{"gene":"FTO","run_date":"2026-06-09T23:54:44","timeline":{"discoveries":[{"year":2013,"finding":"FTO is an Fe(II)- and α-ketoglutarate-dependent enzyme that oxidizes N6-methyladenosine (m6A) in mRNA to generate N6-hydroxymethyladenosine (hm6A) as an intermediate and N6-formyladenosine (f6A) as a further oxidized product, demonstrating a stepwise oxidative demethylation mechanism.","method":"In vitro biochemical assay with Fe(II)/α-KG-dependent dioxygenase activity measurement; detection of hm6A and f6A in mammalian mRNA by mass spectrometry","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution of enzymatic mechanism with identification of reaction intermediates, validated in human cells and mouse tissues","pmids":["23653210"],"is_preprint":false},{"year":2019,"finding":"FTO selectively demethylates the m2-snRNA isoform (N6,2'-O-dimethyladenosine, m6Am) at the adenosine adjacent to the snRNA cap during snRNA biogenesis, controlling the ratio of m1 (Am) to m2 (m6Am) isoforms; inhibition of FTO by the oncometabolite D-2-hydroxyglutarate increases m2-snRNA levels and alters alternative splicing patterns.","method":"Biochemical snRNA isoform profiling; FTO inhibition by D-2-hydroxyglutarate; alternative splicing analysis in cells with altered FTO activity","journal":"Nature chemical biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct enzymatic substrate identification with functional splicing consequence, metabolite-based inhibition experiment, single lab with multiple orthogonal methods","pmids":["30778204"],"is_preprint":false},{"year":2020,"finding":"SFPQ (splicing factor proline/glutamine-rich) is a direct FTO-binding protein identified by site-specific photocrosslinking; SFPQ and FTO co-localize on transcripts genome-wide, and SFPQ overexpression recruits FTO to specific RNA sites, facilitating demethylation of adjacent m6A residues and thereby assisting FTO substrate selectivity.","method":"Genetically encoded site-specific photocrosslinking; CLIP-seq co-localization; overexpression-based m6A demethylation assay","journal":"Cell chemical biology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — site-specific photocrosslinking (near-reconstitution quality) plus transcriptome-wide co-localization and functional demethylation assay, single lab","pmids":["31981477"],"is_preprint":false},{"year":2020,"finding":"FTO demethylates m6A on cyclin D1 mRNA to stabilize it; FTO depletion increases cyclin D1 m6A, accelerates its mRNA degradation, and impairs G1 cell-cycle progression. FTO undergoes casein kinase II-mediated phosphorylation that drives its nuclear translocation during G1 phase, coinciding with low m6A on cyclin D1.","method":"m6A-RIP; cyclin D1 mRNA stability assay; FTO knockdown/KO with cell-cycle phenotype; CK2 phosphorylation and nuclear translocation assay; in vitro and in vivo","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal m6A-RIP, mRNA stability assay, KO phenotype, and phosphorylation mapping in single study with multiple orthogonal methods","pmids":["32268083"],"is_preprint":false},{"year":2021,"finding":"FTO demethylates m6A on FOXJ1 mRNA to stabilize it, acting as a conserved regulator of motile ciliogenesis; Fto depletion in Xenopus embryos and human airway epithelium destabilizes FOXJ1 mRNA, causing motile cilia defects and a shift from ciliated to goblet cells. Fto knockout mice show asthma-like phenotypes upon allergen challenge.","method":"Xenopus loss-of-function; human airway epithelium FTO knockdown; Fto KO mouse allergen model; mRNA stability assay for FOXJ1","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic loss-of-function replicated across three experimental systems (Xenopus, human primary cells, mouse KO) with defined molecular target (FOXJ1 mRNA stability)","pmids":["33761320"],"is_preprint":false},{"year":2014,"finding":"FTO resides in both the nucleus and cytoplasm and contains a mobile fraction that shuttles between compartments, as demonstrated by live-cell GFP-FTO imaging and FLIP (fluorescence loss in photobleaching). Exportin 2 (XPO2) was identified as an FTO binding partner by proteomics. The N-terminus of FTO is required for nucleocytoplasmic shuttling.","method":"Live-cell GFP-FTO imaging; FLIP; proteomic Co-IP identifying XPO2; N-terminal deletion studies","journal":"Bioscience reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct live-cell localization with FLIP and binding partner identification by proteomics, single lab","pmids":["25242086"],"is_preprint":false},{"year":2012,"finding":"FTO localizes to nuclear speckles (enriched in mRNA processing factors) as determined by immunocytochemistry and confocal laser scanning microscopy in HEK293, HeLa, and MCF-7 cells; FTO knockdown alters 3-methyluridine/uridine and pseudouridine/uridine ratios in total brain RNA, indicating broader RNA modification roles.","method":"Immunocytochemistry; confocal laser scanning microscopy; RNA modification analysis (nucleotide ratio measurements)","journal":"European journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — direct subcellular localization by confocal microscopy in multiple cell lines, RNA modification biochemistry, single lab","pmids":["22872099"],"is_preprint":false},{"year":2020,"finding":"NADP directly binds FTO (identified by fluorescence quenching assay) and independently enhances FTO demethylase activity in vitro; NADP promotes mRNA m6A demethylation in vivo, and FTO deletion blocks NADP-enhanced adipogenesis in 3T3-L1 preadipocytes.","method":"Fluorescence quenching binding assay; in vitro demethylation assay; FTO KO adipogenesis rescue experiment","journal":"Nature chemical biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct binding assay plus in vitro enzymatic activity measurement plus genetic rescue, single lab with three orthogonal methods","pmids":["32719557"],"is_preprint":false},{"year":2022,"finding":"FTO mediates m6A demethylation of LINE1 RNA in mouse embryonic stem cells, regulating LINE1 RNA abundance and local chromatin state, which in turn modulates transcription of LINE1-containing genes; FTO-mediated LINE1 RNA demethylation also shapes chromatin and gene expression during mouse oocyte and embryonic development.","method":"m6A-seq in Fto KO mESCs; LINE1 RNA abundance and chromatin state measurement; oocyte and embryo developmental analysis","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide m6A-seq in KO model with chromatin and functional developmental readouts, high-impact journal","pmids":["35511947"],"is_preprint":false},{"year":2019,"finding":"FTO directly binds the inhibitors FB23 and FB23-2 (structure-based design) and selectively inhibits FTO's m6A demethylase activity, suppressing AML cell proliferation and promoting differentiation/apoptosis in vitro and in xenograft mice, mimicking genetic FTO depletion.","method":"Structure-based inhibitor design; direct binding assay; m6A demethylase activity assay; AML cell line and primary blast cell proliferation/differentiation assay; xenograft mouse model","journal":"Cancer cell","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — structure-based design with direct binding, enzymatic activity assay, and in vivo xenograft, replicated on multiple AML models","pmids":["30991027"],"is_preprint":false},{"year":2019,"finding":"FTO demethylase activity is required for its role in cardiac contractile function: FTO overexpression in failing mouse hearts (via AAV9) demethylates cardiac contractile transcripts, prevents their degradation, and improves calcium dynamics and contractile function post-ischemia; an FTO demethylase-inactive mutant (R316A) fails to rescue these effects.","method":"AAV9-mediated FTO overexpression in mouse MI model; m6A-RIP-seq; siRNA knockdown; FTO R316A mutant (demethylase-dead) functional assay; cardiomyocyte calcium/contractility measurements","journal":"Circulation","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — catalytic mutant controls plus in vivo AAV delivery plus m6A-seq in multiple model systems (mouse, pig, human samples)","pmids":["29997116"],"is_preprint":false},{"year":2018,"finding":"FTO demethylase activity (not merely protein expression) is required for its effect on mitochondrial content and triglyceride deposition in hepatocytes: an FTO R316A demethylase-dead mutant fails to reduce mitochondrial content or increase TG, establishing the m6A demethylation mechanism as causal.","method":"FTO wild-type vs. R316A mutant overexpression in hepatocytes; mitochondrial content and TG measurement; m6A quantification","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — catalytic mutant comparison is rigorous but single lab, single experimental system","pmids":["29384213"],"is_preprint":false},{"year":2019,"finding":"FTO overexpression in clear cell renal cell carcinoma (ccRCC) increases PGC-1α expression by reducing m6A levels on its mRNA transcripts, restoring mitochondrial activity, inducing oxidative stress/ROS, and impairing tumor growth.","method":"FTO overexpression in VHL-deficient cells; m6A-RIP on PGC-1α mRNA; mitochondrial activity and ROS assays; in vivo tumor growth","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — m6A-RIP linking FTO to a specific mRNA target with functional mitochondrial readout, single lab","pmids":["30648791"],"is_preprint":false},{"year":2021,"finding":"FTO-mediated m6A demethylation in tumor cells elevates transcription factors c-Jun, JunB, and C/EBPβ, rewiring glycolytic metabolism; FTO knockdown impairs tumor glycolysis and restores CD8+ T cell function, enabling immune surveillance. The small-molecule FTO inhibitor Dac51 recapitulates these effects.","method":"FTO knockdown in tumor cells; metabolic flux assays; CD8+ T cell functional assays; Dac51 inhibitor treatment; checkpoint blockade combination in vivo","journal":"Cell metabolism","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KD and pharmacological inhibition with metabolic and immune functional readouts, single lab","pmids":["33910046"],"is_preprint":false},{"year":2020,"finding":"FTO knockdown inhibits both M1 and M2 macrophage polarization by decreasing phosphorylation of IKKα/β, IκBα, and p65 in the NF-κB pathway, and by reducing mRNA stability of STAT1 (M1) and PPAR-γ (M2) via the m6A reader YTHDF2; YTHDF2 silencing restores STAT1 and PPAR-γ mRNA stability in FTO-depleted cells.","method":"FTO siRNA knockdown; actinomycin D mRNA stability assay; YTHDF2 knockdown epistasis; NF-κB pathway phosphorylation Western blot","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis between FTO and YTHDF2 established by double-knockdown with mRNA stability readout, single lab","pmids":["32018056"],"is_preprint":false},{"year":2021,"finding":"FTO protein is ubiquitinated at K216 by the E3 ligase STRAP under hypoxia, leading to proteasomal degradation of FTO; reduced FTO in colorectal cancer allows m6A methylation of MTA1 mRNA, which is then recognized and stabilized by the m6A reader IGF2BP2, promoting metastasis.","method":"Ubiquitination assay with site-directed K216 mutagenesis; STRAP identified as E3 ligase; m6A-RIP on MTA1 mRNA; IGF2BP2 RIP; in vitro/in vivo metastasis assay","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ubiquitination site mapping and E3 ligase identification with functional m6A-RIP validation, single lab","pmids":["34218271"],"is_preprint":false},{"year":2022,"finding":"FTO demethylates m6A on RUNX2 mRNA in cementoblasts, protecting it from YTHDF2-mediated mRNA degradation; YTHDF2 knockdown rescues RUNX2 expression in FTO-depleted cells. TNF-α inhibits cementoblast differentiation partly through the FTO/RUNX2 axis.","method":"FTO knockdown in OCCM-30 cementoblasts and murine ectopic bone formation; m6A-RIP on RUNX2 mRNA; YTHDF2 knockdown epistasis; mineralization assay; RIP assay showing direct FTO-RUNX2 mRNA binding","journal":"Biochimica et biophysica acta. Molecular cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct RNA binding + YTHDF2 epistasis + in vivo bone formation model, single lab","pmids":["36084732"],"is_preprint":false},{"year":2021,"finding":"FTO demethylates m6A on CerS6 mRNA in intestinal epithelial cells, stabilizing it; FTO deficiency reduces CerS6 expression, leading to sphingosine-1-phosphate (S1P) accumulation that triggers pro-inflammatory macrophage activation and Th17 differentiation, exacerbating colitis.","method":"Intestinal epithelial-specific Fto KO (Villin-Cre); m6A-RIP-seq; CerS6 mRNA stability; S1P measurement; macrophage co-culture; Th17 differentiation assay","journal":"Gut","confidence":"High","confidence_rationale":"Tier 2 / Strong — tissue-specific KO mouse model with m6A-RIP-seq, metabolite measurement, and immune cell functional readouts in a single coherent mechanistic chain","pmids":["37734910"],"is_preprint":false},{"year":2024,"finding":"USP18 deubiquitinates and stabilizes FTO protein; elevated FTO then demethylates m6A on SIRT6 mRNA in a YTHDF2-dependent manner, increasing SIRT6 expression and activating AMPK/PGC-1α/AKT signaling to promote mitophagy and reduce neuronal injury in ischemic stroke models.","method":"Co-IP for USP18-FTO interaction; MeRIP for SIRT6 m6A; YTHDF2 RIP; in vivo MCAO rat model with AAV-USP18/FTO; neurological behavior scoring","journal":"Molecular neurobiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, MeRIP, RIP and in vivo model, but complex multi-step pathway in single lab","pmids":["38340205"],"is_preprint":false},{"year":2024,"finding":"FTO demethylates m6A on ACSL4 and TFRC mRNAs to destabilize them, thereby inhibiting ferroptosis; FTO deficiency in aged livers increases ACSL4 and TFRC expression through m6A-dependent mRNA stabilization, exacerbating ischemia/reperfusion injury. Nicotinamide mononucleotide upregulates FTO demethylase activity.","method":"Mass spectrometry proteomics; FTO overexpression in aged mice; m6A-RIP on ACSL4/TFRC mRNAs; ferroptosis assays; in vivo liver transplant model","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct m6A-RIP on specific targets with ferroptosis functional readout in vivo, single lab","pmids":["38834654"],"is_preprint":false},{"year":2024,"finding":"FTO reduces m6A abundance on GPNMB mRNA to stabilize it from YTHDF2-mediated degradation; GPNMB is packaged into small extracellular vesicles from HCC cells and binds the surface receptor SDC4 on CD8+ T cells, inhibiting their activation and enabling immune evasion.","method":"FTO knockdown/overexpression in HCC cells; m6A-RIP on GPNMB mRNA; sEV isolation and characterization; SDC4 neutralizing antibody; CD8+ T cell activation assay; in vivo tumor model","journal":"Gut","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — m6A-RIP identifies specific mRNA target, functional immune evasion mechanism validated in vitro and in vivo, single lab","pmids":["38839271"],"is_preprint":false},{"year":2024,"finding":"FTO affects endothelial cell function in diabetic retinopathy by modulating CDK2 mRNA stability in an m6A-YTHDF2-dependent manner; elevated FTO (driven by lactate-mediated histone lactylation) reduces m6A on CDK2 mRNA, increasing CDK2 expression, cell cycle progression, and angiogenesis.","method":"MeRIP for CDK2 m6A; YTHDF2 knockdown epistasis; histone lactylation ChIP; in vitro EC assays; zebrafish and mouse in vivo models; FB23-2 FTO inhibitor","journal":"EMBO molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct m6A-RIP on CDK2, lactylation-FTO regulatory link, in vivo models, single lab","pmids":["38297099"],"is_preprint":false},{"year":2024,"finding":"FTO protein stability is regulated by acetylation: lncRNA HOTAIRM1 interacts with FTO and promotes FTO acetylation, enhancing its stability and demethylase activity, leading to m6A demethylation of CD44 pre-mRNA; reduced m6A on CD44 prevents YTHDC1 recognition and causes a splicing switch from CD44S to CD44V, suppressing ferroptosis and promoting radioresistance.","method":"HOTAIRM1-FTO interaction (RIP/pulldown); acetylation assay; m6A-RIP on CD44 mRNA; YTHDC1 knockdown epistasis; alternative splicing analysis; ferroptosis and irradiation assays","journal":"Neoplasia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct protein interaction, post-translational modification (acetylation), m6A-RIP and splicing epistasis in single lab","pmids":["39128424"],"is_preprint":false},{"year":2019,"finding":"FTO CLIP-seq binding peaks contain RRACH motifs; exogenously overexpressed FTO selectively removes m6A from GGACU and RRACU motifs in a concentration-dependent manner, demonstrating sequence-context preferences for FTO demethylation in cells.","method":"CLIP-seq analysis across multiple cell lines; FTO overexpression + m6A-seq; motif enrichment analysis","journal":"RNA biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CLIP-seq with functional demethylation validation in cells, single lab but five datasets analyzed","pmids":["31149892"],"is_preprint":false},{"year":2016,"finding":"FTO knockdown in 3T3-L1 pre-adipocytes suppresses proliferation, reduces PPARγ and GLUT4 expression, and inhibits Akt phosphorylation; FTO overexpression has the opposite effect and PI3K inhibition with wortmannin blocks FTO overexpression-driven Akt phosphorylation, placing FTO upstream of PI3K/Akt in adipocyte differentiation.","method":"Lentiviral FTO knockdown/overexpression in 3T3-L1; Western blot for PPARγ, GLUT4, phospho-Akt; wortmannin epistasis; proliferation and lipid droplet assays","journal":"Nutrients","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic gain/loss-of-function with PI3K inhibitor epistasis and multiple pathway markers, single lab","pmids":["26907332"],"is_preprint":false},{"year":2015,"finding":"FTO deficiency in mice leads to increased UCP-1 expression in white adipose depots and enhanced mitochondrial uncoupling; FTO-deficient human preadipocytes (lentiviral shRNA) show 4-fold higher UCP-1 in mitochondria and increased uncoupling, revealing that FTO suppresses brown/beige adipocyte programming.","method":"Fto-/- mouse adipose tissue analysis; lentiviral shRNA FTO knockdown in human adipocytes; UCP-1 immunostaining; mitochondrial uncoupling assay","journal":"Endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mouse KO and human primary cell KD with direct UCP-1 and mitochondrial functional readout, single lab","pmids":["23751871"],"is_preprint":false},{"year":2021,"finding":"FTO-mediated m6A demethylation of MALAT1 lncRNA in bladder cancer regulates miR-384 and MAL2 expression, promoting bladder cancer tumorigenesis through the MALAT1/miR-384/MAL2 axis.","method":"FTO gain/loss-of-function in vitro and in vivo; m6A-RIP on MALAT1; miR-384 and MAL2 expression assays","journal":"Clinical and translational medicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — m6A-RIP on MALAT1 but mechanistic chain between m6A on MALAT1 and miR-384/MAL2 not fully resolved in abstract, single lab","pmids":["33634966"],"is_preprint":false},{"year":2022,"finding":"FTO inhibition by GSK3β-mediated ubiquitination-proteasomal degradation: E6E7 oncogene activates GSK3β transcription, GSK3β promotes FTO ubiquitination and decreases FTO protein levels; FTO overexpression retains HK2 pre-mRNA in the nucleus, decreasing mature HK2 cytoplasmic mRNA, suggesting FTO controls HK2 mRNA maturation/export.","method":"E6E7 overexpression; GSK3β overexpression and FTO ubiquitination assay; nuclear/cytoplasmic HK2 pre-mRNA fractionation after FTO overexpression; Western blot","journal":"Archives of biochemistry and biophysics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — ubiquitination assay and mRNA fractionation, but GSK3β E3 ligase identity not directly confirmed and mechanism of mRNA retention incomplete, single lab","pmids":["36075458"],"is_preprint":false},{"year":2021,"finding":"FTO demethylates m6A on SIRT6 mRNA in cardiomyocytes; FTO silencing increases m6A on SIRT6 mRNA (bound by YTHDF2, leading to mRNA destabilization), decreasing SIRT6 expression and activating mitophagy-related signaling in sepsis-induced cardiac injury.","method":"MeRIP on SIRT6 mRNA; YTHDF2 RIP; AAV9-FTO overexpression in LPS mouse model; mitophagy TEM; mitochondrial function assays","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MeRIP on specific target plus YTHDF2 RIP plus in vivo AAV model, single lab","pmids":["39308045"],"is_preprint":false},{"year":2023,"finding":"FTO negatively regulates NK cell cytotoxicity by increasing mRNA stability of SOCS family genes (suppressors of cytokine signaling) via m6A demethylation, dampening IL-2/15-driven JAK/STAT signaling; Fto-/- mouse NK cells show hyperactivation and suppress melanoma metastasis in vivo.","method":"Fto KO mouse NK cell functional assays; melanoma metastasis in vivo model; human FTO KD NK cell anti-leukemia assay; SOCS mRNA stability measurement","journal":"EMBO reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO in mice and human KD with defined signaling pathway, in vivo and in vitro concordant, single lab","pmids":["36744362"],"is_preprint":false},{"year":2021,"finding":"FTO demethylates m6A on BNIP3 mRNA in granulosa cells, stabilizing BNIP3 expression and activating autophagy to reduce apoptosis; FTO overexpression decreases BNIP3 expression-driven apoptosis, and FTO inhibition with meclofenamic acid opposes these effects.","method":"FTO overexpression/siRNA knockdown in granulosa cells; BNIP3 mRNA and protein measurement; autophagy assays; MA inhibitor treatment","journal":"Reproductive biology and endocrinology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — functional link between FTO and BNIP3 via m6A inferred but m6A-RIP not explicitly described in abstract, single lab","pmids":["35219326"],"is_preprint":false},{"year":2025,"finding":"H. pylori CagA enhances FTO transcription via the transcription factor c-Jun/Jun proto-oncogene; elevated FTO demethylates m6A on HBEGF mRNA, inhibiting its degradation and facilitating EMT in gastric cancer cells; H. pylori eradication does not fully reverse FTO/HBEGF upregulation, but combined antibiotic + FTO inhibitor (MA) treatment suppresses EMT.","method":"H. pylori infection of GC cell lines; ChIP for c-Jun at FTO promoter; m6A-RIP-seq on HBEGF mRNA; EMT assays in vitro and in vivo; human GC organoids; MA inhibitor","journal":"Cancer communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP, m6A-RIP-seq, and functional EMT assays in multiple model systems including organoids, single lab","pmids":["39960839"],"is_preprint":false},{"year":2022,"finding":"FTO demethylates m6A on ACSL3 and GPX4 mRNAs to decrease their stability in oral squamous cell carcinoma, thereby sensitizing cells to ferroptosis; FTO overexpression enhances ferroptosis susceptibility in vitro and in vivo.","method":"FTO overexpression/knockdown; m6A-RIP on ACSL3 and GPX4 mRNAs; mRNA stability assay; ferroptosis induction assays in vitro and in vivo","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — m6A-RIP on two specific targets with mRNA stability and ferroptosis functional readout, single lab","pmids":["38003537"],"is_preprint":false},{"year":2019,"finding":"FTO fused to dCas9 (RCas9-FTO) retains m6A demethylase activity and achieves sequence-specific demethylation of m6A in RNA in a guide-RNA and PAM-dependent manner, with up to 15-fold preference for target over off-target RNA; the PAM-to-m6A distance influences demethylation efficiency.","method":"RCas9-FTO fusion protein; SCARLET site-specific m6A quantification; in vitro demethylation assay with varying target RNAs","journal":"RNA","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — direct in vitro enzymatic tool validation with quantitative m6A measurement, single lab; primarily a tool paper","pmids":["31263003"],"is_preprint":false},{"year":2021,"finding":"FTO overexpression in granulosa cells reduces m6A modification on FLOT2 mRNA, increasing FLOT2 mRNA stability and expression; elevated FLOT2 mediates FTO-driven proliferation, apoptosis suppression, and insulin resistance in granulosa cells.","method":"FTO overexpression; meRIP assay on FLOT2 mRNA; actinomycin D mRNA stability assay; RIP assay; FLOT2 knockdown rescue","journal":"Reproductive sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — meRIP and stability assay with target-specific rescue, single lab","pmids":["34254281"],"is_preprint":false},{"year":2023,"finding":"FTO co-localizes with and physically interacts with androgen receptor (AR) in granulosa cells (confocal co-localization and Co-IP); FTO knockdown decreases expression of steroid hormone synthetases (CYP11A1, CYP17A1, HSD11B1, HSD3B2) and AR/PSA, reducing androgen production in PCOS models.","method":"Co-IP and confocal co-localization of FTO and AR; FTO siRNA knockdown; Western blot for steroidogenic enzymes and AR/PSA; FTO inhibitor (MA) treatment","journal":"Gynecological endocrinology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP and co-localization with functional knockdown data, but AR as direct FTO substrate or mechanistic basis of interaction not established, single lab","pmids":["37931646"],"is_preprint":false},{"year":2021,"finding":"FTO demethylates m6A on FOXJ1 mRNA in Xenopus embryos, stabilizing the transcript needed for motile ciliogenesis; FTO also promotes adult neurogenesis in mice by demethylating m6A modifications on BDNF pathway component mRNAs, reducing their degradation.","method":"Fto KO mouse; m6A profiling during postnatal neurodevelopment; adult neural stem cell proliferation/differentiation assays; learning/memory behavioral tests","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Fto KO mouse with genome-wide m6A profiling and behavioral readouts, single lab","pmids":["28398475"],"is_preprint":false},{"year":2021,"finding":"Structure-based design identified FTO inhibitors that occupy both the 2-oxoglutarate (2OG) and substrate binding sites of FTO; X-ray crystallography confirmed binding mode and selectivity over PHD2, FIH, and multiple JmjC KDMs.","method":"X-ray crystallography of FTO-inhibitor complexes; biochemical turnover and binding assays; selectivity profiling against related 2OG oxygenases","journal":"Journal of medicinal chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure with functional binding/turnover assays and selectivity profiling, single lab with rigorous structural validation","pmids":["34762429"],"is_preprint":false}],"current_model":"FTO is an Fe(II)- and α-ketoglutarate-dependent dioxygenase (AlkB family) that demethylates N6-methyladenosine (m6A) in mRNA, snRNA, and other RNA species via stepwise oxidation (generating hm6A and f6A intermediates), with substrate selectivity partly determined by the RNA-binding protein SFPQ; it shuttles between the nucleus and cytoplasm (assisted by Exportin 2, regulated by CK2-mediated phosphorylation and acetylation), demethylates specific target mRNAs (including cyclin D1, FOXJ1, RUNX2, PGC-1α, BDNF pathway components, and others) to control their stability, and thereby regulates cell cycle progression, adipogenesis, cardiac function, ciliogenesis, immune cell activity, and cancer cell metabolism—with its activity modulated by NADP binding, ubiquitin-mediated degradation (by STRAP/GSK3β), and small-molecule inhibitors that block its catalytic site."},"narrative":{"mechanistic_narrative":"FTO is an Fe(II)- and α-ketoglutarate-dependent dioxygenase that catalyzes oxidative demethylation of N6-methyladenosine (m6A) in RNA, removing the methyl mark through a stepwise mechanism that generates N6-hydroxymethyladenosine and N6-formyladenosine intermediates [PMID:23653210]. Beyond canonical mRNA m6A, FTO acts on m6Am in snRNA to set the m1/m2 isoform ratio and shape alternative splicing [PMID:30778204], and demethylates LINE1 RNA to modulate local chromatin state and gene transcription in stem cells and early embryos [PMID:35511947]. Its activity is dependent on an intact catalytic center, as the demethylase-dead R316A mutant abolishes its functional effects [PMID:29997116, PMID:29384213], and structure-based inhibitors that occupy the 2-oxoglutarate and substrate pockets block catalysis with selectivity over related 2OG oxygenases [PMID:34762429]. Substrate selectivity in cells is guided by RNA sequence context (RRACH/GGACU motifs) [PMID:31149892] and by the RNA-binding protein SFPQ, which recruits FTO to specific transcripts for demethylation of adjacent m6A sites [PMID:31981477]. FTO shuttles between nucleus and cytoplasm, partitioning into nuclear speckles enriched in RNA-processing factors, with shuttling dependent on its N-terminus and the partner Exportin 2, and regulated by CK2-mediated phosphorylation during the cell cycle [PMID:25242086, PMID:22872099, PMID:32268083]. Mechanistically, FTO demethylation typically stabilizes target mRNAs by removing m6A marks that would otherwise direct YTHDF2-dependent decay; through this logic it stabilizes cyclin D1 to drive G1 progression [PMID:32268083], FOXJ1 to support motile ciliogenesis [PMID:33761320], and many other transcripts governing cardiac contractile function [PMID:29997116], adipocyte and mitochondrial programs [PMID:32719557, PMID:29384213, PMID:23751871], neurogenesis [PMID:28398475], immune cell activity [PMID:32018056, PMID:36744362], ferroptosis [PMID:38834654, PMID:38003537], and cancer metabolism and progression [PMID:33910046, PMID:34218271]. FTO abundance is itself controlled post-translationally by E3-ligase-mediated ubiquitination and proteasomal degradation (STRAP, and a GSK3β-linked pathway) [PMID:34218271, PMID:36075458], by USP18-mediated deubiquitination [PMID:38340205], and by acetylation [PMID:39128424], integrating its m6A-erasing activity into broader physiological and disease signaling.","teleology":[{"year":2013,"claim":"Established the core enzymatic identity of FTO by showing it is an Fe(II)/α-KG dioxygenase that oxidatively demethylates m6A in mRNA via defined reaction intermediates, converting it from a candidate to a bona fide RNA m6A eraser.","evidence":"In vitro dioxygenase assay with mass-spectrometric detection of hm6A and f6A intermediates in mammalian mRNA","pmids":["23653210"],"confidence":"High","gaps":["Does not establish endogenous transcript targets or cellular consequences","Substrate selectivity in vivo not addressed"]},{"year":2014,"claim":"Resolved where FTO acts by demonstrating it dynamically shuttles between nucleus and cytoplasm and identifying Exportin 2 as a transport-relevant partner, framing FTO as a mobile rather than statically nuclear enzyme.","evidence":"Live-cell GFP-FTO imaging, FLIP, proteomic Co-IP, and N-terminal deletion studies","pmids":["25242086"],"confidence":"Medium","gaps":["Functional consequence of shuttling for specific substrates not defined","XPO2 interaction not reciprocally validated"]},{"year":2019,"claim":"Broadened the substrate repertoire beyond mRNA m6A by showing FTO controls snRNA m6Am isoform ratios with downstream splicing consequences and is inhibited by the oncometabolite D-2-HG, linking FTO activity to metabolic context.","evidence":"snRNA isoform profiling, metabolite inhibition, and splicing analysis","pmids":["30778204"],"confidence":"High","gaps":["Generality of m6Am vs m6A preference across substrates not quantified","Physiological relevance of D-2-HG inhibition in normal tissue unclear"]},{"year":2019,"claim":"Defined FTO's in-cell substrate logic by showing CLIP-seq peaks enrich RRACH motifs and overexpressed FTO preferentially demethylates GGACU/RRACU sites, establishing sequence-context preference.","evidence":"CLIP-seq across multiple cell lines with FTO-overexpression m6A-seq and motif enrichment","pmids":["31149892"],"confidence":"Medium","gaps":["Overexpression may not reflect endogenous occupancy","Does not identify cofactors driving in-cell selectivity"]},{"year":2019,"claim":"Provided structural and pharmacological proof of FTO's catalytic pocket as a druggable target, showing inhibitors occupy the 2OG and substrate sites selectively and that catalytic inhibition phenocopies genetic depletion in AML.","evidence":"Structure-based inhibitor design (FB23/FB23-2), X-ray crystallography, binding/turnover assays, and AML xenografts","pmids":["30991027","34762429"],"confidence":"High","gaps":["In vivo selectivity and toxicity profiles beyond AML not established","Resistance mechanisms not characterized"]},{"year":2020,"claim":"Identified a molecular basis for FTO substrate selectivity by showing the RNA-binding protein SFPQ directly binds FTO and recruits it to specific transcripts for adjacent m6A demethylation.","evidence":"Site-specific photocrosslinking, CLIP-seq co-localization, and overexpression-based demethylation assay","pmids":["31981477"],"confidence":"High","gaps":["Whether SFPQ is required for all FTO targets unknown","Structural basis of the FTO-SFPQ interaction not resolved"]},{"year":2020,"claim":"Connected FTO catalysis to cell-cycle control and its own regulation, showing FTO stabilizes cyclin D1 mRNA via demethylation and is driven into the nucleus by CK2 phosphorylation during G1.","evidence":"Reciprocal m6A-RIP, mRNA stability assay, KO cell-cycle phenotype, and CK2 phosphorylation/translocation mapping","pmids":["32268083"],"confidence":"High","gaps":["CK2 phospho-sites' direct effect on enzymatic activity vs localization not separated","Other cell-cycle targets not enumerated"]},{"year":2020,"claim":"Revealed metabolic regulation of FTO by showing NADP directly binds and enhances its demethylase activity and is required for NADP-driven adipogenesis, coupling cofactor availability to m6A erasure.","evidence":"Fluorescence-quenching binding assay, in vitro activity assay, and FTO-KO adipogenesis rescue","pmids":["32719557"],"confidence":"High","gaps":["Structural site of NADP binding not defined","Quantitative contribution of NADP to in vivo activity unclear"]},{"year":2018,"claim":"Used a catalytic-dead control (R316A) to establish that FTO's effects on hepatocyte mitochondrial content and triglyceride deposition are causally driven by m6A demethylation rather than scaffolding.","evidence":"WT vs R316A overexpression in hepatocytes with mitochondrial/TG and m6A measurements","pmids":["29384213"],"confidence":"Medium","gaps":["Specific mRNA targets in hepatocytes not identified","Single experimental system"]},{"year":2021,"claim":"Demonstrated a conserved developmental role by showing FTO stabilizes FOXJ1 mRNA to drive motile ciliogenesis across species, with loss producing cilia defects and asthma-like phenotypes.","evidence":"Loss-of-function in Xenopus, human airway epithelium, and Fto-KO mouse allergen model with FOXJ1 stability assays","pmids":["33761320"],"confidence":"High","gaps":["m6A reader mediating FOXJ1 decay not specified here","Link between cilia defect and asthma phenotype mechanistically indirect"]},{"year":2019,"claim":"Established FTO's role in cardiac function with rigorous catalytic-mutant controls, showing demethylase-active but not R316A FTO stabilizes contractile transcripts and improves post-ischemic function.","evidence":"AAV9 FTO overexpression in mouse MI, m6A-RIP-seq, R316A mutant, and contractility/calcium measurements","pmids":["29997116"],"confidence":"High","gaps":["Full set of cardiac target transcripts not exhaustively defined","Translation to human heart failure therapy untested"]},{"year":2022,"claim":"Extended FTO function to chromatin regulation by showing it demethylates LINE1 RNA to control its abundance and local chromatin state, influencing gene transcription in stem cells and embryos.","evidence":"m6A-seq in Fto-KO mESCs with LINE1 abundance, chromatin-state, and embryonic developmental readouts","pmids":["35511947"],"confidence":"High","gaps":["Mechanism coupling LINE1 RNA m6A to chromatin not fully resolved","Reader proteins for LINE1 m6A unidentified"]},{"year":2021,"claim":"Consolidated the dominant mechanistic motif: FTO demethylation antagonizes YTHDF2-mediated decay, with FTO/YTHDF2 epistasis controlling target mRNA stability across macrophage polarization, osteogenic, and other contexts.","evidence":"mRNA stability assays with YTHDF2 double-knockdown epistasis (STAT1/PPAR-γ, RUNX2) and NF-κB pathway analysis","pmids":["32018056","36084732"],"confidence":"Medium","gaps":["Direct m6A occupancy at all implicated targets not always shown","Reader specificity (YTHDF2 vs others) context-dependent"]},{"year":2021,"claim":"Defined post-translational control of FTO abundance by showing STRAP ubiquitinates FTO at K216 under hypoxia for degradation, with downstream consequences for m6A-dependent metastasis programs.","evidence":"Ubiquitination assay with K216 mutagenesis, E3 ligase identification, and m6A-RIP/IGF2BP2 RIP metastasis assays","pmids":["34218271"],"confidence":"Medium","gaps":["Generality of K216 ubiquitination beyond colorectal cancer unknown","Relationship to other FTO degradation routes unclear"]},{"year":2024,"claim":"Expanded the FTO regulatory network by identifying deubiquitination (USP18) and acetylation (HOTAIRM1-driven) as stabilizing modifications that tune FTO activity in ischemic and radioresistance contexts.","evidence":"Co-IP, MeRIP, RIP epistasis, splicing analysis, and in vivo disease models","pmids":["38340205","39128424"],"confidence":"Medium","gaps":["Acetylation site(s) and their effect on catalysis not mapped","Interplay among ubiquitination, deubiquitination, and acetylation not integrated"]},{"year":2024,"claim":"Positioned FTO as a regulator of ferroptosis and immune evasion by demethylating distinct target mRNAs (ACSL4/TFRC, ACSL3/GPX4, CD44, GPNMB) to either suppress or sensitize ferroptosis and to control CD8+ T cell activation across tissue contexts.","evidence":"m6A-RIP on specific targets, ferroptosis assays, sEV/SDC4 immune assays, and in vivo disease models","pmids":["38834654","38003537","38839271"],"confidence":"Medium","gaps":["Context-dependent (pro- vs anti-ferroptotic) outcomes not mechanistically reconciled","Single-lab target validations"]},{"year":null,"claim":"It remains unresolved how FTO's broad in-cell target selectivity is determined across tissues, and how its many post-translational regulators (phosphorylation, ubiquitination, deubiquitination, acetylation) and cofactors (NADP) are coordinately integrated to direct context-specific m6A erasure.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking recruitment cofactors (SFPQ) to tissue-specific targets","Quantitative hierarchy among regulatory PTMs unknown","Distinction between m6A vs m6Am vs ncRNA substrate preference in vivo unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016491","term_label":"oxidoreductase activity","supporting_discovery_ids":[0,1,7,37]},{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[0,1,8,23,33]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[2,23]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0,37]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[3,5,6]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[5]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[6]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,1,2,8]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[3]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[9,13,15,31]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[14,29,13,20]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[19,30,32]}],"complexes":[],"partners":["SFPQ","XPO2","AR"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9C0B1","full_name":"Alpha-ketoglutarate-dependent dioxygenase FTO","aliases":["Fat mass and obesity-associated protein","U6 small nuclear RNA (2'-O-methyladenosine-N(6)-)-demethylase FTO","U6 small nuclear RNA N(6)-methyladenosine-demethylase FTO","mRNA (2'-O-methyladenosine-N(6)-)-demethylase FTO","m6A(m)-demethylase FTO","mRNA N(6)-methyladenosine demethylase FTO","tRNA N1-methyl adenine demethylase FTO"],"length_aa":505,"mass_kda":58.3,"function":"RNA demethylase that mediates oxidative demethylation of different RNA species, such as mRNAs, tRNAs and snRNAs, and acts as a regulator of fat mass, adipogenesis and energy homeostasis (PubMed:22002720, PubMed:25452335, PubMed:26457839, PubMed:26458103, PubMed:28002401, PubMed:30197295). Specifically demethylates N(6)-methyladenosine (m6A) RNA, the most prevalent internal modification of messenger RNA (mRNA) in higher eukaryotes (PubMed:22002720, PubMed:25452335, PubMed:26457839, PubMed:26458103, PubMed:30197295). M6A demethylation by FTO affects mRNA expression and stability (PubMed:30197295). Also able to demethylate m6A in U6 small nuclear RNA (snRNA) (PubMed:30197295). Mediates demethylation of N(6),2'-O-dimethyladenosine cap (m6A(m)), by demethylating the N(6)-methyladenosine at the second transcribed position of mRNAs and U6 snRNA (PubMed:28002401, PubMed:30197295). Demethylation of m6A(m) in the 5'-cap by FTO affects mRNA stability by promoting susceptibility to decapping (PubMed:28002401). Also acts as a tRNA demethylase by removing N(1)-methyladenine from various tRNAs (PubMed:30197295). Has no activity towards 1-methylguanine (PubMed:20376003). Has no detectable activity towards double-stranded DNA (PubMed:20376003). Also able to repair alkylated DNA and RNA by oxidative demethylation: demethylates single-stranded RNA containing 3-methyluracil, single-stranded DNA containing 3-methylthymine and has low demethylase activity towards single-stranded DNA containing 1-methyladenine or 3-methylcytosine (PubMed:18775698, PubMed:20376003). Ability to repair alkylated DNA and RNA is however unsure in vivo (PubMed:18775698, PubMed:20376003). Involved in the regulation of fat mass, adipogenesis and body weight, thereby contributing to the regulation of body size and body fat accumulation (PubMed:18775698, PubMed:20376003). Involved in the regulation of thermogenesis and the control of adipocyte differentiation into brown or white fat cells (PubMed:26287746). Regulates activity of the dopaminergic midbrain circuitry via its ability to demethylate m6A in mRNAs (By similarity). Plays an oncogenic role in a number of acute myeloid leukemias by enhancing leukemic oncogene-mediated cell transformation: acts by mediating m6A demethylation of target transcripts such as MYC, CEBPA, ASB2 and RARA, leading to promote their expression (PubMed:28017614, PubMed:29249359)","subcellular_location":"Nucleus; Nucleus speckle; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q9C0B1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/FTO","classification":"Not Classified","n_dependent_lines":4,"n_total_lines":1208,"dependency_fraction":0.0033112582781456954},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/FTO","total_profiled":1310},"omim":[{"mim_id":"617885","title":"BODY MASS INDEX QUANTITATIVE TRAIT LOCUS 19; BMIQ19","url":"https://www.omim.org/entry/617885"},{"mim_id":"612985","title":"IROQUOIS HOMEOBOX PROTEIN 3; IRX3","url":"https://www.omim.org/entry/612985"},{"mim_id":"612938","title":"GROWTH RETARDATION, DEVELOPMENTAL DELAY, AND FACIAL DYSMORPHISM; GDFD","url":"https://www.omim.org/entry/612938"},{"mim_id":"612883","title":"MENARCHE, AGE AT, QUANTITATIVE TRAIT LOCUS 3; MENAQ3","url":"https://www.omim.org/entry/612883"},{"mim_id":"612882","title":"MENARCHE, AGE AT, QUANTITATIVE TRAIT LOCUS 2; MENAQ2","url":"https://www.omim.org/entry/612882"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"},{"location":"Vesicles","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/FTO"},"hgnc":{"alias_symbol":["KIAA1752","MGC5149","ALKBH9","IFEX9"],"prev_symbol":[]},"alphafold":{"accession":"Q9C0B1","domains":[{"cath_id":"2.60.120.590","chopping":"10-164_195-253_263-323","consensus_level":"high","plddt":94.4275,"start":10,"end":323},{"cath_id":"1.20.58.1470","chopping":"332-465","consensus_level":"high","plddt":95.9921,"start":332,"end":465}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9C0B1","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9C0B1-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9C0B1-F1-predicted_aligned_error_v6.png","plddt_mean":91.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=FTO","jax_strain_url":"https://www.jax.org/strain/search?query=FTO"},"sequence":{"accession":"Q9C0B1","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9C0B1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9C0B1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9C0B1"}},"corpus_meta":[{"pmid":"26287746","id":"PMC_26287746","title":"FTO Obesity Variant Circuitry and Adipocyte Browning in Humans.","date":"2015","source":"The New England journal of medicine","url":"https://pubmed.ncbi.nlm.nih.gov/26287746","citation_count":1029,"is_preprint":false},{"pmid":"30991027","id":"PMC_30991027","title":"Small-Molecule Targeting of Oncogenic FTO Demethylase in Acute Myeloid Leukemia.","date":"2019","source":"Cancer cell","url":"https://pubmed.ncbi.nlm.nih.gov/30991027","citation_count":730,"is_preprint":false},{"pmid":"32531268","id":"PMC_32531268","title":"Targeting FTO Suppresses Cancer Stem Cell Maintenance and Immune Evasion.","date":"2020","source":"Cancer cell","url":"https://pubmed.ncbi.nlm.nih.gov/32531268","citation_count":631,"is_preprint":false},{"pmid":"29997116","id":"PMC_29997116","title":"FTO-Dependent N6-Methyladenosine Regulates Cardiac Function During Remodeling and Repair.","date":"2019","source":"Circulation","url":"https://pubmed.ncbi.nlm.nih.gov/29997116","citation_count":505,"is_preprint":false},{"pmid":"24247219","id":"PMC_24247219","title":"The bigger picture of FTO: the first GWAS-identified obesity gene.","date":"2013","source":"Nature reviews. Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/24247219","citation_count":475,"is_preprint":false},{"pmid":"23653210","id":"PMC_23653210","title":"FTO-mediated formation of N6-hydroxymethyladenosine and N6-formyladenosine in mammalian RNA.","date":"2013","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/23653210","citation_count":385,"is_preprint":false},{"pmid":"33910046","id":"PMC_33910046","title":"Tumors exploit FTO-mediated regulation of glycolytic metabolism to evade immune surveillance.","date":"2021","source":"Cell metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/33910046","citation_count":302,"is_preprint":false},{"pmid":"28398475","id":"PMC_28398475","title":"Fat mass and obesity-associated (FTO) protein regulates adult neurogenesis.","date":"2017","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/28398475","citation_count":258,"is_preprint":false},{"pmid":"20381893","id":"PMC_20381893","title":"The genetics of obesity: FTO leads the way.","date":"2010","source":"Trends in genetics : TIG","url":"https://pubmed.ncbi.nlm.nih.gov/20381893","citation_count":258,"is_preprint":false},{"pmid":"35511947","id":"PMC_35511947","title":"FTO mediates LINE1 m6A demethylation and chromatin regulation in mESCs and mouse development.","date":"2022","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/35511947","citation_count":242,"is_preprint":false},{"pmid":"30778204","id":"PMC_30778204","title":"FTO controls reversible m6Am RNA methylation during snRNA biogenesis.","date":"2019","source":"Nature chemical biology","url":"https://pubmed.ncbi.nlm.nih.gov/30778204","citation_count":232,"is_preprint":false},{"pmid":"18838977","id":"PMC_18838977","title":"The FTO gene and measured food intake in children.","date":"2008","source":"International journal of obesity 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metastasis.","date":"2021","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/34218271","citation_count":123,"is_preprint":false},{"pmid":"29384213","id":"PMC_29384213","title":"FTO reduces mitochondria and promotes hepatic fat accumulation through RNA demethylation.","date":"2018","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/29384213","citation_count":122,"is_preprint":false},{"pmid":"33304380","id":"PMC_33304380","title":"FTO - A Common Genetic Basis for Obesity and Cancer.","date":"2020","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/33304380","citation_count":117,"is_preprint":false},{"pmid":"38297099","id":"PMC_38297099","title":"Lactylation-driven FTO targets CDK2 to aggravate microvascular anomalies in diabetic retinopathy.","date":"2024","source":"EMBO molecular 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FTO undergoes casein kinase II-mediated phosphorylation that drives its nuclear translocation during G1 phase, coinciding with low m6A on cyclin D1.\",\n      \"method\": \"m6A-RIP; cyclin D1 mRNA stability assay; FTO knockdown/KO with cell-cycle phenotype; CK2 phosphorylation and nuclear translocation assay; in vitro and in vivo\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal m6A-RIP, mRNA stability assay, KO phenotype, and phosphorylation mapping in single study with multiple orthogonal methods\",\n      \"pmids\": [\"32268083\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FTO demethylates m6A on FOXJ1 mRNA to stabilize it, acting as a conserved regulator of motile ciliogenesis; Fto depletion in Xenopus embryos and human airway epithelium destabilizes FOXJ1 mRNA, causing motile cilia defects and a shift from ciliated to goblet cells. Fto knockout mice show asthma-like phenotypes upon allergen challenge.\",\n      \"method\": \"Xenopus loss-of-function; human airway epithelium FTO knockdown; Fto KO mouse allergen model; mRNA stability assay for FOXJ1\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic loss-of-function replicated across three experimental systems (Xenopus, human primary cells, mouse KO) with defined molecular target (FOXJ1 mRNA stability)\",\n      \"pmids\": [\"33761320\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"FTO resides in both the nucleus and cytoplasm and contains a mobile fraction that shuttles between compartments, as demonstrated by live-cell GFP-FTO imaging and FLIP (fluorescence loss in photobleaching). Exportin 2 (XPO2) was identified as an FTO binding partner by proteomics. The N-terminus of FTO is required for nucleocytoplasmic shuttling.\",\n      \"method\": \"Live-cell GFP-FTO imaging; FLIP; proteomic Co-IP identifying XPO2; N-terminal deletion studies\",\n      \"journal\": \"Bioscience reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct live-cell localization with FLIP and binding partner identification by proteomics, single lab\",\n      \"pmids\": [\"25242086\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"FTO localizes to nuclear speckles (enriched in mRNA processing factors) as determined by immunocytochemistry and confocal laser scanning microscopy in HEK293, HeLa, and MCF-7 cells; FTO knockdown alters 3-methyluridine/uridine and pseudouridine/uridine ratios in total brain RNA, indicating broader RNA modification roles.\",\n      \"method\": \"Immunocytochemistry; confocal laser scanning microscopy; RNA modification analysis (nucleotide ratio measurements)\",\n      \"journal\": \"European journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — direct subcellular localization by confocal microscopy in multiple cell lines, RNA modification biochemistry, single lab\",\n      \"pmids\": [\"22872099\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"NADP directly binds FTO (identified by fluorescence quenching assay) and independently enhances FTO demethylase activity in vitro; NADP promotes mRNA m6A demethylation in vivo, and FTO deletion blocks NADP-enhanced adipogenesis in 3T3-L1 preadipocytes.\",\n      \"method\": \"Fluorescence quenching binding assay; in vitro demethylation assay; FTO KO adipogenesis rescue experiment\",\n      \"journal\": \"Nature chemical biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct binding assay plus in vitro enzymatic activity measurement plus genetic rescue, single lab with three orthogonal methods\",\n      \"pmids\": [\"32719557\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"FTO mediates m6A demethylation of LINE1 RNA in mouse embryonic stem cells, regulating LINE1 RNA abundance and local chromatin state, which in turn modulates transcription of LINE1-containing genes; FTO-mediated LINE1 RNA demethylation also shapes chromatin and gene expression during mouse oocyte and embryonic development.\",\n      \"method\": \"m6A-seq in Fto KO mESCs; LINE1 RNA abundance and chromatin state measurement; oocyte and embryo developmental analysis\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide m6A-seq in KO model with chromatin and functional developmental readouts, high-impact journal\",\n      \"pmids\": [\"35511947\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"FTO directly binds the inhibitors FB23 and FB23-2 (structure-based design) and selectively inhibits FTO's m6A demethylase activity, suppressing AML cell proliferation and promoting differentiation/apoptosis in vitro and in xenograft mice, mimicking genetic FTO depletion.\",\n      \"method\": \"Structure-based inhibitor design; direct binding assay; m6A demethylase activity assay; AML cell line and primary blast cell proliferation/differentiation assay; xenograft mouse model\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — structure-based design with direct binding, enzymatic activity assay, and in vivo xenograft, replicated on multiple AML models\",\n      \"pmids\": [\"30991027\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"FTO demethylase activity is required for its role in cardiac contractile function: FTO overexpression in failing mouse hearts (via AAV9) demethylates cardiac contractile transcripts, prevents their degradation, and improves calcium dynamics and contractile function post-ischemia; an FTO demethylase-inactive mutant (R316A) fails to rescue these effects.\",\n      \"method\": \"AAV9-mediated FTO overexpression in mouse MI model; m6A-RIP-seq; siRNA knockdown; FTO R316A mutant (demethylase-dead) functional assay; cardiomyocyte calcium/contractility measurements\",\n      \"journal\": \"Circulation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — catalytic mutant controls plus in vivo AAV delivery plus m6A-seq in multiple model systems (mouse, pig, human samples)\",\n      \"pmids\": [\"29997116\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"FTO demethylase activity (not merely protein expression) is required for its effect on mitochondrial content and triglyceride deposition in hepatocytes: an FTO R316A demethylase-dead mutant fails to reduce mitochondrial content or increase TG, establishing the m6A demethylation mechanism as causal.\",\n      \"method\": \"FTO wild-type vs. R316A mutant overexpression in hepatocytes; mitochondrial content and TG measurement; m6A quantification\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — catalytic mutant comparison is rigorous but single lab, single experimental system\",\n      \"pmids\": [\"29384213\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"FTO overexpression in clear cell renal cell carcinoma (ccRCC) increases PGC-1α expression by reducing m6A levels on its mRNA transcripts, restoring mitochondrial activity, inducing oxidative stress/ROS, and impairing tumor growth.\",\n      \"method\": \"FTO overexpression in VHL-deficient cells; m6A-RIP on PGC-1α mRNA; mitochondrial activity and ROS assays; in vivo tumor growth\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — m6A-RIP linking FTO to a specific mRNA target with functional mitochondrial readout, single lab\",\n      \"pmids\": [\"30648791\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FTO-mediated m6A demethylation in tumor cells elevates transcription factors c-Jun, JunB, and C/EBPβ, rewiring glycolytic metabolism; FTO knockdown impairs tumor glycolysis and restores CD8+ T cell function, enabling immune surveillance. The small-molecule FTO inhibitor Dac51 recapitulates these effects.\",\n      \"method\": \"FTO knockdown in tumor cells; metabolic flux assays; CD8+ T cell functional assays; Dac51 inhibitor treatment; checkpoint blockade combination in vivo\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KD and pharmacological inhibition with metabolic and immune functional readouts, single lab\",\n      \"pmids\": [\"33910046\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"FTO knockdown inhibits both M1 and M2 macrophage polarization by decreasing phosphorylation of IKKα/β, IκBα, and p65 in the NF-κB pathway, and by reducing mRNA stability of STAT1 (M1) and PPAR-γ (M2) via the m6A reader YTHDF2; YTHDF2 silencing restores STAT1 and PPAR-γ mRNA stability in FTO-depleted cells.\",\n      \"method\": \"FTO siRNA knockdown; actinomycin D mRNA stability assay; YTHDF2 knockdown epistasis; NF-κB pathway phosphorylation Western blot\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis between FTO and YTHDF2 established by double-knockdown with mRNA stability readout, single lab\",\n      \"pmids\": [\"32018056\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FTO protein is ubiquitinated at K216 by the E3 ligase STRAP under hypoxia, leading to proteasomal degradation of FTO; reduced FTO in colorectal cancer allows m6A methylation of MTA1 mRNA, which is then recognized and stabilized by the m6A reader IGF2BP2, promoting metastasis.\",\n      \"method\": \"Ubiquitination assay with site-directed K216 mutagenesis; STRAP identified as E3 ligase; m6A-RIP on MTA1 mRNA; IGF2BP2 RIP; in vitro/in vivo metastasis assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ubiquitination site mapping and E3 ligase identification with functional m6A-RIP validation, single lab\",\n      \"pmids\": [\"34218271\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"FTO demethylates m6A on RUNX2 mRNA in cementoblasts, protecting it from YTHDF2-mediated mRNA degradation; YTHDF2 knockdown rescues RUNX2 expression in FTO-depleted cells. TNF-α inhibits cementoblast differentiation partly through the FTO/RUNX2 axis.\",\n      \"method\": \"FTO knockdown in OCCM-30 cementoblasts and murine ectopic bone formation; m6A-RIP on RUNX2 mRNA; YTHDF2 knockdown epistasis; mineralization assay; RIP assay showing direct FTO-RUNX2 mRNA binding\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct RNA binding + YTHDF2 epistasis + in vivo bone formation model, single lab\",\n      \"pmids\": [\"36084732\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FTO demethylates m6A on CerS6 mRNA in intestinal epithelial cells, stabilizing it; FTO deficiency reduces CerS6 expression, leading to sphingosine-1-phosphate (S1P) accumulation that triggers pro-inflammatory macrophage activation and Th17 differentiation, exacerbating colitis.\",\n      \"method\": \"Intestinal epithelial-specific Fto KO (Villin-Cre); m6A-RIP-seq; CerS6 mRNA stability; S1P measurement; macrophage co-culture; Th17 differentiation assay\",\n      \"journal\": \"Gut\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — tissue-specific KO mouse model with m6A-RIP-seq, metabolite measurement, and immune cell functional readouts in a single coherent mechanistic chain\",\n      \"pmids\": [\"37734910\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"USP18 deubiquitinates and stabilizes FTO protein; elevated FTO then demethylates m6A on SIRT6 mRNA in a YTHDF2-dependent manner, increasing SIRT6 expression and activating AMPK/PGC-1α/AKT signaling to promote mitophagy and reduce neuronal injury in ischemic stroke models.\",\n      \"method\": \"Co-IP for USP18-FTO interaction; MeRIP for SIRT6 m6A; YTHDF2 RIP; in vivo MCAO rat model with AAV-USP18/FTO; neurological behavior scoring\",\n      \"journal\": \"Molecular neurobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, MeRIP, RIP and in vivo model, but complex multi-step pathway in single lab\",\n      \"pmids\": [\"38340205\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FTO demethylates m6A on ACSL4 and TFRC mRNAs to destabilize them, thereby inhibiting ferroptosis; FTO deficiency in aged livers increases ACSL4 and TFRC expression through m6A-dependent mRNA stabilization, exacerbating ischemia/reperfusion injury. Nicotinamide mononucleotide upregulates FTO demethylase activity.\",\n      \"method\": \"Mass spectrometry proteomics; FTO overexpression in aged mice; m6A-RIP on ACSL4/TFRC mRNAs; ferroptosis assays; in vivo liver transplant model\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct m6A-RIP on specific targets with ferroptosis functional readout in vivo, single lab\",\n      \"pmids\": [\"38834654\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FTO reduces m6A abundance on GPNMB mRNA to stabilize it from YTHDF2-mediated degradation; GPNMB is packaged into small extracellular vesicles from HCC cells and binds the surface receptor SDC4 on CD8+ T cells, inhibiting their activation and enabling immune evasion.\",\n      \"method\": \"FTO knockdown/overexpression in HCC cells; m6A-RIP on GPNMB mRNA; sEV isolation and characterization; SDC4 neutralizing antibody; CD8+ T cell activation assay; in vivo tumor model\",\n      \"journal\": \"Gut\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — m6A-RIP identifies specific mRNA target, functional immune evasion mechanism validated in vitro and in vivo, single lab\",\n      \"pmids\": [\"38839271\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FTO affects endothelial cell function in diabetic retinopathy by modulating CDK2 mRNA stability in an m6A-YTHDF2-dependent manner; elevated FTO (driven by lactate-mediated histone lactylation) reduces m6A on CDK2 mRNA, increasing CDK2 expression, cell cycle progression, and angiogenesis.\",\n      \"method\": \"MeRIP for CDK2 m6A; YTHDF2 knockdown epistasis; histone lactylation ChIP; in vitro EC assays; zebrafish and mouse in vivo models; FB23-2 FTO inhibitor\",\n      \"journal\": \"EMBO molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct m6A-RIP on CDK2, lactylation-FTO regulatory link, in vivo models, single lab\",\n      \"pmids\": [\"38297099\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FTO protein stability is regulated by acetylation: lncRNA HOTAIRM1 interacts with FTO and promotes FTO acetylation, enhancing its stability and demethylase activity, leading to m6A demethylation of CD44 pre-mRNA; reduced m6A on CD44 prevents YTHDC1 recognition and causes a splicing switch from CD44S to CD44V, suppressing ferroptosis and promoting radioresistance.\",\n      \"method\": \"HOTAIRM1-FTO interaction (RIP/pulldown); acetylation assay; m6A-RIP on CD44 mRNA; YTHDC1 knockdown epistasis; alternative splicing analysis; ferroptosis and irradiation assays\",\n      \"journal\": \"Neoplasia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct protein interaction, post-translational modification (acetylation), m6A-RIP and splicing epistasis in single lab\",\n      \"pmids\": [\"39128424\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"FTO CLIP-seq binding peaks contain RRACH motifs; exogenously overexpressed FTO selectively removes m6A from GGACU and RRACU motifs in a concentration-dependent manner, demonstrating sequence-context preferences for FTO demethylation in cells.\",\n      \"method\": \"CLIP-seq analysis across multiple cell lines; FTO overexpression + m6A-seq; motif enrichment analysis\",\n      \"journal\": \"RNA biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CLIP-seq with functional demethylation validation in cells, single lab but five datasets analyzed\",\n      \"pmids\": [\"31149892\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"FTO knockdown in 3T3-L1 pre-adipocytes suppresses proliferation, reduces PPARγ and GLUT4 expression, and inhibits Akt phosphorylation; FTO overexpression has the opposite effect and PI3K inhibition with wortmannin blocks FTO overexpression-driven Akt phosphorylation, placing FTO upstream of PI3K/Akt in adipocyte differentiation.\",\n      \"method\": \"Lentiviral FTO knockdown/overexpression in 3T3-L1; Western blot for PPARγ, GLUT4, phospho-Akt; wortmannin epistasis; proliferation and lipid droplet assays\",\n      \"journal\": \"Nutrients\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic gain/loss-of-function with PI3K inhibitor epistasis and multiple pathway markers, single lab\",\n      \"pmids\": [\"26907332\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"FTO deficiency in mice leads to increased UCP-1 expression in white adipose depots and enhanced mitochondrial uncoupling; FTO-deficient human preadipocytes (lentiviral shRNA) show 4-fold higher UCP-1 in mitochondria and increased uncoupling, revealing that FTO suppresses brown/beige adipocyte programming.\",\n      \"method\": \"Fto-/- mouse adipose tissue analysis; lentiviral shRNA FTO knockdown in human adipocytes; UCP-1 immunostaining; mitochondrial uncoupling assay\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mouse KO and human primary cell KD with direct UCP-1 and mitochondrial functional readout, single lab\",\n      \"pmids\": [\"23751871\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FTO-mediated m6A demethylation of MALAT1 lncRNA in bladder cancer regulates miR-384 and MAL2 expression, promoting bladder cancer tumorigenesis through the MALAT1/miR-384/MAL2 axis.\",\n      \"method\": \"FTO gain/loss-of-function in vitro and in vivo; m6A-RIP on MALAT1; miR-384 and MAL2 expression assays\",\n      \"journal\": \"Clinical and translational medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — m6A-RIP on MALAT1 but mechanistic chain between m6A on MALAT1 and miR-384/MAL2 not fully resolved in abstract, single lab\",\n      \"pmids\": [\"33634966\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"FTO inhibition by GSK3β-mediated ubiquitination-proteasomal degradation: E6E7 oncogene activates GSK3β transcription, GSK3β promotes FTO ubiquitination and decreases FTO protein levels; FTO overexpression retains HK2 pre-mRNA in the nucleus, decreasing mature HK2 cytoplasmic mRNA, suggesting FTO controls HK2 mRNA maturation/export.\",\n      \"method\": \"E6E7 overexpression; GSK3β overexpression and FTO ubiquitination assay; nuclear/cytoplasmic HK2 pre-mRNA fractionation after FTO overexpression; Western blot\",\n      \"journal\": \"Archives of biochemistry and biophysics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — ubiquitination assay and mRNA fractionation, but GSK3β E3 ligase identity not directly confirmed and mechanism of mRNA retention incomplete, single lab\",\n      \"pmids\": [\"36075458\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FTO demethylates m6A on SIRT6 mRNA in cardiomyocytes; FTO silencing increases m6A on SIRT6 mRNA (bound by YTHDF2, leading to mRNA destabilization), decreasing SIRT6 expression and activating mitophagy-related signaling in sepsis-induced cardiac injury.\",\n      \"method\": \"MeRIP on SIRT6 mRNA; YTHDF2 RIP; AAV9-FTO overexpression in LPS mouse model; mitophagy TEM; mitochondrial function assays\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MeRIP on specific target plus YTHDF2 RIP plus in vivo AAV model, single lab\",\n      \"pmids\": [\"39308045\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FTO negatively regulates NK cell cytotoxicity by increasing mRNA stability of SOCS family genes (suppressors of cytokine signaling) via m6A demethylation, dampening IL-2/15-driven JAK/STAT signaling; Fto-/- mouse NK cells show hyperactivation and suppress melanoma metastasis in vivo.\",\n      \"method\": \"Fto KO mouse NK cell functional assays; melanoma metastasis in vivo model; human FTO KD NK cell anti-leukemia assay; SOCS mRNA stability measurement\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO in mice and human KD with defined signaling pathway, in vivo and in vitro concordant, single lab\",\n      \"pmids\": [\"36744362\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FTO demethylates m6A on BNIP3 mRNA in granulosa cells, stabilizing BNIP3 expression and activating autophagy to reduce apoptosis; FTO overexpression decreases BNIP3 expression-driven apoptosis, and FTO inhibition with meclofenamic acid opposes these effects.\",\n      \"method\": \"FTO overexpression/siRNA knockdown in granulosa cells; BNIP3 mRNA and protein measurement; autophagy assays; MA inhibitor treatment\",\n      \"journal\": \"Reproductive biology and endocrinology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — functional link between FTO and BNIP3 via m6A inferred but m6A-RIP not explicitly described in abstract, single lab\",\n      \"pmids\": [\"35219326\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"H. pylori CagA enhances FTO transcription via the transcription factor c-Jun/Jun proto-oncogene; elevated FTO demethylates m6A on HBEGF mRNA, inhibiting its degradation and facilitating EMT in gastric cancer cells; H. pylori eradication does not fully reverse FTO/HBEGF upregulation, but combined antibiotic + FTO inhibitor (MA) treatment suppresses EMT.\",\n      \"method\": \"H. pylori infection of GC cell lines; ChIP for c-Jun at FTO promoter; m6A-RIP-seq on HBEGF mRNA; EMT assays in vitro and in vivo; human GC organoids; MA inhibitor\",\n      \"journal\": \"Cancer communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP, m6A-RIP-seq, and functional EMT assays in multiple model systems including organoids, single lab\",\n      \"pmids\": [\"39960839\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"FTO demethylates m6A on ACSL3 and GPX4 mRNAs to decrease their stability in oral squamous cell carcinoma, thereby sensitizing cells to ferroptosis; FTO overexpression enhances ferroptosis susceptibility in vitro and in vivo.\",\n      \"method\": \"FTO overexpression/knockdown; m6A-RIP on ACSL3 and GPX4 mRNAs; mRNA stability assay; ferroptosis induction assays in vitro and in vivo\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — m6A-RIP on two specific targets with mRNA stability and ferroptosis functional readout, single lab\",\n      \"pmids\": [\"38003537\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"FTO fused to dCas9 (RCas9-FTO) retains m6A demethylase activity and achieves sequence-specific demethylation of m6A in RNA in a guide-RNA and PAM-dependent manner, with up to 15-fold preference for target over off-target RNA; the PAM-to-m6A distance influences demethylation efficiency.\",\n      \"method\": \"RCas9-FTO fusion protein; SCARLET site-specific m6A quantification; in vitro demethylation assay with varying target RNAs\",\n      \"journal\": \"RNA\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — direct in vitro enzymatic tool validation with quantitative m6A measurement, single lab; primarily a tool paper\",\n      \"pmids\": [\"31263003\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FTO overexpression in granulosa cells reduces m6A modification on FLOT2 mRNA, increasing FLOT2 mRNA stability and expression; elevated FLOT2 mediates FTO-driven proliferation, apoptosis suppression, and insulin resistance in granulosa cells.\",\n      \"method\": \"FTO overexpression; meRIP assay on FLOT2 mRNA; actinomycin D mRNA stability assay; RIP assay; FLOT2 knockdown rescue\",\n      \"journal\": \"Reproductive sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — meRIP and stability assay with target-specific rescue, single lab\",\n      \"pmids\": [\"34254281\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FTO co-localizes with and physically interacts with androgen receptor (AR) in granulosa cells (confocal co-localization and Co-IP); FTO knockdown decreases expression of steroid hormone synthetases (CYP11A1, CYP17A1, HSD11B1, HSD3B2) and AR/PSA, reducing androgen production in PCOS models.\",\n      \"method\": \"Co-IP and confocal co-localization of FTO and AR; FTO siRNA knockdown; Western blot for steroidogenic enzymes and AR/PSA; FTO inhibitor (MA) treatment\",\n      \"journal\": \"Gynecological endocrinology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP and co-localization with functional knockdown data, but AR as direct FTO substrate or mechanistic basis of interaction not established, single lab\",\n      \"pmids\": [\"37931646\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FTO demethylates m6A on FOXJ1 mRNA in Xenopus embryos, stabilizing the transcript needed for motile ciliogenesis; FTO also promotes adult neurogenesis in mice by demethylating m6A modifications on BDNF pathway component mRNAs, reducing their degradation.\",\n      \"method\": \"Fto KO mouse; m6A profiling during postnatal neurodevelopment; adult neural stem cell proliferation/differentiation assays; learning/memory behavioral tests\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Fto KO mouse with genome-wide m6A profiling and behavioral readouts, single lab\",\n      \"pmids\": [\"28398475\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Structure-based design identified FTO inhibitors that occupy both the 2-oxoglutarate (2OG) and substrate binding sites of FTO; X-ray crystallography confirmed binding mode and selectivity over PHD2, FIH, and multiple JmjC KDMs.\",\n      \"method\": \"X-ray crystallography of FTO-inhibitor complexes; biochemical turnover and binding assays; selectivity profiling against related 2OG oxygenases\",\n      \"journal\": \"Journal of medicinal chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure with functional binding/turnover assays and selectivity profiling, single lab with rigorous structural validation\",\n      \"pmids\": [\"34762429\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FTO is an Fe(II)- and α-ketoglutarate-dependent dioxygenase (AlkB family) that demethylates N6-methyladenosine (m6A) in mRNA, snRNA, and other RNA species via stepwise oxidation (generating hm6A and f6A intermediates), with substrate selectivity partly determined by the RNA-binding protein SFPQ; it shuttles between the nucleus and cytoplasm (assisted by Exportin 2, regulated by CK2-mediated phosphorylation and acetylation), demethylates specific target mRNAs (including cyclin D1, FOXJ1, RUNX2, PGC-1α, BDNF pathway components, and others) to control their stability, and thereby regulates cell cycle progression, adipogenesis, cardiac function, ciliogenesis, immune cell activity, and cancer cell metabolism—with its activity modulated by NADP binding, ubiquitin-mediated degradation (by STRAP/GSK3β), and small-molecule inhibitors that block its catalytic site.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"FTO is an Fe(II)- and \\u03b1-ketoglutarate-dependent dioxygenase that catalyzes oxidative demethylation of N6-methyladenosine (m6A) in RNA, removing the methyl mark through a stepwise mechanism that generates N6-hydroxymethyladenosine and N6-formyladenosine intermediates [#0]. Beyond canonical mRNA m6A, FTO acts on m6Am in snRNA to set the m1/m2 isoform ratio and shape alternative splicing [#1], and demethylates LINE1 RNA to modulate local chromatin state and gene transcription in stem cells and early embryos [#8]. Its activity is dependent on an intact catalytic center, as the demethylase-dead R316A mutant abolishes its functional effects [#10, #11], and structure-based inhibitors that occupy the 2-oxoglutarate and substrate pockets block catalysis with selectivity over related 2OG oxygenases [#37]. Substrate selectivity in cells is guided by RNA sequence context (RRACH/GGACU motifs) [#23] and by the RNA-binding protein SFPQ, which recruits FTO to specific transcripts for demethylation of adjacent m6A sites [#2]. FTO shuttles between nucleus and cytoplasm, partitioning into nuclear speckles enriched in RNA-processing factors, with shuttling dependent on its N-terminus and the partner Exportin 2, and regulated by CK2-mediated phosphorylation during the cell cycle [#5, #6, #3]. Mechanistically, FTO demethylation typically stabilizes target mRNAs by removing m6A marks that would otherwise direct YTHDF2-dependent decay; through this logic it stabilizes cyclin D1 to drive G1 progression [#3], FOXJ1 to support motile ciliogenesis [#4], and many other transcripts governing cardiac contractile function [#10], adipocyte and mitochondrial programs [#7, #11, #25], neurogenesis [#36], immune cell activity [#14, #29], ferroptosis [#19, #32], and cancer metabolism and progression [#13, #15]. FTO abundance is itself controlled post-translationally by E3-ligase-mediated ubiquitination and proteasomal degradation (STRAP, and a GSK3\\u03b2-linked pathway) [#15, #27], by USP18-mediated deubiquitination [#18], and by acetylation [#22], integrating its m6A-erasing activity into broader physiological and disease signaling.\",\n  \"teleology\": [\n    {\n      \"year\": 2013,\n      \"claim\": \"Established the core enzymatic identity of FTO by showing it is an Fe(II)/\\u03b1-KG dioxygenase that oxidatively demethylates m6A in mRNA via defined reaction intermediates, converting it from a candidate to a bona fide RNA m6A eraser.\",\n      \"evidence\": \"In vitro dioxygenase assay with mass-spectrometric detection of hm6A and f6A intermediates in mammalian mRNA\",\n      \"pmids\": [\"23653210\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not establish endogenous transcript targets or cellular consequences\", \"Substrate selectivity in vivo not addressed\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Resolved where FTO acts by demonstrating it dynamically shuttles between nucleus and cytoplasm and identifying Exportin 2 as a transport-relevant partner, framing FTO as a mobile rather than statically nuclear enzyme.\",\n      \"evidence\": \"Live-cell GFP-FTO imaging, FLIP, proteomic Co-IP, and N-terminal deletion studies\",\n      \"pmids\": [\"25242086\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of shuttling for specific substrates not defined\", \"XPO2 interaction not reciprocally validated\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Broadened the substrate repertoire beyond mRNA m6A by showing FTO controls snRNA m6Am isoform ratios with downstream splicing consequences and is inhibited by the oncometabolite D-2-HG, linking FTO activity to metabolic context.\",\n      \"evidence\": \"snRNA isoform profiling, metabolite inhibition, and splicing analysis\",\n      \"pmids\": [\"30778204\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generality of m6Am vs m6A preference across substrates not quantified\", \"Physiological relevance of D-2-HG inhibition in normal tissue unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined FTO's in-cell substrate logic by showing CLIP-seq peaks enrich RRACH motifs and overexpressed FTO preferentially demethylates GGACU/RRACU sites, establishing sequence-context preference.\",\n      \"evidence\": \"CLIP-seq across multiple cell lines with FTO-overexpression m6A-seq and motif enrichment\",\n      \"pmids\": [\"31149892\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Overexpression may not reflect endogenous occupancy\", \"Does not identify cofactors driving in-cell selectivity\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Provided structural and pharmacological proof of FTO's catalytic pocket as a druggable target, showing inhibitors occupy the 2OG and substrate sites selectively and that catalytic inhibition phenocopies genetic depletion in AML.\",\n      \"evidence\": \"Structure-based inhibitor design (FB23/FB23-2), X-ray crystallography, binding/turnover assays, and AML xenografts\",\n      \"pmids\": [\"30991027\", \"34762429\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo selectivity and toxicity profiles beyond AML not established\", \"Resistance mechanisms not characterized\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified a molecular basis for FTO substrate selectivity by showing the RNA-binding protein SFPQ directly binds FTO and recruits it to specific transcripts for adjacent m6A demethylation.\",\n      \"evidence\": \"Site-specific photocrosslinking, CLIP-seq co-localization, and overexpression-based demethylation assay\",\n      \"pmids\": [\"31981477\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether SFPQ is required for all FTO targets unknown\", \"Structural basis of the FTO-SFPQ interaction not resolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Connected FTO catalysis to cell-cycle control and its own regulation, showing FTO stabilizes cyclin D1 mRNA via demethylation and is driven into the nucleus by CK2 phosphorylation during G1.\",\n      \"evidence\": \"Reciprocal m6A-RIP, mRNA stability assay, KO cell-cycle phenotype, and CK2 phosphorylation/translocation mapping\",\n      \"pmids\": [\"32268083\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"CK2 phospho-sites' direct effect on enzymatic activity vs localization not separated\", \"Other cell-cycle targets not enumerated\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Revealed metabolic regulation of FTO by showing NADP directly binds and enhances its demethylase activity and is required for NADP-driven adipogenesis, coupling cofactor availability to m6A erasure.\",\n      \"evidence\": \"Fluorescence-quenching binding assay, in vitro activity assay, and FTO-KO adipogenesis rescue\",\n      \"pmids\": [\"32719557\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural site of NADP binding not defined\", \"Quantitative contribution of NADP to in vivo activity unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Used a catalytic-dead control (R316A) to establish that FTO's effects on hepatocyte mitochondrial content and triglyceride deposition are causally driven by m6A demethylation rather than scaffolding.\",\n      \"evidence\": \"WT vs R316A overexpression in hepatocytes with mitochondrial/TG and m6A measurements\",\n      \"pmids\": [\"29384213\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific mRNA targets in hepatocytes not identified\", \"Single experimental system\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrated a conserved developmental role by showing FTO stabilizes FOXJ1 mRNA to drive motile ciliogenesis across species, with loss producing cilia defects and asthma-like phenotypes.\",\n      \"evidence\": \"Loss-of-function in Xenopus, human airway epithelium, and Fto-KO mouse allergen model with FOXJ1 stability assays\",\n      \"pmids\": [\"33761320\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"m6A reader mediating FOXJ1 decay not specified here\", \"Link between cilia defect and asthma phenotype mechanistically indirect\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Established FTO's role in cardiac function with rigorous catalytic-mutant controls, showing demethylase-active but not R316A FTO stabilizes contractile transcripts and improves post-ischemic function.\",\n      \"evidence\": \"AAV9 FTO overexpression in mouse MI, m6A-RIP-seq, R316A mutant, and contractility/calcium measurements\",\n      \"pmids\": [\"29997116\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full set of cardiac target transcripts not exhaustively defined\", \"Translation to human heart failure therapy untested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Extended FTO function to chromatin regulation by showing it demethylates LINE1 RNA to control its abundance and local chromatin state, influencing gene transcription in stem cells and embryos.\",\n      \"evidence\": \"m6A-seq in Fto-KO mESCs with LINE1 abundance, chromatin-state, and embryonic developmental readouts\",\n      \"pmids\": [\"35511947\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism coupling LINE1 RNA m6A to chromatin not fully resolved\", \"Reader proteins for LINE1 m6A unidentified\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Consolidated the dominant mechanistic motif: FTO demethylation antagonizes YTHDF2-mediated decay, with FTO/YTHDF2 epistasis controlling target mRNA stability across macrophage polarization, osteogenic, and other contexts.\",\n      \"evidence\": \"mRNA stability assays with YTHDF2 double-knockdown epistasis (STAT1/PPAR-\\u03b3, RUNX2) and NF-\\u03baB pathway analysis\",\n      \"pmids\": [\"32018056\", \"36084732\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct m6A occupancy at all implicated targets not always shown\", \"Reader specificity (YTHDF2 vs others) context-dependent\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined post-translational control of FTO abundance by showing STRAP ubiquitinates FTO at K216 under hypoxia for degradation, with downstream consequences for m6A-dependent metastasis programs.\",\n      \"evidence\": \"Ubiquitination assay with K216 mutagenesis, E3 ligase identification, and m6A-RIP/IGF2BP2 RIP metastasis assays\",\n      \"pmids\": [\"34218271\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Generality of K216 ubiquitination beyond colorectal cancer unknown\", \"Relationship to other FTO degradation routes unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Expanded the FTO regulatory network by identifying deubiquitination (USP18) and acetylation (HOTAIRM1-driven) as stabilizing modifications that tune FTO activity in ischemic and radioresistance contexts.\",\n      \"evidence\": \"Co-IP, MeRIP, RIP epistasis, splicing analysis, and in vivo disease models\",\n      \"pmids\": [\"38340205\", \"39128424\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Acetylation site(s) and their effect on catalysis not mapped\", \"Interplay among ubiquitination, deubiquitination, and acetylation not integrated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Positioned FTO as a regulator of ferroptosis and immune evasion by demethylating distinct target mRNAs (ACSL4/TFRC, ACSL3/GPX4, CD44, GPNMB) to either suppress or sensitize ferroptosis and to control CD8+ T cell activation across tissue contexts.\",\n      \"evidence\": \"m6A-RIP on specific targets, ferroptosis assays, sEV/SDC4 immune assays, and in vivo disease models\",\n      \"pmids\": [\"38834654\", \"38003537\", \"38839271\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Context-dependent (pro- vs anti-ferroptotic) outcomes not mechanistically reconciled\", \"Single-lab target validations\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how FTO's broad in-cell target selectivity is determined across tissues, and how its many post-translational regulators (phosphorylation, ubiquitination, deubiquitination, acetylation) and cofactors (NADP) are coordinately integrated to direct context-specific m6A erasure.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking recruitment cofactors (SFPQ) to tissue-specific targets\", \"Quantitative hierarchy among regulatory PTMs unknown\", \"Distinction between m6A vs m6Am vs ncRNA substrate preference in vivo unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [0, 1, 7, 37]},\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [0, 1, 8, 23, 33]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [2, 23]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 37]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [3, 5, 6]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 1, 2, 8]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [9, 13, 15, 31]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [14, 29, 13, 20]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [19, 30, 32]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"SFPQ\", \"XPO2\", \"AR\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}