Affinage

FTO

Alpha-ketoglutarate-dependent dioxygenase FTO · UniProt Q9C0B1

Length
505 aa
Mass
58.3 kDa
Annotated
2026-06-09
100 papers in source corpus 38 papers cited in narrative 38 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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.

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 2013 High

    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

    PMID:23653210

    Open questions at the time
    • Does not establish endogenous transcript targets or cellular consequences
    • Substrate selectivity in vivo not addressed
  2. 2014 Medium

    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

    PMID:25242086

    Open questions at the time
    • Functional consequence of shuttling for specific substrates not defined
    • XPO2 interaction not reciprocally validated
  3. 2019 High

    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

    PMID:30778204

    Open questions at the time
    • Generality of m6Am vs m6A preference across substrates not quantified
    • Physiological relevance of D-2-HG inhibition in normal tissue unclear
  4. 2019 Medium

    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

    PMID:31149892

    Open questions at the time
    • Overexpression may not reflect endogenous occupancy
    • Does not identify cofactors driving in-cell selectivity
  5. 2019 High

    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

    PMID:30991027 PMID:34762429

    Open questions at the time
    • In vivo selectivity and toxicity profiles beyond AML not established
    • Resistance mechanisms not characterized
  6. 2020 High

    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

    PMID:31981477

    Open questions at the time
    • Whether SFPQ is required for all FTO targets unknown
    • Structural basis of the FTO-SFPQ interaction not resolved
  7. 2020 High

    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

    PMID:32268083

    Open questions at the time
    • CK2 phospho-sites' direct effect on enzymatic activity vs localization not separated
    • Other cell-cycle targets not enumerated
  8. 2020 High

    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

    PMID:32719557

    Open questions at the time
    • Structural site of NADP binding not defined
    • Quantitative contribution of NADP to in vivo activity unclear
  9. 2018 Medium

    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

    PMID:29384213

    Open questions at the time
    • Specific mRNA targets in hepatocytes not identified
    • Single experimental system
  10. 2021 High

    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

    PMID:33761320

    Open questions at the time
    • m6A reader mediating FOXJ1 decay not specified here
    • Link between cilia defect and asthma phenotype mechanistically indirect
  11. 2019 High

    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

    PMID:29997116

    Open questions at the time
    • Full set of cardiac target transcripts not exhaustively defined
    • Translation to human heart failure therapy untested
  12. 2022 High

    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

    PMID:35511947

    Open questions at the time
    • Mechanism coupling LINE1 RNA m6A to chromatin not fully resolved
    • Reader proteins for LINE1 m6A unidentified
  13. 2021 Medium

    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

    PMID:32018056 PMID:36084732

    Open questions at the time
    • Direct m6A occupancy at all implicated targets not always shown
    • Reader specificity (YTHDF2 vs others) context-dependent
  14. 2021 Medium

    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

    PMID:34218271

    Open questions at the time
    • Generality of K216 ubiquitination beyond colorectal cancer unknown
    • Relationship to other FTO degradation routes unclear
  15. 2024 Medium

    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

    PMID:38340205 PMID:39128424

    Open questions at the time
    • Acetylation site(s) and their effect on catalysis not mapped
    • Interplay among ubiquitination, deubiquitination, and acetylation not integrated
  16. 2024 Medium

    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

    PMID:38003537 PMID:38834654 PMID:38839271

    Open questions at the time
    • Context-dependent (pro- vs anti-ferroptotic) outcomes not mechanistically reconciled
    • Single-lab target validations

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140098 catalytic activity, acting on RNA 5 GO:0016491 oxidoreductase activity 4 GO:0003723 RNA binding 2 GO:0016787 hydrolase activity 2
Localization
GO:0005634 nucleus 3 GO:0005654 nucleoplasm 1 GO:0005829 cytosol 1
Pathway
R-HSA-1643685 Disease 4 R-HSA-168256 Immune System 4 R-HSA-8953854 Metabolism of RNA 4 R-HSA-5357801 Programmed Cell Death 3 R-HSA-1640170 Cell Cycle 1
Partners
ARSFPQXPO2

Evidence

Reading pass · 38 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2013 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. In vitro biochemical assay with Fe(II)/α-KG-dependent dioxygenase activity measurement; detection of hm6A and f6A in mammalian mRNA by mass spectrometry Nature communications High 23653210
2019 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. Biochemical snRNA isoform profiling; FTO inhibition by D-2-hydroxyglutarate; alternative splicing analysis in cells with altered FTO activity Nature chemical biology High 30778204
2020 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. Genetically encoded site-specific photocrosslinking; CLIP-seq co-localization; overexpression-based m6A demethylation assay Cell chemical biology High 31981477
2020 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. 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 Cell reports High 32268083
2021 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. Xenopus loss-of-function; human airway epithelium FTO knockdown; Fto KO mouse allergen model; mRNA stability assay for FOXJ1 Developmental cell High 33761320
2014 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. Live-cell GFP-FTO imaging; FLIP; proteomic Co-IP identifying XPO2; N-terminal deletion studies Bioscience reports Medium 25242086
2012 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. Immunocytochemistry; confocal laser scanning microscopy; RNA modification analysis (nucleotide ratio measurements) European journal of human genetics Medium 22872099
2020 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. Fluorescence quenching binding assay; in vitro demethylation assay; FTO KO adipogenesis rescue experiment Nature chemical biology High 32719557
2022 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. m6A-seq in Fto KO mESCs; LINE1 RNA abundance and chromatin state measurement; oocyte and embryo developmental analysis Science High 35511947
2019 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. Structure-based inhibitor design; direct binding assay; m6A demethylase activity assay; AML cell line and primary blast cell proliferation/differentiation assay; xenograft mouse model Cancer cell High 30991027
2019 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. AAV9-mediated FTO overexpression in mouse MI model; m6A-RIP-seq; siRNA knockdown; FTO R316A mutant (demethylase-dead) functional assay; cardiomyocyte calcium/contractility measurements Circulation High 29997116
2018 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. FTO wild-type vs. R316A mutant overexpression in hepatocytes; mitochondrial content and TG measurement; m6A quantification Journal of cellular biochemistry Medium 29384213
2019 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. FTO overexpression in VHL-deficient cells; m6A-RIP on PGC-1α mRNA; mitochondrial activity and ROS assays; in vivo tumor growth Journal of cellular and molecular medicine Medium 30648791
2021 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. FTO knockdown in tumor cells; metabolic flux assays; CD8+ T cell functional assays; Dac51 inhibitor treatment; checkpoint blockade combination in vivo Cell metabolism Medium 33910046
2020 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. FTO siRNA knockdown; actinomycin D mRNA stability assay; YTHDF2 knockdown epistasis; NF-κB pathway phosphorylation Western blot Cellular signalling Medium 32018056
2021 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. 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 Oncogene Medium 34218271
2022 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. 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 Biochimica et biophysica acta. Molecular cell research Medium 36084732
2021 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. Intestinal epithelial-specific Fto KO (Villin-Cre); m6A-RIP-seq; CerS6 mRNA stability; S1P measurement; macrophage co-culture; Th17 differentiation assay Gut High 37734910
2024 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. Co-IP for USP18-FTO interaction; MeRIP for SIRT6 m6A; YTHDF2 RIP; in vivo MCAO rat model with AAV-USP18/FTO; neurological behavior scoring Molecular neurobiology Medium 38340205
2024 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. Mass spectrometry proteomics; FTO overexpression in aged mice; m6A-RIP on ACSL4/TFRC mRNAs; ferroptosis assays; in vivo liver transplant model Nature communications Medium 38834654
2024 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. 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 Gut Medium 38839271
2024 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. MeRIP for CDK2 m6A; YTHDF2 knockdown epistasis; histone lactylation ChIP; in vitro EC assays; zebrafish and mouse in vivo models; FB23-2 FTO inhibitor EMBO molecular medicine Medium 38297099
2024 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. HOTAIRM1-FTO interaction (RIP/pulldown); acetylation assay; m6A-RIP on CD44 mRNA; YTHDC1 knockdown epistasis; alternative splicing analysis; ferroptosis and irradiation assays Neoplasia Medium 39128424
2019 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. CLIP-seq analysis across multiple cell lines; FTO overexpression + m6A-seq; motif enrichment analysis RNA biology Medium 31149892
2016 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. Lentiviral FTO knockdown/overexpression in 3T3-L1; Western blot for PPARγ, GLUT4, phospho-Akt; wortmannin epistasis; proliferation and lipid droplet assays Nutrients Medium 26907332
2015 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. Fto-/- mouse adipose tissue analysis; lentiviral shRNA FTO knockdown in human adipocytes; UCP-1 immunostaining; mitochondrial uncoupling assay Endocrinology Medium 23751871
2021 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. FTO gain/loss-of-function in vitro and in vivo; m6A-RIP on MALAT1; miR-384 and MAL2 expression assays Clinical and translational medicine Low 33634966
2022 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. E6E7 overexpression; GSK3β overexpression and FTO ubiquitination assay; nuclear/cytoplasmic HK2 pre-mRNA fractionation after FTO overexpression; Western blot Archives of biochemistry and biophysics Low 36075458
2021 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. MeRIP on SIRT6 mRNA; YTHDF2 RIP; AAV9-FTO overexpression in LPS mouse model; mitophagy TEM; mitochondrial function assays Journal of cellular physiology Medium 39308045
2023 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. Fto KO mouse NK cell functional assays; melanoma metastasis in vivo model; human FTO KD NK cell anti-leukemia assay; SOCS mRNA stability measurement EMBO reports Medium 36744362
2021 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. FTO overexpression/siRNA knockdown in granulosa cells; BNIP3 mRNA and protein measurement; autophagy assays; MA inhibitor treatment Reproductive biology and endocrinology Low 35219326
2025 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. 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 Cancer communications Medium 39960839
2022 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. FTO overexpression/knockdown; m6A-RIP on ACSL3 and GPX4 mRNAs; mRNA stability assay; ferroptosis induction assays in vitro and in vivo International journal of molecular sciences Medium 38003537
2019 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. RCas9-FTO fusion protein; SCARLET site-specific m6A quantification; in vitro demethylation assay with varying target RNAs RNA Medium 31263003
2021 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. FTO overexpression; meRIP assay on FLOT2 mRNA; actinomycin D mRNA stability assay; RIP assay; FLOT2 knockdown rescue Reproductive sciences Medium 34254281
2023 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. 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 Gynecological endocrinology Low 37931646
2021 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. Fto KO mouse; m6A profiling during postnatal neurodevelopment; adult neural stem cell proliferation/differentiation assays; learning/memory behavioral tests Human molecular genetics Medium 28398475
2021 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. X-ray crystallography of FTO-inhibitor complexes; biochemical turnover and binding assays; selectivity profiling against related 2OG oxygenases Journal of medicinal chemistry High 34762429

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2015 FTO Obesity Variant Circuitry and Adipocyte Browning in Humans. The New England journal of medicine 1029 26287746
2019 Small-Molecule Targeting of Oncogenic FTO Demethylase in Acute Myeloid Leukemia. Cancer cell 730 30991027
2020 Targeting FTO Suppresses Cancer Stem Cell Maintenance and Immune Evasion. Cancer cell 631 32531268
2019 FTO-Dependent N6-Methyladenosine Regulates Cardiac Function During Remodeling and Repair. Circulation 505 29997116
2013 The bigger picture of FTO: the first GWAS-identified obesity gene. Nature reviews. Endocrinology 475 24247219
2013 FTO-mediated formation of N6-hydroxymethyladenosine and N6-formyladenosine in mammalian RNA. Nature communications 385 23653210
2021 Tumors exploit FTO-mediated regulation of glycolytic metabolism to evade immune surveillance. Cell metabolism 302 33910046
2017 Fat mass and obesity-associated (FTO) protein regulates adult neurogenesis. Human molecular genetics 258 28398475
2010 The genetics of obesity: FTO leads the way. Trends in genetics : TIG 258 20381893
2022 FTO mediates LINE1 m6A demethylation and chromatin regulation in mESCs and mouse development. Science (New York, N.Y.) 242 35511947
2019 FTO controls reversible m6Am RNA methylation during snRNA biogenesis. Nature chemical biology 232 30778204
2008 The FTO gene and measured food intake in children. International journal of obesity (2005) 227 18838977
2022 FTO in cancer: functions, molecular mechanisms, and therapeutic implications. Trends in cancer 210 35346615
2020 N6-methyladenosine demethylase FTO promotes M1 and M2 macrophage activation. Cellular signalling 162 32018056
2022 FTO m6A Demethylase in Obesity and Cancer: Implications and Underlying Molecular Mechanisms. International journal of molecular sciences 160 35409166
2014 FTO and obesity: mechanisms of association. Current diabetes reports 147 24627050
2019 N6-methyladenosine demethylase FTO suppresses clear cell renal cell carcinoma through a novel FTO-PGC-1α signalling axis. Journal of cellular and molecular medicine 137 30648791
2015 The 'Fat Mass and Obesity Related' (FTO) gene: Mechanisms of Impact on Obesity and Energy Balance. Current obesity reports 125 26627093
2021 FTO downregulation mediated by hypoxia facilitates colorectal cancer metastasis. Oncogene 123 34218271
2018 FTO reduces mitochondria and promotes hepatic fat accumulation through RNA demethylation. Journal of cellular biochemistry 122 29384213
2020 FTO - A Common Genetic Basis for Obesity and Cancer. Frontiers in genetics 117 33304380
2024 Lactylation-driven FTO targets CDK2 to aggravate microvascular anomalies in diabetic retinopathy. EMBO molecular medicine 114 38297099
2021 FTO modifies the m6A level of MALAT and promotes bladder cancer progression. Clinical and translational medicine 114 33634966
2022 FTO Prevents Thyroid Cancer Progression by SLC7A11 m6A Methylation in a Ferroptosis-Dependent Manner. Frontiers in endocrinology 109 35721711
2018 Fat Mass and Obesity Associated (FTO) Gene and Hepatic Glucose and Lipid Metabolism. Nutrients 108 30388740
2020 NADP modulates RNA m6A methylation and adipogenesis via enhancing FTO activity. Nature chemical biology 105 32719557
2018 Critical Enzymatic Functions of FTO in Obesity and Cancer. Frontiers in endocrinology 105 30105001
2018 Novel positioning from obesity to cancer: FTO, an m6A RNA demethylase, regulates tumour progression. Journal of cancer research and clinical oncology 101 30465076
2013 FTO deficiency induces UCP-1 expression and mitochondrial uncoupling in adipocytes. Endocrinology 78 23751871
2023 Arbutin alleviates fatty liver by inhibiting ferroptosis via FTO/SLC7A11 pathway. Redox biology 77 37984229
2016 Hypomorphism of Fto and Rpgrip1l causes obesity in mice. The Journal of clinical investigation 77 27064284
2014 Obesity and FTO: Changing Focus at a Complex Locus. Cell metabolism 76 25448700
2020 FTO Demethylates Cyclin D1 mRNA and Controls Cell-Cycle Progression. Cell reports 75 32268083
2014 Fat mass and obesity-related (FTO) shuttles between the nucleus and cytoplasm. Bioscience reports 72 25242086
2024 FTO deficiency in older livers exacerbates ferroptosis during ischaemia/reperfusion injury by upregulating ACSL4 and TFRC. Nature communications 70 38834654
2014 Single nucleotide polymorphisms of the FTO gene and cancer risk: an overview. Molecular biology reports 68 25387436
2011 From GWAS to biology: lessons from FTO. Annals of the New York Academy of Sciences 67 21388413
2011 FTO is expressed in neurones throughout the brain and its expression is unaltered by fasting. PloS one 66 22140494
2023 LncRNA FTO-IT1 promotes glycolysis and progression of hepatocellular carcinoma through modulating FTO-mediated N6-methyladenosine modification on GLUT1 and PKM2. Journal of experimental & clinical cancer research : CR 62 37840133
2022 Studies on the fat mass and obesity-associated (FTO) gene and its impact on obesity-associated diseases. Genes & diseases 62 37554175
2015 Milk: an epigenetic amplifier of FTO-mediated transcription? Implications for Western diseases. Journal of translational medicine 62 26691922
2019 Loss of Endothelial FTO Antagonizes Obesity-Induced Metabolic and Vascular Dysfunction. Circulation research 60 31801409
2010 Where to go with FTO? Trends in endocrinology and metabolism: TEM 60 21131211
2017 FTO associations with obesity and telomere length. Journal of biomedical science 56 28859657
2024 Targeting the oncogenic m6A demethylase FTO suppresses tumourigenesis and potentiates immune response in hepatocellular carcinoma. Gut 54 38839271
2014 The fat mass and obesity-associated (FTO) gene: Obesity and beyond? Biochimica et biophysica acta 54 24518103
2012 FTO levels affect RNA modification and the transcriptome. European journal of human genetics : EJHG 54 22872099
2020 FTO Facilitates Lung Adenocarcinoma Cell Progression by Activating Cell Migration Through mRNA Demethylation. OncoTargets and therapy 50 32110044
2024 Disruption of CerS6-mediated sphingolipid metabolism by FTO deficiency aggravates ulcerative colitis. Gut 48 37734910
2019 The dynamics of FTO binding and demethylation from the m6A motifs. RNA biology 47 31149892
2013 The biology of FTO: from nucleic acid demethylase to amino acid sensor. Diabetologia 46 23896822
2021 Targeting the RNA demethylase FTO for cancer therapy. RSC chemical biology 44 34704042
2019 Sequence-specific m6A demethylation in RNA by FTO fused to RCas9. RNA (New York, N.Y.) 42 31263003
2020 The Potential Role of N6-Methyladenosine (m6A) Demethylase Fat Mass and Obesity-Associated Gene (FTO) in Human Cancers. OncoTargets and therapy 41 33364780
2021 N6-methyladenosine Demethylase FTO Induces the Dysfunctions of Ovarian Granulosa Cells by Upregulating Flotillin 2. Reproductive sciences (Thousand Oaks, Calif.) 36 34254281
2020 SFPQ Is an FTO-Binding Protein that Facilitates the Demethylation Substrate Preference. Cell chemical biology 36 31981477
2020 Decreased expression of m6A demethylase FTO in ovarian aging. Archives of gynecology and obstetrics 36 33221958
2023 FTO Sensitizes Oral Squamous Cell Carcinoma to Ferroptosis via Suppressing ACSL3 and GPX4. International journal of molecular sciences 35 38003537
2021 RNA demethylation by FTO stabilizes the FOXJ1 mRNA for proper motile ciliogenesis. Developmental cell 35 33761320
2023 Emerging Role and Mechanism of the FTO Gene in Cardiovascular Diseases. Biomolecules 32 37238719
2013 Common variant of FTO gene, rs9939609, and obesity in Pakistani females. BioMed research international 32 24102053
2023 FTO negatively regulates the cytotoxic activity of natural killer cells. EMBO reports 31 36744362
2019 FTO: An Emerging Molecular Player in Neuropsychiatric Diseases. Neuroscience 31 31442565
2015 Pharmacological inhibition of FTO. PloS one 31 25830347
2024 USP18 Stabilized FTO Protein to Activate Mitophagy in Ischemic Stroke Through Repressing m6A Modification of SIRT6. Molecular neurobiology 30 38340205
2024 A covalent compound selectively inhibits RNA demethylase ALKBH5 rather than FTO. RSC chemical biology 30 38576724
2022 Emerging Roles of FTO in Neuropsychiatric Disorders. BioMed research international 30 35528183
2020 Association between FTO gene polymorphisms and breast cancer: the role of estrogen. Expert review of endocrinology & metabolism 30 32089015
2016 The Fto Gene Regulates the Proliferation and Differentiation of Pre-Adipocytes in Vitro. Nutrients 30 26907332
2023 FTO: a critical role in obesity and obesity-related diseases. The British journal of nutrition 29 36944362
2022 Discovery of novel mRNA demethylase FTO inhibitors against esophageal cancer. Journal of enzyme inhibition and medicinal chemistry 29 35833378
2018 The Fat Mass- and Obesity-Associated (FTO) Gene to Obesity: Lessons from Mouse Models. Obesity (Silver Spring, Md.) 29 30311736
2023 Potential Roles of m6A and FTO in Synaptic Connectivity and Major Depressive Disorder. International journal of molecular sciences 28 37047192
2022 Oncogenic and Tumor-Suppressive Functions of the RNA Demethylase FTO. Cancer research 28 35303057
2014 Association between fat mass- and obesity-associated (FTO) gene polymorphism and polycystic ovary syndrome: a meta-analysis. PloS one 28 24466303
2022 FGF2 Is Protective Towards Cisplatin-Induced KGN Cell Toxicity by Promoting FTO Expression and Autophagy. Frontiers in endocrinology 27 35784556
2023 The rs1421085 variant within FTO promotes brown fat thermogenesis. Nature metabolism 26 37460841
2012 FTO, RNA epigenetics and epilepsy. Epigenetics 26 22948233
2021 The multifaceted functions of the Fat mass and Obesity-associated protein (FTO) in normal and cancer cells. RNA biology 25 35067178
2010 Expression studies of the obesity candidate gene FTO in pig. Animal biotechnology 24 20024787
2022 FTO protects human granulosa cells from chemotherapy-induced cytotoxicity. Reproductive biology and endocrinology : RB&E 23 35219326
2021 Roles of N6-Methyladenosine Demethylase FTO in Malignant Tumors Progression. OncoTargets and therapy 23 34556998
2024 FTO in health and disease. Frontiers in cell and developmental biology 22 39744011
2015 Fatmass and obesity associated (FTO) gene regulates gluconeogenesis in chicken embryo fibroblast cells. Comparative biochemistry and physiology. Part A, Molecular & integrative physiology 22 25465531
2013 Programming effects of FTO in the development of obesity. Acta physiologica (Oxford, England) 22 24219661
2024 LncRNA HOTAIRM1 promotes radioresistance in nasopharyngeal carcinoma by modulating FTO acetylation-dependent alternative splicing of CD44. Neoplasia (New York, N.Y.) 21 39128424
2022 Targeting FTO Suppresses Pancreatic Carcinogenesis via Regulating Stem Cell Maintenance and EMT Pathway. Cancers 21 36497402
2023 N6-methyladenosine demethylase FTO related to hyperandrogenism in PCOS via AKT pathway. Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology 20 37931646
2022 E6E7 regulates the HK2 expression in cervical cancer via GSK3β/FTO signal. Archives of biochemistry and biophysics 20 36075458
2024 Fat mass and obesity-associated protein (FTO) mediated m6A modification of circFAM192A promoted gastric cancer proliferation by suppressing SLC7A5 decay. Molecular biomedicine 19 38556586
2024 Discovery of a potent PROTAC degrader for RNA demethylase FTO as antileukemic therapy. Acta pharmaceutica Sinica. B 19 39807332
2021 Structure-Based Design of Selective Fat Mass and Obesity Associated Protein (FTO) Inhibitors. Journal of medicinal chemistry 19 34762429
2024 N6-methyladenosine demethyltransferase FTO alleviates sepsis by upregulating BNIP3 to induce mitophagy. Journal of cellular physiology 18 39308045
2023 FTO Gene Polymorphisms at the Crossroads of Metabolic Pathways of Obesity and Epigenetic Influences. Food technology and biotechnology 18 37200795
2023 Association of FTO gene variant rs9939609 with polycystic ovary syndrome from Gujarat, India. BMC medical genomics 18 37710301
2022 FTO/RUNX2 signaling axis promotes cementoblast differentiation under normal and inflammatory condition. Biochimica et biophysica acta. Molecular cell research 17 36084732
2014 GNB3 and FTO Polymorphisms and Pregnancy Weight Gain in Black Women. Biological research for nursing 17 25510251
2013 Association between fat-mass-and-obesity-associated (FTO) gene and hip fracture susceptibility. Clinical endocrinology 17 24106974
2025 Helicobacter pylori CagA elevates FTO to induce gastric cancer progression via a "hit-and-run" paradigm. Cancer communications (London, England) 16 39960839
2023 m6A demethylase FTO and osteoporosis: potential therapeutic interventions. Frontiers in cell and developmental biology 16 38020896

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