-CoA/5-ALA rescue; lipidomics, EM of ER/Golgi, SCD silencing and D-2HG/oleic acid treatment","pmids":["33254233","33504762"],"confidence":"Medium","gaps":["Single-lab mechanistic chains","Therapeutic relevance of OGDH/SCD axes untested clinically"]},{"year":2023,"claim":"Defined IDH1-isoform-specific lipid metabolism vulnerabilities, including a defective reductive carboxylation/NADPH state that creates ACC1 synthetic lethality in mutant AML.","evidence":"Primary AML blast metabolomics, isotope tracing, genetic and pharmacological ACC1 inhibition, lipid-free-diet xenografts and venetoclax combination","pmids":["36355448"],"confidence":"Medium","gaps":["Single-lab study","Clinical translatability of ACC1 targeting not established"]},{"year":2024,"claim":"Established that mutant IDH1 suppresses innate and antitumor immunity through CGAS promoter methylation/viral mimicry, IRF3/7 silencing, and reversible dampening of innate immune gene expression.","evidence":"DNA methylation and TE-RT/cGAMP assays with mIDH1 inhibitor rescue and in vivo immune readouts; 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glioma and their modulations by IDH1 mutation, histology, and treatment.","date":"2022","source":"JCI insight","url":"https://pubmed.ncbi.nlm.nih.gov/34941573","citation_count":21,"is_preprint":false},{"pmid":"32333643","id":"PMC_32333643","title":"IDH1 and IDH2 mutations in lung adenocarcinomas: Evidences of subclonal evolution.","date":"2020","source":"Cancer medicine","url":"https://pubmed.ncbi.nlm.nih.gov/32333643","citation_count":21,"is_preprint":false},{"pmid":"32224866","id":"PMC_32224866","title":"mTORC2/Rac1 Pathway Predisposes Cancer Aggressiveness in IDH1-Mutated Glioma.","date":"2020","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/32224866","citation_count":21,"is_preprint":false},{"pmid":"24887488","id":"PMC_24887488","title":"Mutation and expression analysis of the IDH1, IDH2, DNMT3A, and MYD88 genes in colorectal 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Chondrosarcoma JJ012 Cells.","date":"2022","source":"Disease markers","url":"https://pubmed.ncbi.nlm.nih.gov/35198082","citation_count":16,"is_preprint":false},{"pmid":"31983120","id":"PMC_31983120","title":"IDH1 mutation promotes proliferation and migration of glioma cells via EMT induction.","date":"2019","source":"Journal of B.U.ON. : official journal of the Balkan Union of Oncology","url":"https://pubmed.ncbi.nlm.nih.gov/31983120","citation_count":16,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":50045,"output_tokens":7471,"usd":0.1311,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":17011,"output_tokens":5031,"usd":0.105415,"stage2_stop_reason":"end_turn"},"total_usd":0.236515,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2009,\n      \"finding\": \"Cancer-associated IDH1 mutations at R132 result in loss of the normal isocitrate-to-α-ketoglutarate oxidative decarboxylation activity and acquisition of a neomorphic NADPH-dependent ability to reduce α-ketoglutarate to R(-)-2-hydroxyglutarate (2HG). Crystal structure of R132H IDH1 shows active-site residues are repositioned to accommodate this new reaction.\",\n      \"method\": \"In vitro enzymatic assay of mutant vs wild-type IDH1, X-ray crystallography of IDH1 R132H, metabolite profiling of glioma cells\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro enzymatic reconstitution, crystal structure, and metabolite confirmation in tumor tissue; independently replicated across many subsequent studies\",\n      \"pmids\": [\"19935646\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"IDH1 R132 mutations reduce the enzymatic activity of the encoded protein for the normal isocitrate-to-α-ketoglutarate reaction, demonstrated in cultured glioma cells transfected with normal and mutant IDH1/IDH2 constructs.\",\n      \"method\": \"Enzymatic activity assay in transfected glioma cells\",\n      \"journal\": \"The New England journal of medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct enzymatic assay in cellular system, replicated by multiple labs\",\n      \"pmids\": [\"19228619\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Expression of 2HG-producing IDH1 mutant alleles in cells induces global DNA hypermethylation and impairs TET2 catalytic function, placing mutant IDH1 upstream of TET2 in the epigenetic pathway; IDH1/2 mutations are mutually exclusive with TET2 loss-of-function mutations in AML, supporting epistatic equivalence.\",\n      \"method\": \"Expression of mutant IDH alleles in cells, TET2 catalytic activity assay, genome-wide DNA methylation profiling, genetic epistasis analysis in AML cohort\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (cell-based expression, enzymatic assay, methylation profiling, clinical genetic epistasis), replicated concept across labs\",\n      \"pmids\": [\"21130701\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Introduction of mutant IDH1 into primary human astrocytes alters specific histone marks, induces extensive DNA hypermethylation, and remodels the methylome in a fashion mirroring G-CIMP in lower-grade gliomas, establishing that a single IDH1 mutation is sufficient to establish the glioma CpG island methylator phenotype.\",\n      \"method\": \"Stable expression of mutant IDH1 in primary astrocytes, genome-wide DNA methylation profiling, histone mark analysis\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct gain-of-function expression, genome-wide methylation readout, matched to primary tumor data\",\n      \"pmids\": [\"22343889\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"IDH1 mediates reductive carboxylation of glutamine-derived α-ketoglutarate to isocitrate/citrate for de novo lipid synthesis under hypoxia; this IDH1-dependent reductive pathway is the predominant route for acetyl-CoA production for lipogenesis when oxidative TCA cycle activity is suppressed.\",\n      \"method\": \"13C isotope tracing (metabolic flux analysis) in human cell lines under normoxia/hypoxia, genetic knockdown of IDH1\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — isotope tracing with enzymatic attribution, multiple cell lines, loss-of-function validation\",\n      \"pmids\": [\"22101433\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Conditional knock-in of IDH1 R132H in murine hematopoietic cells produces increased haematopoietic progenitors, splenomegaly, anaemia, and a hypermethylated histone and DNA methylation signature resembling human IDH1-mutant AML, demonstrating in vivo leukemogenic effects of the mutation.\",\n      \"method\": \"Conditional knock-in mouse model (Vav-KI and LysM-KI), histone and DNA methylation analysis, flow cytometry of haematopoietic compartments\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetically faithful knock-in mouse, multiple orthogonal readouts, first in vivo demonstration\",\n      \"pmids\": [\"22763442\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Allosteric mutant-IDH1-selective inhibitors bind an allosteric pocket on IDH1 that is only accessible because the R132H oncogenic mutation destabilizes an IDH1 'regulatory segment'; this destabilization is not recapitulated in the analogous IDH2 segment, explaining isoform selectivity. Crystal structures of IDH1 with two structurally distinct inhibitors reveal the plasticity of the allosteric site.\",\n      \"method\": \"X-ray crystallography of IDH1 R132H with inhibitors, mutagenesis of regulatory segment, binding and enzymatic inhibition assays\",\n      \"journal\": \"Structure\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structures with functional validation, mutagenesis, multiple inhibitor scaffolds\",\n      \"pmids\": [\"28132785\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"IDH1 mutation reduces pyruvate dehydrogenase (PDH) activity through increased PDH inhibitory phosphorylation and upregulation of pyruvate dehydrogenase kinase-3, leading to MRS-detectable reprogramming of pyruvate metabolism; pharmacological restoration of PDH activity abolishes the clonogenic advantage conferred by IDH1 mutation.\",\n      \"method\": \"Hyperpolarized 13C-MRS, PDH activity assay, immunoblotting, clonogenic assay, dichloroacetate pharmacological rescue, patient-derived neurosphere models\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods in single lab, functional rescue experiment\",\n      \"pmids\": [\"26045167\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SIRT2 deacetylates IDH1 at lysine 224; deacetylation at K224 promotes IDH1 enzymatic activity and α-KG production, while K224 acetylation suppresses activity. IDH1 acetylation inversely regulates HIF1α-dependent SRC transcription and modulates cellular redox homeostasis; IDH1 hyperacetylation is associated with CRC progression.\",\n      \"method\": \"Proteomics screen, Co-IP/deacetylation assay with SIRT2, acetylation-mimetic/resistant K224 mutants, in vitro enzymatic assay, luciferase reporter, in vitro and in vivo invasion assays\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, enzymatic assay with mutagenesis, in vitro and in vivo functional validation in single lab\",\n      \"pmids\": [\"32141187\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"IDH1 mutation reduces NADPH production capacity and increases reactive oxygen species, leading to higher sensitivity to ionizing radiation; exogenous D-2HG recapitulates this radiosensitization in wild-type cells, and the effect is independent of the DNA hypermethylation phenotype.\",\n      \"method\": \"ROS measurement, DNA double-strand break quantification, clonogenic radiation survival assay in IDH1-heterozygous and wild-type cells, IDH1 R132H inhibitor AGI-5198 rescue experiments, D-2HG exogenous treatment\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal functional assays in single lab, pharmacological and metabolite rescue\",\n      \"pmids\": [\"26363012\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Selective suppression of endogenous mutant IDH1 expression in HT1080 cells (native IDH1 R132C heterozygous mutation) significantly inhibits cell proliferation and reduces clonogenic potential, demonstrating that continued expression of mutant IDH1 is required for maintaining tumor cell growth.\",\n      \"method\": \"Inducible shRNA knockdown of endogenous mutant IDH1 in native heterozygous cancer cell line, proliferation and clonogenic assays\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — endogenous loss-of-function in native mutant cell line, two orthogonal growth readouts, single lab\",\n      \"pmids\": [\"22885298\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"2HG produced by IDH1 R132Q mutation binds to Cdc42 and prevents Cdc42 from disrupting MLK3 auto-inhibition, thereby blocking the MLK3→MKK4/7→JNK→Bim apoptotic cascade specifically activated by serum starvation, promoting cell survival; this mechanism was demonstrated to contribute to tumorigenesis in allograft models.\",\n      \"method\": \"IDH1-R132Q knock-in mouse cells, JNK/Bim pathway biochemical analysis, 2HG-Cdc42 binding assay, MLK3 activity assay, allograft tumor model, immunohistochemistry of human glioma\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knock-in cells, biochemical pathway dissection, in vivo allograft confirmation; single lab\",\n      \"pmids\": [\"28402860\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"D-2HG produced by mutant IDH1 inhibits oxoglutarate dehydrogenase (OGDH) activity, reducing succinyl-CoA production, which attenuates heme biosynthesis in erythroid cells; succinyl-CoA or 5-ALA supplementation rescues erythropoiesis in IDH1-mutant cells, and heme deficiency leads to impaired heme oxygenase-1 expression and excess ROS accumulation causing erythroid cell death.\",\n      \"method\": \"IDH1 R132H conditional knock-in mice, OGDH activity assay, succinyl-CoA metabolite measurement, heme biosynthesis assay, erythroid differentiation assay, succinyl-CoA/5-ALA rescue experiments\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — genetically faithful mouse model, enzymatic assay of OGDH, metabolite rescue experiments, multiple orthogonal mechanistic readouts\",\n      \"pmids\": [\"33254233\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Mutant IDH1 drives increased monounsaturated fatty acids (MUFA) and their phospholipids via D-2HG-induced stearyl-CoA desaturase (SCD) overexpression, causing ER and Golgi dilation; inhibition of mutant IDH1 or SCD silencing restores organelle morphology, while D-2HG or oleic acid treatment induces organelle defects in IDH1-mutant cells.\",\n      \"method\": \"Lipidomics, electron microscopy of ER/Golgi, SCD siRNA knockdown, IDH1 inhibitor treatment, D-2HG and oleic acid exogenous treatment, cell viability assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (lipidomics, microscopy, genetic and pharmacological rescue) in single lab\",\n      \"pmids\": [\"33504762\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Mutant IDH1 epigenetically silences the cytoplasmic dsDNA sensor CGAS via selective CpG hypermethylation of its promoter; mIDH1 inhibition restores CGAS expression and derepresses transposable elements (TEs), whose reverse-transcriptase-derived dsDNA activates cGAS, triggering viral mimicry and antitumor immunity.\",\n      \"method\": \"DNA methylation analysis, CGAS expression rescue by mIDH1 inhibition, TE-RT activity assay, cGAS pathway activation (cGAMP measurement), in vivo immunological readouts in IDH1-mutant tumor models\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — pharmacological and genetic mIDH1 inhibition, mechanistic pathway linking CGAS methylation to TE-RT-dsDNA-cGAS axis, multiple orthogonal methods\",\n      \"pmids\": [\"38991060\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"D-2HG produced by mutant IDH1 enhances binding of DNMT1 to IRF3/7 promoters, downregulating IRF3 and IRF7 expression, thereby impairing type I interferon antiviral responses in glioma cells and increasing susceptibility to viral infection.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP) of DNMT1 at IRF3/7 promoters, IRF3/7 expression analysis, IFN pathway activation assay, in vitro viral infection assay, mouse glioma model with oncolytic virus\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP mechanistic evidence, functional IFN assay, in vivo validation; single lab\",\n      \"pmids\": [\"37880243\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Mutant IDH1-dependent epigenomic reprogramming in human astrocytes and glioma tumorspheres establishes genome-wide coordinate changes in histone marks and chromatin states; prolonged exposure to mutant IDH1 results in irreversible genomic and epigenetic alterations, and mutant IDH1 establishes a CD24+ proliferative stem-like cell population.\",\n      \"method\": \"Human astrocyte and tumorsphere model systems with inducible mutant IDH1 expression, ATAC-seq, ChIP-seq for multiple histone marks, RNA-seq, DNA methylation profiling, IDH1 inhibitor reversal experiments\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — comprehensive multiomics, inducible expression and reversal experiments, multiple orthogonal epigenomic methods in single well-designed study\",\n      \"pmids\": [\"29180699\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"IDH1 mutation drives promoter hypermethylation of the MCT4-encoding gene SLC16A3 (but via a different mechanism for MCT1/SLC16A1), leading to reduced monocarboxylate transporter expression and decreased hyperpolarized pyruvate-to-lactate flux in IDH1-mutant cells.\",\n      \"method\": \"Hyperpolarized 13C-MRS, qRT-PCR, promoter methylation analysis, cell lysate enzymatic comparison, patient TCGA data correlation\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — 13C metabolic flux, promoter methylation, and functional assays; single lab with TCGA validation\",\n      \"pmids\": [\"27144334\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Mutant IDH1 specifically reduces fatty acid levels and induces a switch to β-oxidation in AML blasts (distinct from mIDH2), depleting NADPH via defective reductive carboxylation not rescued by ivosidenib; targeting ACC1 (acetyl-CoA carboxylase 1) is synthetic lethal with mIDH1 in vitro and in xenograft models.\",\n      \"method\": \"Metabolomics of primary AML blasts and cell lines, isotope tracing, genetic ACC1 knockdown, pharmacological ACC1 inhibition, lipid-free diet xenograft model, combination with venetoclax\",\n      \"journal\": \"Cancer discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — primary patient metabolomics, isotope tracing, genetic and pharmacological validation; single lab study\",\n      \"pmids\": [\"36355448\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"IDH1 R132H cooperates with PDGFA overexpression and loss of Cdkn2a, Atrx, and Pten to promote glioma development in vivo; immortal astrocytes expressing IDH1 R132H alone show elevated 2HG, reduced NADPH, and increased proliferation and anchorage-independent growth but do not form gliomas alone.\",\n      \"method\": \"In vitro astrocyte transformation assays (soft agar, proliferation), in vivo mouse glioma model with cooperating genetic alterations, 2HG and NADPH measurement\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo tumor formation with defined genetic cooperators, metabolite validation; single lab\",\n      \"pmids\": [\"29719265\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Scutellarin (Scu) activates wild-type IDH1 by selectively modifying Cys297, promoting active IDH1 dimer formation and increasing α-KG production; elevated α-KG leads to ubiquitination and degradation of HIF1α, inhibiting glycolysis and activating the tumor immune microenvironment in HCC.\",\n      \"method\": \"Proteomic microarray, covalent modification site mapping (Cys297), dimerization assay, α-KG enzymatic assay, HIF1α ubiquitination assay, in vitro and in vivo HCC models\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — site-specific covalent modification identified, enzymatic activation validated, downstream pathway confirmed; single lab\",\n      \"pmids\": [\"38622131\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"HuR (ELAVL1) RNA-binding protein stabilizes both wild-type and mutant IDH1 mRNAs in heterozygous IDH1-mutant cancer cells; genetic suppression of HuR (siRNA or CRISPR) simultaneously downregulates both IDH1 isoforms, reduces 2HG levels, and impairs proliferation and invasion, with cells being especially sensitive to combined HuR-loss and IDH1 inhibitor treatment.\",\n      \"method\": \"Ribonucleoprotein immunoprecipitation (RIP) assay, CRISPR HuR deletion, siRNA knockdown, metabolomics (2HG, pentose phosphate pathway metabolites), proliferation and invasion assays\",\n      \"journal\": \"Molecular cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP assay demonstrates direct mRNA binding, genetic suppression with multiple methods, metabolic readout; single lab\",\n      \"pmids\": [\"30266754\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Acquired resistance to ivosidenib in IDH1 R132C-mutated cholangiocarcinoma occurs via secondary IDH1 D279N mutation; the double-mutant IDH1 R132H/D279N produces 2HG less efficiently but retains ability to produce 2HG and promote cellular transformation in the presence of ivosidenib due to impaired ivosidenib binding. An irreversible IDH1 inhibitor (LY3410738) overcomes this resistance.\",\n      \"method\": \"Generation of double-mutant IDH1 expressing cells, 2HG production assay, cellular transformation assay, ivosidenib and LY3410738 binding/inhibition assays\",\n      \"journal\": \"NPJ precision oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — engineered double-mutant cells, enzymatic assay, functional transformation assay, drug binding comparison; single lab\",\n      \"pmids\": [\"36056177\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IDH1 K93 deacetylation (assessed by mutation at K93) reduces IDH1 enzymatic activity and promotes NETosis (neutrophil extracellular trap formation) in dHL-60 cells; deacetylation of IDH1 and MDH1 was detected in acute liver failure mouse models and was associated with worsened disease progression.\",\n      \"method\": \"Immunoprecipitation to detect acetylation, K93 mutation to mimic deacetylation, NETosis markers (immunofluorescence, western blotting), LPS/D-gal mouse ALF model\",\n      \"journal\": \"Cellular & molecular biology letters\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP/mutation approach, single lab, mechanistic link is suggestive but limited in rigor\",\n      \"pmids\": [\"38172700\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"D-2HG produced by mutant IDH1 increases neuronal firing rate 4–6-fold in cultured rat cortical neurons, an effect completely blocked by the selective NMDA receptor antagonist AP5, suggesting D-2HG acts as an NMDA receptor agonist mimicking glutamate.\",\n      \"method\": \"Microelectrode array recording of rat cortical neurons, exogenous D-2HG treatment, AP5 (NMDA antagonist) pharmacological rescue\",\n      \"journal\": \"Neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct electrophysiological measurement with pharmacological dissection; single lab, in vitro neuronal model\",\n      \"pmids\": [\"28404805\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"D-2HG inhibits platelet aggregation and blood clotting via a novel calcium-dependent, methylation-independent mechanism; mutant IDH1 gliomas show F3 (tissue factor) gene promoter hypermethylation and reduced tissue factor protein expression, reducing thrombotic tendency.\",\n      \"method\": \"In vitro platelet aggregation assay with D-2HG, clotting time assay, F3 promoter methylation analysis, TF protein IHC, mutant IDH1 glioma mouse engraftment with bleeding time measurement\",\n      \"journal\": \"Acta neuropathologica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro functional assays, in vivo bleeding time, promoter methylation, and protein expression; single lab with clinical cohort validation\",\n      \"pmids\": [\"27664011\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Expression of IDH1 R132H mutant in Drosophila hemocytes results in higher numbers of circulating blood cells; neurological and wing-expansion defects from mutant Idh expression are rescued by genetic modulation of superoxide dismutase 2, p53, and apoptotic caspase cascade mediators; coexpression of D-2HG dehydrogenase abolishes all mutant Idh phenotypes.\",\n      \"method\": \"UAS-Gal4 Drosophila expression system, D-2HG metabolite measurement, genetic epistasis with sod2, p53, and caspase pathway components, D-2HG dehydrogenase coexpression rescue\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Drosophila genetic model with epistasis analysis and metabolite rescue; ortholog study with well-defined pathway placement\",\n      \"pmids\": [\"25398939\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ATRX loss primes IDH1 R132H glioma cells for innate immune recognition via dsRNA agonism, while IDH1 R132H expression reversibly dampens baseline innate immune gene expression and cytokine production; pharmacological or genetic inhibition of IDH1 R132H restores innate immune gene expression without interfering with ATRX-deficiency-mediated dsRNA sensitivity.\",\n      \"method\": \"Isogenic astrocytoma cell lines with combinatorial IDH1 R132H and ATRX loss (lentivirus/CRISPR), innate immune gene expression (qRT-PCR), cytokine profiling, dsRNA agonist treatment, IDH1 inhibitor rescue, in vivo xenograft T-cell infiltration\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — isogenic genetic dissection, pharmacological rescue, in vivo validation; single lab\",\n      \"pmids\": [\"38272925\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Wild-type IDH1 supports PDAC cell survival after chemotherapy by sustaining mitochondrial function through α-ketoglutarate anaplerosis and maintaining antioxidant defense via NADPH generation; chemotherapy induces wild-type IDH1 expression as a resistance mechanism, and pharmacological IDH1 inhibition with ivosidenib synergizes with chemotherapy in murine PDAC models.\",\n      \"method\": \"ROS measurement after chemotherapy, TCA cycle activity assay, IDH1 induction by Western blot, siRNA knockdown of IDH1, ivosidenib pharmacological inhibition, in vivo synergy in murine PDAC models\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple biochemical readouts, genetic and pharmacological validation, in vivo confirmation; single lab\",\n      \"pmids\": [\"38843355\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IDH1 normally catalyzes NADP+-dependent oxidative decarboxylation of isocitrate to α-ketoglutarate and NADPH in the cytoplasm; cancer-associated R132 mutations simultaneously abolish this activity and confer a neomorphic ability to reduce α-ketoglutarate to the oncometabolite R-2-hydroxyglutarate (2HG), which competitively inhibits α-ketoglutarate-dependent dioxygenases (TET family DNA hydroxylases, histone demethylases) causing genome-wide DNA and histone hypermethylation, silences the innate immune sensor CGAS, disrupts heme biosynthesis via OGDH inhibition, impairs antiviral IRF3/7 signaling via DNMT1 recruitment, promotes organelle dysmorphia via SCD-dependent MUFA accumulation, modulates NADPH-dependent redox balance affecting ROS sensitivity and lipid synthesis, and blocks apoptotic signaling by binding Cdc42 to suppress the MLK3-JNK pathway, collectively driving epigenetic reprogramming, differentiation block, and tumor progression; wild-type IDH1 additionally supports cancer cell survival under metabolic stress through NADPH production and anaplerosis, and IDH1 enzymatic activity is itself regulated by SIRT2-mediated deacetylation at K224 and by the RNA-binding protein HuR.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"IDH1 is a cytoplasmic NADP+-dependent enzyme whose oncogenic R132 mutations exemplify a gain-of-function neomorphic activity that reprograms cellular metabolism and epigenetics across multiple tumor types [#0]. The mutant enzyme loses normal isocitrate-to-\\u03b1-ketoglutarate oxidative decarboxylation and instead reduces \\u03b1-ketoglutarate to the oncometabolite R(-)-2-hydroxyglutarate (2HG), a reaction enabled by repositioning of active-site residues seen crystallographically [#0, #1]. 2HG competitively inhibits \\u03b1-ketoglutarate-dependent dioxygenases, impairing TET2 catalysis and driving genome-wide DNA hypermethylation and histone-mark remodeling sufficient to establish the glioma CpG-island methylator phenotype and a proliferative stem-like state [#2, #3, #16]. This epigenetic reprogramming underlies several immune phenotypes: mutant IDH1 silences the cytoplasmic dsDNA sensor CGAS by promoter hypermethylation, suppresses transposable-element-driven viral mimicry [#14], dampens baseline innate immune gene expression [#27], and impairs type I interferon responses through 2HG-enhanced DNMT1 binding at IRF3/7 promoters [#15]. Beyond chromatin, 2HG produces metabolic and signaling consequences independent of methylation, including inhibition of OGDH to attenuate succinyl-CoA-dependent heme biosynthesis [#12], SCD-driven monounsaturated fatty acid accumulation causing ER and Golgi dilation [#13], reduced NADPH and elevated ROS conferring radiosensitivity [#9], and binding of Cdc42 to block the MLK3\\u2192JNK\\u2192Bim apoptotic cascade [#11]. Continued mutant IDH1 expression is required to maintain tumor growth [#10], and mutant-selective allosteric inhibitors exploit a regulatory-segment destabilization unique to mutant IDH1 [#6]. Wild-type IDH1 retains physiological importance, mediating hypoxic reductive carboxylation of glutamine-derived \\u03b1-ketoglutarate for lipogenesis [#4] and supporting cancer cell survival through anaplerosis and NADPH-dependent antioxidant defense [#28]; its enzymatic output is regulated by SIRT2-mediated K224 deacetylation [#8] and its mRNA stabilized by HuR [#21].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 2009,\n      \"claim\": \"Established the central paradox of IDH1 in cancer\\u2014that R132 mutations both abolish normal activity and create a neomorphic reaction\\u2014which redefined how a metabolic enzyme can act as an oncogene.\",\n      \"evidence\": \"In vitro enzymatic assays of mutant vs wild-type protein, X-ray crystallography of R132H, and metabolite profiling in glioma cells and tissue\",\n      \"pmids\": [\"19935646\", \"19228619\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not connect 2HG production to downstream epigenetic or signaling effectors\", \"Did not address whether 2HG is necessary for transformation in vivo\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Placed mutant IDH1 upstream of TET2 and DNA methylation, explaining how a metabolic lesion produces an epigenetic phenotype and why IDH and TET2 mutations are mutually exclusive.\",\n      \"evidence\": \"Mutant allele expression in cells, TET2 catalytic assay, genome-wide methylation profiling, and genetic epistasis in an AML cohort\",\n      \"pmids\": [\"21130701\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not demonstrate sufficiency of the methylation phenotype for tumor initiation\", \"Did not resolve which specific dioxygenases dominate the phenotype\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Demonstrated that a single mutant IDH1 allele is sufficient to establish the glioma CIMP and is leukemogenic in vivo, and that mutant expression is continuously required for tumor maintenance.\",\n      \"evidence\": \"Stable expression in primary astrocytes with methylome profiling, conditional knock-in mouse models with hematopoietic readouts, and inducible shRNA suppression of endogenous mutant in a native heterozygous line\",\n      \"pmids\": [\"22343889\", \"22763442\", \"22885298\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Astrocyte/mouse systems do not fully recapitulate human tumor heterogeneity\", \"Did not define cooperating lesions needed for full malignancy\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Revealed that wild-type IDH1 has a distinct physiological role in hypoxic reductive carboxylation for lipogenesis, separating wild-type from mutant function.\",\n      \"evidence\": \"13C isotope tracing under normoxia/hypoxia with IDH1 knockdown in multiple human cell lines\",\n      \"pmids\": [\"22101433\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address how this pathway interacts with mutant alleles in heterozygous cells\", \"In vivo relevance of reductive carboxylation not established here\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined the structural basis for mutant-selective inhibition, showing R132H destabilizes a regulatory segment to open an allosteric pocket absent in IDH2.\",\n      \"evidence\": \"X-ray crystallography of R132H with two distinct inhibitor scaffolds, regulatory-segment mutagenesis, and enzymatic inhibition assays\",\n      \"pmids\": [\"28132785\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address resistance mechanisms to allosteric inhibitors\", \"Selectivity in cellular and in vivo contexts not the focus\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed mutant IDH1 drives coordinate, eventually irreversible epigenomic reprogramming and establishes a stem-like proliferative population, but requires cooperating lesions for gliomagenesis.\",\n      \"evidence\": \"Inducible mutant expression in astrocytes/tumorspheres with ATAC-seq, ChIP-seq, RNA-seq, methylation profiling and inhibitor reversal; separate in vivo model with PDGFA, Cdkn2a, Atrx, Pten alterations\",\n      \"pmids\": [\"29180699\", \"29719265\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Determinants of reversible vs irreversible epigenetic state not fully resolved\", \"Precise cooperating-lesion hierarchy not defined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified methylation-independent metabolic and redox consequences of 2HG, including PDH suppression and NADPH depletion driving radiosensitivity.\",\n      \"evidence\": \"Hyperpolarized 13C-MRS, PDH activity assays, ROS and DSB quantification, clonogenic radiation survival with inhibitor and exogenous D-2HG rescue\",\n      \"pmids\": [\"26045167\", \"26363012\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab studies without independent replication\", \"Relative contribution of metabolic vs epigenetic effects to tumor phenotype unquantified\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Extended the methylation reach of mutant IDH1 to metabolite-transporter and coagulation genes, linking it to altered lactate flux and reduced thrombotic tendency.\",\n      \"evidence\": \"Hyperpolarized 13C-MRS with SLC16A3/SLC16A1 promoter methylation analysis; platelet aggregation, clotting, F3 promoter methylation and in vivo bleeding-time assays\",\n      \"pmids\": [\"27144334\", \"27664011\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab observations\", \"Causal contribution of these axes to clinical phenotypes not established\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Uncovered a non-epigenetic survival mechanism in which 2HG binds Cdc42 to block the MLK3\\u2192JNK\\u2192Bim apoptotic cascade.\",\n      \"evidence\": \"R132Q knock-in cells, 2HG-Cdc42 binding and MLK3 activity assays, JNK/Bim pathway analysis, and allograft tumor model\",\n      \"pmids\": [\"28402860\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab biochemistry without independent confirmation\", \"Generalizability beyond serum-starvation context unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified post-transcriptional and post-translational regulation of IDH1 itself via HuR mRNA stabilization and SIRT2-mediated K224 deacetylation.\",\n      \"evidence\": \"RIP assays with CRISPR/siRNA HuR suppression and metabolomics; proteomics screen with reciprocal SIRT2 Co-IP, K224 acetyl-mimetic/resistant mutants, enzymatic and in vivo invasion assays\",\n      \"pmids\": [\"30266754\", \"32141187\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab findings\", \"Physiological stimuli regulating these modifications not defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed 2HG inhibits OGDH to disrupt succinyl-CoA-dependent heme biosynthesis and drives SCD-dependent MUFA accumulation causing organelle dysmorphia, broadening the metabolic consequences of mutant IDH1.\",\n      \"evidence\": \"R132H knock-in mice with OGDH assay, succinyl-CoA/5-ALA rescue; lipidomics, EM of ER/Golgi, SCD silencing and D-2HG/oleic acid treatment\",\n      \"pmids\": [\"33254233\", \"33504762\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab mechanistic chains\", \"Therapeutic relevance of OGDH/SCD axes untested clinically\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined IDH1-isoform-specific lipid metabolism vulnerabilities, including a defective reductive carboxylation/NADPH state that creates ACC1 synthetic lethality in mutant AML.\",\n      \"evidence\": \"Primary AML blast metabolomics, isotope tracing, genetic and pharmacological ACC1 inhibition, lipid-free-diet xenografts and venetoclax combination\",\n      \"pmids\": [\"36355448\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab study\", \"Clinical translatability of ACC1 targeting not established\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established that mutant IDH1 suppresses innate and antitumor immunity through CGAS promoter methylation/viral mimicry, IRF3/7 silencing, and reversible dampening of innate immune gene expression.\",\n      \"evidence\": \"DNA methylation and TE-RT/cGAMP assays with mIDH1 inhibitor rescue and in vivo immune readouts; DNMT1 ChIP at IRF3/7 with viral infection models; isogenic IDH1/ATRX cell lines with cytokine profiling and xenograft T-cell infiltration\",\n      \"pmids\": [\"38991060\", \"37880243\", \"38272925\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Convergence of these immune mechanisms in a single tumor not integrated\", \"Most evidence from single labs in model systems\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Characterized wild-type IDH1 as a chemoresistance factor and a pharmacologically activatable tumor-suppressive node, and defined a clinical resistance mechanism to ivosidenib.\",\n      \"evidence\": \"PDAC chemotherapy models with IDH1 knockdown/ivosidenib synergy; Scutellarin covalent Cys297 activation with HIF1\\u03b1 degradation in HCC; engineered R132C/D279N double-mutant cells with drug binding and the irreversible inhibitor LY3410738\",\n      \"pmids\": [\"38843355\", \"38622131\", \"36056177\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab studies\", \"Frequency and clinical impact of D279N resistance not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the diverse epigenetic, metabolic, redox, and immune effects of 2HG are quantitatively integrated to determine tumor type-specific phenotypes and therapeutic vulnerability remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying model weighting epigenetic vs non-epigenetic 2HG effects\", \"Determinants of which dioxygenases/pathways dominate in a given tissue undefined\", \"Mechanisms governing reversibility of mutant IDH1 phenotypes incompletely mapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [0, 1, 4]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [4, 12, 18, 28]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [2, 3, 16]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 5, 10]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [14, 15, 27]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"SIRT2\", \"ELAVL1\", \"Cdc42\", \"DNMT1\"],\n    \"other_free_text\": []\n  }\n}\n```","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":6,"faith_total":6,"faith_pct":100.0}}