{"gene":"YTHDF2","run_date":"2026-04-28T23:00:23","timeline":{"discoveries":[{"year":2019,"finding":"YTHDF2 binds m6A-modified mRNAs and decreases their half-life; in AML, YTHDF2 targets include Tnfrsf2 (TNF receptor) mRNA, whose upregulation upon Ythdf2 deficiency primes leukemic stem cells for apoptosis.","method":"m6A-seq, RNA stability assays, conditional knockout mouse models, human AML xenograft transplantation","journal":"Cell stem cell","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (m6A-seq, KO mouse, xenograft), independent functional validation of target","pmids":["31031138"],"is_preprint":false},{"year":2018,"finding":"YTHDF2 directly binds m6A modification sites in the EGFR 3'-UTR and promotes EGFR mRNA degradation, suppressing MEK/ERK activation in hepatocellular carcinoma cells.","method":"m6A-RIP, RNA stability assay, overexpression/knockdown with downstream signaling readouts","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 — single lab, multiple complementary assays (m6A-RIP + stability + signaling)","pmids":["30423408"],"is_preprint":false},{"year":2019,"finding":"YTHDF2 promotes decay of m6A-containing IL11 and SERPINE2 mRNAs in hepatocytes, and its transcription is repressed by HIF-2α; administration of a HIF-2α antagonist restores YTHDF2-dependent mRNA decay.","method":"m6A-IP with high-throughput sequencing, RNA stability assay, conditional hepatocyte knockout, HIF-2α antagonist (PT2385) treatment","journal":"Molecular cancer","confidence":"High","confidence_rationale":"Tier 2 — multi-omic m6A profiling plus in vivo KO plus pharmacological epistasis","pmids":["31735169"],"is_preprint":false},{"year":2021,"finding":"EGFR/SRC/ERK signaling phosphorylates YTHDF2 at serine 39 and threonine 381, stabilizing YTHDF2 protein; stabilized YTHDF2 promotes m6A-dependent decay of LXRA and HIVEP2 mRNAs in glioblastoma.","method":"Phosphorylation mapping by mass spectrometry, site-directed mutagenesis, RIP, m6A sequencing, in vivo tumorigenesis assay","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1/2 — MS-identified phosphosites validated by mutagenesis, multiple downstream functional assays","pmids":["33420027"],"is_preprint":false},{"year":2018,"finding":"Conditional knockout of mouse Ythdf2 increases HSC numbers; knockdown of human YTHDF2 expands cord blood HSCs ex vivo by stabilizing m6A-marked mRNAs encoding transcription factors (e.g., Tal1) critical for self-renewal.","method":"Conditional KO mouse, limiting dilution transplantation, m6A-seq in HSPCs, siRNA knockdown rescue","journal":"Cell research","confidence":"High","confidence_rationale":"Tier 2 — in vivo KO plus human ex vivo expansion plus m6A-seq plus epistasis rescue","pmids":["30065315"],"is_preprint":false},{"year":2021,"finding":"YTHDF2 is SUMOylated in vivo and in vitro at K571; SUMOylation (induced by hypoxia) increases YTHDF2 binding affinity for m6A-modified mRNAs without affecting ubiquitination or localization, leading to enhanced mRNA degradation.","method":"In vitro SUMOylation assay, in vivo SUMOylation, site-directed mutagenesis (K571), m6A-RIP, mRNA stability assay","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution of SUMOylation, mutagenesis of SUMOylation site, functional binding assay","pmids":["33577677"],"is_preprint":false},{"year":2021,"finding":"FBW7 E3 ubiquitin ligase directly interacts with YTHDF2, inducing its proteasomal degradation and thereby reducing YTHDF2-mediated BMF mRNA decay in ovarian cancer.","method":"IP-mass spectrometry, co-IP, western blot, in vitro and in vivo tumorigenesis assays, m6A-RIP-seq, RNA-seq","journal":"Molecular cancer","confidence":"High","confidence_rationale":"Tier 1/2 — MS identification of interaction, co-IP validation, functional rescue experiments","pmids":["33658012"],"is_preprint":false},{"year":2019,"finding":"YTHDF2 recognizes N1-methyladenosine (m1A)-modified sequences in addition to m6A; YTHDF2 depletion increases abundance of endogenously m1A-modified transcripts, indicating YTHDF2-dependent destabilization of m1A-containing mRNAs.","method":"Chemical proteomics pulldown, recombinant protein binding assay, YTHDF2 knockdown with transcript-level quantification","journal":"ACS chemical biology","confidence":"Medium","confidence_rationale":"Tier 2 — biochemical binding characterization plus cellular loss-of-function, but single lab","pmids":["31815430"],"is_preprint":false},{"year":2020,"finding":"YTHDF2 promotes mRNA decay of WEE1 (a negative cell cycle regulator containing m6A) to accelerate mitotic entry; CDK1 activity stabilizes YTHDF2 protein, forming a CDK1–YTHDF2–WEE1 feedforward loop; CUL1, CUL4A, DDB1, and SKP2 E3 ligase components mediate YTHDF2 proteolysis.","method":"YTHDF2 siRNA depletion, m6A-seq, RNA stability assay, CDK1 inhibitor treatment, co-IP with E3 components","journal":"PLoS biology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods, pharmacological and genetic epistasis, E3 complex identification by co-IP","pmids":["32267835"],"is_preprint":false},{"year":2020,"finding":"YTHDF2 and YTHDF3 are both required for somatic cell reprogramming; YTHDF2 recruits the CCR4-NOT deadenylase complex to promote deadenylation and mRNA clearance of somatic genes (e.g., Tead2, Tgfb1), facilitating mesenchymal-to-epithelial transition during iPSC generation.","method":"CRISPR/siRNA KD of Ythdf2/3 in reprogramming assay, scRNA-seq, co-IP with CCR4-NOT, mRNA stability assay","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 — genetic requirement shown, CCR4-NOT interaction validated by co-IP, target mRNAs identified by sequencing","pmids":["32905781"],"is_preprint":false},{"year":2021,"finding":"YTHDF2 recognizes m6A-modified PER1 and TP53 mRNAs and promotes their degradation, contributing to ocular melanoma tumorigenesis driven by elevated histone lactylation.","method":"m6A-RIP, RNA stability assay, overexpression/knockdown in vitro and in vivo","journal":"Genome biology","confidence":"Medium","confidence_rationale":"Tier 2 — direct m6A-RIP on specific targets plus functional rescue, single lab","pmids":["33726814"],"is_preprint":false},{"year":2021,"finding":"YTHDF2 is required for TNBC cell survival; disrupting YTHDF2-dependent mRNA degradation stabilizes MAPK pathway mRNAs, inducing EMT and increasing global translation, ultimately causing ER stress-induced apoptosis.","method":"Pooled CRISPR-Cas9 screen, eCLIP, m6A-seq, scRibo-STAMP, in vivo tumor models","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1/2 — CRISPR screen plus eCLIP mapping plus ribosome profiling at single-cell resolution","pmids":["34216543"],"is_preprint":false},{"year":2023,"finding":"O-GlcNAcylation of YTHDF2 at serine 263 (by OGT) enhances its protein stability by inhibiting ubiquitination; O-GlcNAcylated YTHDF2 stabilizes MCM2 and MCM5 mRNAs in an m6A-dependent manner to promote cell cycle progression.","method":"Co-IP, mass spectrometry, site-directed mutagenesis (S263), OGT inhibitor treatment, MeRIP, RNA stability assay","journal":"Signal transduction and targeted therapy","confidence":"High","confidence_rationale":"Tier 1/2 — MS identification, mutagenesis, pharmacological inhibition of OGT, multi-omic validation","pmids":["36765030"],"is_preprint":false},{"year":2021,"finding":"Ythdf2-deficient HSCs chronically upregulate multiple m6A-modified inflammation-related transcripts, activating proinflammatory pathways; YTHDF2 is required to protect HSCs from inflammation-induced dysfunction and experimentally induced inflammation increases YTHDF2 expression.","method":"Conditional Ythdf2 KO mouse, serial transplantation, transcriptomic profiling, experimental inflammation induction","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 — in vivo KO with functional HSC readout, serial transplant, multi-condition epistasis","pmids":["33156926"],"is_preprint":false},{"year":2023,"finding":"YTHDF2 deficiency in tumor-associated macrophages (TAMs) reprograms them toward an antitumoral phenotype by targeting IFN-γ–STAT1 signaling; YTHDF2 expression in TAMs is regulated by IL-10–STAT3 signaling.","method":"Myeloid-specific Ythdf2 KO, flow cytometry, in vivo tumor models, STAT1/STAT3 signaling pathway analyses, TLR9-siRNA targeting","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 — cell-type-specific KO with defined signaling pathway, in vivo rescue, pharmacological targeting","pmids":["36658237"],"is_preprint":false},{"year":2023,"finding":"Ionizing radiation induces YTHDF2 expression in MDSCs via NF-κB signaling; YTHDF2 in turn directly binds and degrades transcripts encoding negative regulators of NF-κB, creating an IR–YTHDF2–NF-κB feedforward circuit.","method":"Myeloid-specific Ythdf2 KO, RNA-seq, m6A-RIP, in vivo tumor irradiation models, NF-κB inhibitor treatment","journal":"Cancer cell","confidence":"High","confidence_rationale":"Tier 2 — genetic KO, m6A-RIP identification of targets, in vivo epistasis with pharmacological NF-κB inhibition","pmids":["37236197"],"is_preprint":false},{"year":2019,"finding":"YTHDF2 knockdown in LPS-stimulated macrophages increases mRNA stability of MAP2K4 and MAP4K4, activating MAPK and NF-κB signaling to enhance proinflammatory cytokine expression.","method":"siRNA knockdown, mRNA stability assay, signaling pathway inhibitors, cytokine measurement","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 3 — single lab, siRNA KD with mRNA stability measurements and pathway inhibitor rescue","pmids":["30875984"],"is_preprint":false},{"year":2022,"finding":"X-ray crystallography of small-molecule fragment ligands bound to the YTH domain of YTHDF2 revealed the m6A-binding pocket; fragment ligands compete with m6A-RNA for binding.","method":"X-ray crystallography, fluorescence-based competitive binding assay","journal":"ACS medicinal chemistry letters","confidence":"High","confidence_rationale":"Tier 1 — crystal structures at high resolution with quantified binding affinities","pmids":["36110386"],"is_preprint":false},{"year":2021,"finding":"YTHDF2 mediates decay of m6A-modified CBS mRNA by binding within its CDS; in gastric cancer under hypoxia, lncRNA CBSLR interacts with YTHDF2 to enhance its binding to CBS mRNA, reducing CBS protein levels and leading to ferroptosis resistance.","method":"RIP, m6A-RIP, RNA stability assay, lncRNA pulldown, in vitro and in vivo cancer models","journal":"Journal of advanced research","confidence":"Medium","confidence_rationale":"Tier 2/3 — direct YTHDF2-RIP on CBS mRNA, lncRNA interaction identified, single lab","pmids":["35499052"],"is_preprint":false},{"year":2020,"finding":"Mouse Ythdf2 knockout in spermatogonia leads to downregulated matrix metallopeptidase expression (Mmp3, Mmp13, Adamts1, Adamts9); m6A-IP-PCR and RIP-PCR confirm YTHDF2 binds and promotes degradation of these m6A-marked mRNAs, regulating cell adhesion and proliferation.","method":"CRISPR/Cas9 KO in spermatogonia, m6A-IP-PCR, RIP-PCR, rescue with Mmp13 inhibition","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 — genetic KO, m6A-RIP target validation, partial rescue experiment","pmids":["31959747"],"is_preprint":false},{"year":2023,"finding":"YTHDF2 directly binds the m6A-modified CDS of DDX58 (RIG-I) mRNA and promotes its degradation; YTHDF2 depletion in bladder cancer stabilizes RIG-I, activating innate immune signaling and recruiting CD8+ T cells.","method":"MeRIP-seq, RNA-seq, RIP, RNA stability assay, in vivo orthotopic tumor model","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 — multi-omic target identification, direct RIP on RIG-I mRNA, in vivo immune phenotyping","pmids":["36939388"],"is_preprint":false},{"year":2024,"finding":"YTHDF2 facilitates translation of m6A-modified ETV5 mRNA by recognizing its 5'-UTR m6A and recruiting eIF3B, elevating ETV5 expression which transcriptionally induces PD-L1 and VEGFA in HCC.","method":"MeRIP-seq, RIP, co-IP with eIF3B, polysome profiling, in vivo HCC models","journal":"Advanced science","confidence":"High","confidence_rationale":"Tier 2 — direct binding in 5'-UTR shown by RIP, eIF3B interaction by co-IP, translational output measured","pmids":["38247171"],"is_preprint":false},{"year":2022,"finding":"YTHDF2 acts as a B cell-intrinsic factor required for GC B cell fate commitment; Ythdf2-deficient B cells fail to enter GCs because they cannot attenuate the plasmablast genetic program; YTHDF2 targets m6A-methylated plasmablast-regulating transcripts for decay.","method":"Conditional B-cell Ythdf2 KO, scRNA-seq, YTHDF2 binding site analysis, in vivo GC response","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 — in vivo B cell KO, scRNA-seq-based target identification, clear differentiation phenotype","pmids":["35508130"],"is_preprint":false},{"year":2023,"finding":"YTHDF2 promotes miR-126 maturation from pre-miR-126 by recognizing m6A modification within pre-miR-126 and recruiting AGO2, a regulator of pre-miRNA processing, in AML cells.","method":"RIP, m6A-RIP on pre-miRNA, AGO2 co-IP, rescue with miR-126 overexpression","journal":"Genes & diseases","confidence":"Medium","confidence_rationale":"Tier 2/3 — novel mechanism of pre-miRNA processing, but single lab; AGO2 interaction validated by co-IP","pmids":["37588203"],"is_preprint":false},{"year":2021,"finding":"Germ cell-specific Ythdf2 knockout mice are male sterile; YTHDF2 mediates timely clearance of phase-specific m6A-marked transcripts during spermatogenesis (differentiated spermatogonia to pachytene spermatocyte transition); loss of YTHDF2 leads to persistence of mRNAs mainly enriched in transcription regulation.","method":"Conditional KO (Vasa-Cre, Stra8-Cre), RNA-seq, YTHDF2-RIP-seq, MeRIP-qPCR, sperm functional assays","journal":"Cell proliferation","confidence":"High","confidence_rationale":"Tier 2 — multiple Cre drivers, RIP-seq genome-wide target identification, functional fertility phenotype","pmids":["34850470"],"is_preprint":false},{"year":2023,"finding":"HSP90β physically interacts with both YTHDF2 and the E3 ligase STUB1 in the cytoplasm, competitively inhibiting STUB1-mediated ubiquitination and degradation of YTHDF2, thereby stabilizing YTHDF2 protein in HCC.","method":"Co-IP, domain-mapping co-IP, ubiquitination assay, HSP90 inhibitor treatment","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal co-IP, domain mapping, ubiquitination assay, single lab","pmids":["37515378"],"is_preprint":false},{"year":2021,"finding":"PBRM1 (SWI/SNF component) interacts with YTHDF2 and is required for YTHDF2 binding to m6A-modified HIF-1α mRNA; YTHDF2 promotes HIF-1α mRNA translation rather than decay, and YTHDF2 depletion reduces HIF-1α protein.","method":"Co-IP, polysome/translation assay, m6A-RIP, siRNA depletion","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2/3 — co-IP of PBRM1-YTHDF2 validated, translational role shown by polysome assay, single lab","pmids":["34200988"],"is_preprint":false},{"year":2024,"finding":"YTHDF2 promotes nuclear nascent RNA synthesis in CD8+ T cells in an m6A-recognition-dependent manner and interacts with IKZF1/3 to sustain transcription of their target genes; nuclear YTHDF2 also orchestrates chromatin changes promoting T cell polyfunctionality.","method":"T cell-specific KO, ChIP-seq, m6A-seq, YTHDF2 co-IP with IKZF1/3, nascent RNA assays, in vivo tumor models with lenalidomide rescue","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — genetic KO, multi-omic profiling, direct protein interaction by co-IP, pharmacological rescue in vivo","pmids":["39500904"],"is_preprint":false},{"year":2024,"finding":"YTHDF2 functions as a dual reader: it destabilizes m6A-modified mRNAs (canonical) while stabilizing m5C-modified mRNAs by recruiting PABPC1, thereby enhancing expression and ATP synthesis in B cell malignancies.","method":"RIP-seq, m5C-seq, co-IP with PABPC1, mRNA stability assays, YTHDF2 overexpression/KO in B cell transformation models","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1/2 — genome-wide sequencing for both m5C and m6A targets, PABPC1 interaction by co-IP, overexpression-induced transformation is a strong functional readout","pmids":["39694037"],"is_preprint":false},{"year":2023,"finding":"YTHDF2 promotes degradation of Hmox1 (heme oxygenase 1) mRNA in an m6A-dependent manner in alveolar macrophages, and myeloid-specific Ythdf2 KO elevates Hmox1, attenuating alternative macrophage activation and protecting from pulmonary hypertension.","method":"Myeloid-specific Ythdf2 KO (Lyz2-Cre), m6A-RIP, mRNA stability assay, Hmox1 inhibitor rescue, in vivo PH model","journal":"Redox biology","confidence":"High","confidence_rationale":"Tier 2 — cell-type-specific in vivo KO, direct m6A-RIP on Hmox1, pharmacological epistasis","pmids":["36801705"],"is_preprint":false},{"year":2024,"finding":"YTHDF2 promotes m6A-dependent decay of TGF-β signaling pathway component mRNAs (ligands, receptors, transcription regulators) in hippocampal NSCs; Ythdf2 deletion elevates TGF-β signaling and increases quiescence acquisition.","method":"Conditional Ythdf2 KO in NSCs, m6A-seq, YTHDF2-RIP-seq, mRNA decay profiling, TGF-β pathway inhibitor rescue","journal":"Cell stem cell","confidence":"High","confidence_rationale":"Tier 2 — conditional KO, multi-modal sequencing, pathway epistasis with inhibitor rescue","pmids":["39476834"],"is_preprint":false},{"year":2024,"finding":"YTHDF2 forms a complex with eIF3F and DDX1 to enhance translation of m6A-modified mRNAs encoding microtubule-associated proteins, driving cancer progression and paclitaxel resistance independently of RNA decay.","method":"Co-IP (YTHDF2-eIF3F, YTHDF2-DDX1), polysome profiling, m6A-seq, RNA stability assay (ruling out decay), in vivo tumor models, virtual screening for inhibitor","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1/2 — co-IP of translation complex, polysome profiling, m6A-seq, stability assay controls, in vivo validation","pmids":["40480228"],"is_preprint":false},{"year":2024,"finding":"YTHDF2 stabilizes Cx3cl1 (CX3CL1) mRNA in an m6A-dependent manner in peritumoral hepatocytes, facilitating CD8+ T cell recruitment; oxaliplatin upregulates YTHDF2 expression via cGAS-STING signaling.","method":"Liver-specific Ythdf2 KO mouse, tumor-bearing model, m6A-RIP, RNA stability assay, cGAS-STING pathway analysis","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 2 — cell-type-specific KO, m6A-RIP target validation, upstream pathway epistasis, single lab","pmids":["39237909"],"is_preprint":false},{"year":2024,"finding":"Smooth muscle cell-specific Ythdf2 deficiency ameliorates pulmonary vascular remodeling; Ythdf2 paradoxically stabilizes Myadm mRNA in an m6A-dependent manner in PASMCs, promoting cell proliferation via suppression of the cell cycle inhibitor p21.","method":"SM-specific Ythdf2 KO (SM22α-Cre), proteomics, m6A-seq, RIP, mRNA stability assay, in vivo PH model","journal":"Hypertension","confidence":"High","confidence_rationale":"Tier 2 — cell-type-specific in vivo KO, proteomics + m6A-seq + RIP for target identification, mechanistic chain to p21","pmids":["38832511"],"is_preprint":false},{"year":2024,"finding":"YTHDF2 controls mRNA stability of the ubiquitin ligase ASB2 in skeletal muscle; muscle-specific YTHDF2 deletion impairs postnatal muscle growth and hypertrophic response by activating SMAD3-dependent TGF-β anti-growth program.","method":"Muscle-specific Ythdf2 KO, m6A-RIP, mRNA stability assay, SMAD3 readout, hypertrophy stimulus model","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — in vivo KO with clear growth phenotype, direct m6A-RIP on ASB2 mRNA, signaling pathway linkage","pmids":["38467649"],"is_preprint":false},{"year":2023,"finding":"YTHDF2 promotes degradation of m6A-modified DAPK3 mRNA by binding its 3'-UTR, driving gallbladder cancer progression and gemcitabine resistance.","method":"RIP-seq, MeRIP-seq, RNA-seq integration, RNA stability assay, in vitro/in vivo functional assays","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2 — multi-omic target identification, direct RIP validation, in vivo xenograft, single lab","pmids":["37700438"],"is_preprint":false},{"year":2023,"finding":"YTHDF2 binds m6A-modified Ythdf2/YTHDF2 mRNA as part of an autoregulatory loop in CD8+ T cells, reinforcing its own expression; this nuclear function requires m6A recognition by the YTH domain.","method":"m6A-seq, YTHDF2 nuclear localization demonstrated, domain mutagenesis, T cell-specific KO","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 — genetic and domain-mutagenesis evidence, but autoregulation is a secondary finding within a larger study","pmids":["39500904"],"is_preprint":false},{"year":2023,"finding":"Ythdf2 binds m6A sites in STK11 mRNA and recruits AGO2 to form a silencing complex promoting STK11 mRNA degradation; loss of Ythdf2 stabilizes STK11, activates AMPK/mTOR, and impairs myoblast differentiation.","method":"Co-IP of Ythdf2-Ago2, RIP, m6A-RIP, RNA stability assay, AMPK/mTOR pathway readouts","journal":"International journal of biological macromolecules","confidence":"Medium","confidence_rationale":"Tier 2/3 — Ago2 interaction validated by co-IP, m6A-RIP target confirmation, pathway epistasis, single lab","pmids":["37884231"],"is_preprint":false},{"year":2024,"finding":"YTHDF2 mediates m6A-dependent degradation of SLC7A11 mRNA in Sertoli cells, as shown by RIP experiments demonstrating direct binding; this is exploited by BPF toxin to disrupt blood-testis barrier integrity.","method":"MeRIP, RIP, FTO overexpression/KD, in vivo/in vitro models","journal":"Environmental pollution","confidence":"Low","confidence_rationale":"Tier 3 — RIP showing binding, mechanistic context is toxicology model, single lab","pmids":["38996995"],"is_preprint":false},{"year":2023,"finding":"YTHDF2 promotes degradation of CDKN1B mRNA in an m6A-dependent manner in intrahepatic cholangiocarcinoma, identified by integration of RNA-seq, MeRIP-seq, and anti-YTHDF2 RIP-seq.","method":"MeRIP-seq, RNA-seq, anti-YTHDF2 RIP-seq integration, RNA stability assay, PDX model","journal":"Clinical and translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 — multi-omic triple sequencing approach plus PDX validation, single lab","pmids":["35696608"],"is_preprint":false},{"year":2023,"finding":"YBX2 interacts with YTHDF2 through its cold-shock domain and recruits YTHDF2 to cytoplasmic granules; YTHDF2 knockdown ameliorates YBX2-induced HSPA6 mRNA destabilization in endometrial cancer cells.","method":"Co-IP, RNA pulldown, YTHDF2 KD rescue, mRNA stability assay","journal":"Experimental cell research","confidence":"Low","confidence_rationale":"Tier 3 — co-IP of YBX2-YTHDF2, stability rescue, but single lab, single method per finding","pmids":["37030331"],"is_preprint":false},{"year":2024,"finding":"YTHDF2 cardiomyocyte-specific knockout drives cardiac dysfunction; YTHDF2 normally binds m6A-modified Myzap mRNA and controls its stability, and loss of YTHDF2 leads to upregulation of MYZAP, causing adverse cardiac remodeling.","method":"Cardiomyocyte-specific Ythdf2 KO, proteomics, m6A-RIP on Myzap mRNA, in vivo cardiac function measurements","journal":"JACC. Basic to translational science","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo KO with cardiac phenotype, proteomics target identification, m6A-RIP validation, single lab","pmids":["37791304"],"is_preprint":false},{"year":2024,"finding":"Lactylation of YTHDF2 (mediated by elevated lactate) increases its protein levels in cardiomyocytes; the intrinsically disordered region of YTHDF2 (not its m6A-binding activity) is required for its role in upregulating G3BP1 to control cardiomyocyte size and OGD/R-induced apoptosis.","method":"Lactylation detection, domain-deletion mutants lacking m6A binding, G3BP1 pathway readout, OGD/R cardiomyocyte model","journal":"Basic research in cardiology","confidence":"Medium","confidence_rationale":"Tier 2 — domain mutants dissecting m6A-dependent vs -independent functions, lactylation assay, single lab","pmids":["38563985"],"is_preprint":false},{"year":2024,"finding":"IFN-γ induces autophagic degradation of tumoral YTHDF2, sensitizing tumor cells to CD8+ T cell-mediated cytotoxicity; tumoral YTHDF2 deficiency promotes macrophage recruitment via CX3CL1 and enhances mitochondrial respiration in CD8+ T cells by impairing tumor glycolysis.","method":"Tumoral Ythdf2 KO, co-culture assays, autophagy inhibitors, metabolic assays, in vivo immunocompetent tumor models","journal":"Science immunology","confidence":"High","confidence_rationale":"Tier 2 — in vivo tumoral KO, mechanistic autophagy pathway for YTHDF2 degradation, metabolic consequence measured","pmids":["38820140"],"is_preprint":false}],"current_model":"YTHDF2 is a cytoplasmic (and, in certain contexts, nuclear) m6A reader that primarily recruits the CCR4-NOT deadenylase complex to promote decay of m6A-modified mRNAs, but can also stabilize mRNAs bearing m5C modifications via PABPC1 recruitment or enhance translation of m6A-modified mRNAs by interacting with eIF3F/DDX1; its activity and stability are regulated by multiple post-translational modifications including SUMOylation at K571 (increasing m6A-RNA binding affinity), O-GlcNAcylation at S263 (blocking ubiquitination), phosphorylation at S39/T381 by EGFR/SRC/ERK (stabilizing the protein), CDK1-dependent stabilization during mitosis, and proteasomal degradation mediated by FBW7 and CUL1/CUL4A–DDB1–SKP2 E3 complexes, placing YTHDF2 at the intersection of cell-cycle control, stem cell self-renewal, immune regulation, and oncogenesis through coordinated post-transcriptional gene expression programs."},"narrative":{"teleology":[{"year":2018,"claim":"Establishing YTHDF2 as a physiological regulator of HSC self-renewal resolved how m6A-dependent mRNA turnover controls stem cell pool size — YTHDF2 loss stabilized m6A-marked transcription factor mRNAs (e.g., Tal1), expanding functional HSCs ex vivo and in vivo.","evidence":"Conditional Ythdf2 KO mouse with limiting-dilution transplantation and m6A-seq in HSPCs","pmids":["30065315"],"confidence":"High","gaps":["Identity of all HSC-relevant YTHDF2 target mRNAs not fully catalogued","Whether YTHDF2 acts exclusively through decay in HSCs or also through translational regulation was not addressed"]},{"year":2018,"claim":"Demonstrating that YTHDF2 binds m6A sites in EGFR 3′-UTR and accelerates EGFR mRNA degradation linked YTHDF2-mediated decay to oncogenic signaling suppression in hepatocellular carcinoma.","evidence":"m6A-RIP, RNA stability assay, and downstream MEK/ERK signaling readouts in HCC cells","pmids":["30423408"],"confidence":"Medium","gaps":["Single-lab study without independent replication","Structural basis of YTHDF2 selectivity for EGFR mRNA over other m6A targets not determined"]},{"year":2019,"claim":"Identification of Tnfrsf2 as a YTHDF2-degraded target in AML established that YTHDF2 suppresses apoptotic priming in leukemic stem cells, providing a disease-specific mechanistic rationale for targeting YTHDF2 in AML.","evidence":"m6A-seq, RNA stability assays, conditional KO mouse models, human AML xenograft transplantation","pmids":["31031138"],"confidence":"High","gaps":["Whether all AML subtypes depend on YTHDF2 equally was not tested","Redundancy with YTHDF1/3 in AML context not resolved"]},{"year":2019,"claim":"Discovery that YTHDF2 recognizes m1A in addition to m6A broadened the epitranscriptomic reader specificity of the YTH domain beyond a single modification.","evidence":"Chemical proteomics pulldown and recombinant protein binding assay with m1A probes, followed by cellular knockdown","pmids":["31815430"],"confidence":"Medium","gaps":["Structural basis for m1A recognition not resolved","Physiological relevance of m1A reading in vivo not established"]},{"year":2019,"claim":"Showing that YTHDF2 knockdown in macrophages stabilizes MAP2K4/MAP4K4 mRNAs and hyperactivates MAPK/NF-κB signaling revealed YTHDF2 as a tonic suppressor of inflammatory gene expression programs.","evidence":"siRNA knockdown, mRNA stability assay, signaling pathway inhibitors in LPS-stimulated macrophages","pmids":["30875984"],"confidence":"Medium","gaps":["Macrophage-specific YTHDF2 KO was not used","Direct m6A-RIP on MAP2K4/MAP4K4 not performed in this study"]},{"year":2020,"claim":"The CDK1–YTHDF2–WEE1 feedforward loop established that YTHDF2-mediated mRNA decay is integrated into cell cycle control: CDK1 stabilizes YTHDF2, which degrades WEE1 mRNA to accelerate mitotic entry, while CUL1/CUL4A–DDB1–SKP2 E3 complexes degrade YTHDF2 to reset the cycle.","evidence":"siRNA depletion, m6A-seq, RNA stability assay, CDK1 inhibitor treatment, co-IP with E3 ligase components","pmids":["32267835"],"confidence":"High","gaps":["Direct phosphorylation of YTHDF2 by CDK1 not demonstrated","Relative contributions of CUL1 vs CUL4A complexes not disentangled"]},{"year":2020,"claim":"Establishing that YTHDF2 recruits the CCR4-NOT deadenylase complex to degrade somatic gene mRNAs during iPSC reprogramming defined the effector mechanism for YTHDF2-mediated mRNA clearance.","evidence":"CRISPR/siRNA KD in reprogramming, scRNA-seq, co-IP with CCR4-NOT subunits, mRNA stability assay","pmids":["32905781"],"confidence":"High","gaps":["Whether CCR4-NOT is the universal YTHDF2 decay effector or context-specific was not resolved","Contribution of YTHDF3 versus YTHDF2 to CCR4-NOT recruitment not fully separated"]},{"year":2021,"claim":"Mapping EGFR/SRC/ERK-dependent phosphorylation of YTHDF2 at S39 and T381 revealed how oncogenic signaling stabilizes the reader protein, amplifying m6A-dependent mRNA decay in glioblastoma.","evidence":"Phosphorylation mapping by mass spectrometry, site-directed mutagenesis, RIP, m6A-seq, in vivo tumorigenesis","pmids":["33420027"],"confidence":"High","gaps":["Whether phosphorylation alters YTHDF2 substrate specificity or just abundance was not clarified","Kinase-dead rescue experiments not performed"]},{"year":2021,"claim":"Identification of K571 SUMOylation as a hypoxia-induced modification that increases YTHDF2's m6A-binding affinity without affecting stability established a distinct post-translational control axis that tunes reader activity rather than abundance.","evidence":"In vitro and in vivo SUMOylation assays, K571 mutagenesis, m6A-RIP, mRNA stability assay","pmids":["33577677"],"confidence":"High","gaps":["SUMO E3 ligase identity not determined","Whether SUMOylation affects YTHDF2 interactome (e.g., CCR4-NOT recruitment) not tested"]},{"year":2021,"claim":"Demonstrating that FBW7 targets YTHDF2 for proteasomal degradation added a tumor-suppressive E3 ligase axis to YTHDF2 regulation, connecting FBW7 loss in ovarian cancer to aberrant m6A-reader accumulation.","evidence":"IP-mass spectrometry, co-IP, ubiquitination assays, in vitro/in vivo tumorigenesis, m6A-RIP-seq","pmids":["33658012"],"confidence":"High","gaps":["FBW7 degron motif on YTHDF2 not mapped","Whether FBW7-mediated regulation is phosphodegron-dependent (as for canonical FBW7 substrates) not determined"]},{"year":2021,"claim":"Ythdf2 conditional KO in HSCs revealed chronic upregulation of m6A-modified inflammation transcripts, establishing YTHDF2 as a guardian that dampens inflammatory signaling to preserve HSC fitness during stress.","evidence":"Conditional Ythdf2 KO mouse, serial transplantation, transcriptomic profiling, experimental inflammation","pmids":["33156926"],"confidence":"High","gaps":["Whether anti-inflammatory function of YTHDF2 in HSCs is separable from its role in self-renewal not tested","Direct demonstration that specific inflammation transcripts are m6A-marked and YTHDF2-bound was limited"]},{"year":2021,"claim":"Germ cell-specific Ythdf2 KO demonstrated male infertility from failure to clear phase-specific transcripts during spermatogenesis, establishing a non-redundant developmental role for YTHDF2 in germ cell differentiation.","evidence":"Multiple Cre drivers (Vasa-Cre, Stra8-Cre), RIP-seq, MeRIP-qPCR, fertility assays","pmids":["34850470"],"confidence":"High","gaps":["Redundancy with YTHDF1/3 in spermatogenesis not systematically addressed","Whether YTHDF2 acts solely through decay or also translation in spermatocytes not resolved"]},{"year":2021,"claim":"A CRISPR screen in TNBC revealed that YTHDF2 is essential for cancer cell viability: its loss stabilizes MAPK pathway mRNAs, induces EMT, increases global translation, and triggers lethal ER stress — demonstrating that YTHDF2 buffers translational homeostasis.","evidence":"Pooled CRISPR screen, eCLIP, m6A-seq, scRibo-STAMP, in vivo tumor models","pmids":["34216543"],"confidence":"High","gaps":["Whether ER stress is a universal consequence of YTHDF2 loss or TNBC-specific not established","Mechanism linking stabilized mRNAs to increased global translation not fully resolved"]},{"year":2022,"claim":"Structural determination of small-molecule fragments bound to the YTHDF2 YTH domain m6A pocket enabled pharmacological targeting, providing the first atomic-resolution view of druggable YTHDF2 interfaces.","evidence":"X-ray crystallography and fluorescence-based competitive binding assay","pmids":["36110386"],"confidence":"High","gaps":["No cell-active inhibitor demonstrated","Fragment affinity was modest; drug-like optimization not achieved"]},{"year":2022,"claim":"B cell-specific Ythdf2 KO showed failure of GC B cell commitment because plasmablast-program transcripts were not cleared, revealing YTHDF2 as a fate switch in humoral immunity.","evidence":"Conditional B-cell Ythdf2 KO, scRNA-seq, YTHDF2 binding-site analysis, in vivo GC response","pmids":["35508130"],"confidence":"High","gaps":["Whether YTHDF2 also functions at later GC stages (e.g., affinity maturation) not investigated","Specific m6A sites on plasmablast transcripts not mapped at nucleotide resolution"]},{"year":2023,"claim":"O-GlcNAcylation of YTHDF2 at S263 by OGT was shown to stabilize YTHDF2 by blocking ubiquitination, linking nutrient sensing to m6A-reader abundance and cell cycle progression via MCM2/MCM5 mRNA stabilization.","evidence":"MS identification of S263 O-GlcNAcylation, site-directed mutagenesis, OGT inhibitor, MeRIP, RNA stability assay","pmids":["36765030"],"confidence":"High","gaps":["Which E3 ligase is blocked by O-GlcNAcylation at S263 not identified","Whether S263 O-GlcNAcylation affects YTHDF2 RNA-binding specificity not tested"]},{"year":2023,"claim":"Myeloid-specific Ythdf2 KO reprogrammed tumor-associated macrophages toward antitumoral phenotypes via IFN-γ–STAT1 signaling, and YTHDF2 expression was regulated by IL-10–STAT3, establishing a macrophage-intrinsic m6A-dependent immune checkpoint.","evidence":"Myeloid-specific Ythdf2 KO, flow cytometry, in vivo tumor models, STAT1/STAT3 signaling analysis","pmids":["36658237"],"confidence":"High","gaps":["Specific m6A-modified STAT1 pathway mRNAs targeted by YTHDF2 not comprehensively identified","Whether this mechanism operates across all tumor types not tested"]},{"year":2023,"claim":"An IR–YTHDF2–NF-κB feedforward circuit in MDSCs demonstrated that ionizing radiation induces YTHDF2 via NF-κB, and YTHDF2 then degrades negative regulators of NF-κB, amplifying immunosuppression.","evidence":"Myeloid-specific Ythdf2 KO, RNA-seq, m6A-RIP, in vivo tumor irradiation, NF-κB inhibitor","pmids":["37236197"],"confidence":"High","gaps":["Identities of all NF-κB negative regulators targeted by YTHDF2 not exhaustively mapped","Therapeutic window for combining YTHDF2 inhibition with radiotherapy not defined"]},{"year":2023,"claim":"HSP90β was shown to competitively block STUB1-mediated ubiquitination of YTHDF2, adding a chaperone-dependent stabilization mechanism to the growing repertoire of YTHDF2 post-translational regulation.","evidence":"Reciprocal co-IP, domain mapping, ubiquitination assay, HSP90 inhibitor treatment in HCC","pmids":["37515378"],"confidence":"Medium","gaps":["Whether HSP90β stabilization of YTHDF2 is constitutive or signal-regulated not determined","Interaction interface on YTHDF2 not mapped"]},{"year":2024,"claim":"Discovery that YTHDF2 recognizes m5C-modified mRNAs and stabilizes them by recruiting PABPC1 — opposite to its canonical m6A-mediated decay — established YTHDF2 as a dual-modification reader with modification-dependent functional polarity, driving B cell malignancy.","evidence":"RIP-seq, m5C-seq, co-IP with PABPC1, mRNA stability assays, YTHDF2 OE/KO in B cell transformation models","pmids":["39694037"],"confidence":"High","gaps":["Structural basis for m5C recognition by the YTH domain not determined","Whether m5C reading by YTHDF2 operates broadly or is restricted to B cell lineage not tested"]},{"year":2024,"claim":"Identification of a YTHDF2–eIF3F–DDX1 translation complex demonstrated a decay-independent translational enhancement function for YTHDF2 on m6A-modified mRNAs encoding microtubule-associated proteins, explaining paclitaxel resistance.","evidence":"Co-IP of complex components, polysome profiling, m6A-seq, RNA stability assay ruling out decay, in vivo tumor models","pmids":["40480228"],"confidence":"High","gaps":["Whether eIF3F/DDX1 complex is the same as the eIF3B-dependent translation pathway reported in HCC not clarified","Structural basis of YTHDF2–eIF3F interaction unknown"]},{"year":2024,"claim":"Nuclear YTHDF2 in CD8+ T cells was shown to promote nascent RNA synthesis by interacting with IKZF1/3 and sustaining their transcriptional programs, expanding YTHDF2's functional repertoire beyond cytoplasmic mRNA fate determination.","evidence":"T cell-specific KO, ChIP-seq, m6A-seq, YTHDF2 co-IP with IKZF1/3, nascent RNA assays, in vivo lenalidomide rescue","pmids":["39500904"],"confidence":"High","gaps":["Whether nuclear YTHDF2 directly contacts chromatin or acts through IKZF1/3 intermediaries not resolved","How YTHDF2 nuclear import is regulated remains unknown"]},{"year":2024,"claim":"IFN-γ-induced autophagic degradation of tumoral YTHDF2 was shown to sensitize tumors to CD8+ T cell killing, revealing a non-proteasomal degradation pathway that connects immune cytokine signaling to m6A reader abundance in the tumor microenvironment.","evidence":"Tumoral Ythdf2 KO, co-culture assays, autophagy inhibitors, metabolic assays, in vivo immunocompetent models","pmids":["38820140"],"confidence":"High","gaps":["Selective autophagy receptor mediating YTHDF2 degradation not identified","Whether autophagic degradation of YTHDF2 operates in non-tumor cell types not tested"]},{"year":2024,"claim":"YTHDF2-dependent decay of TGF-β pathway mRNAs in hippocampal neural stem cells demonstrated that YTHDF2 controls the balance between NSC activation and quiescence, extending its stem cell regulatory role beyond the hematopoietic system.","evidence":"Conditional Ythdf2 KO in NSCs, m6A-seq, YTHDF2-RIP-seq, mRNA decay profiling, TGF-β inhibitor rescue","pmids":["39476834"],"confidence":"High","gaps":["Whether YTHDF2 regulates NSC quiescence in aging or disease contexts not tested","Redundancy with YTHDF1/3 in NSCs not addressed"]},{"year":null,"claim":"Key unresolved questions include: (1) the structural basis for YTHDF2's dual recognition of m6A and m5C and how modification identity switches its output from decay to stabilization; (2) how nuclear versus cytoplasmic YTHDF2 pools are partitioned and whether translational, transcriptional, and decay functions are mutually exclusive or co-occurring; (3) whether the multiple E3 ligase systems (FBW7, SKP2, STUB1) and post-translational modifications act hierarchically or in parallel across tissues.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model for m5C recognition by YTH domain","Nuclear import/export mechanism undetermined","Integrated model of PTM crosstalk on YTHDF2 lacking"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,1,4,5,7,28]},{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[0,9,11,20]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[21,31]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[27]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,9,25,31]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[27,36]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,9,11,20,28,30]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[8,12]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[14,15,22,27]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,3,16]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[6,8,25]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[11,43]}],"complexes":["CCR4-NOT deadenylase complex","YTHDF2–eIF3F–DDX1 translation complex"],"partners":["CNOT1","EIF3F","EIF3B","DDX1","PABPC1","IKZF1","FBW7","HSP90AB1"],"other_free_text":[]},"mechanistic_narrative":"YTHDF2 is a cytoplasmic m6A reader protein that serves as a central post-transcriptional regulator, primarily accelerating mRNA decay but also modulating translation and miRNA maturation in a context-dependent manner. Its canonical function involves binding m6A-modified mRNAs through its YTH domain and recruiting the CCR4-NOT deadenylase complex to promote deadenylation and degradation of target transcripts — a mechanism demonstrated across hematopoietic stem cells, immune cells, germ cells, and multiple cancer types [PMID:32905781, PMID:31031138, PMID:34850470]. Beyond decay, YTHDF2 enhances translation of specific m6A-modified mRNAs by recruiting eIF3B or forming a complex with eIF3F and DDX1 [PMID:38247171, PMID:40480228], stabilizes m5C-modified mRNAs through PABPC1 recruitment [PMID:39694037], and operates in the nucleus to sustain transcription via interaction with IKZF1/3 in CD8+ T cells [PMID:39500904]. YTHDF2 protein stability and activity are extensively regulated by post-translational modifications — including EGFR/SRC/ERK-mediated phosphorylation at S39/T381 [PMID:33420027], SUMOylation at K571 that enhances m6A-RNA binding under hypoxia [PMID:33577677], O-GlcNAcylation at S263 that blocks ubiquitination [PMID:36765030], CDK1-dependent stabilization during mitosis [PMID:32267835], and proteasomal degradation directed by FBW7, CUL1/CUL4A–DDB1–SKP2, and STUB1 E3 ligase complexes [PMID:33658012, PMID:32267835, PMID:37515378]."},"prefetch_data":{"uniprot":{"accession":"Q9Y5A9","full_name":"YTH domain-containing family protein 2","aliases":["CLL-associated antigen KW-14","High-glucose-regulated protein 8","Renal carcinoma antigen NY-REN-2"],"length_aa":579,"mass_kda":62.3,"function":"Specifically recognizes and binds N6-methyladenosine (m6A)-containing RNAs, and regulates their stability (PubMed:24284625, PubMed:26046440, PubMed:26318451, PubMed:32492408). M6A is a modification present at internal sites of mRNAs and some non-coding RNAs and plays a role in mRNA stability and processing (PubMed:22575960, PubMed:24284625, PubMed:25412658, PubMed:25412661, PubMed:32492408). Acts as a regulator of mRNA stability by promoting degradation of m6A-containing mRNAs via interaction with the CCR4-NOT and ribonuclease P/MRP complexes, depending on the context (PubMed:24284625, PubMed:26046440, PubMed:27558897, PubMed:30930054, PubMed:32492408). The YTHDF paralogs (YTHDF1, YTHDF2 and YTHDF3) share m6A-containing mRNAs targets and act redundantly to mediate mRNA degradation and cellular differentiation (PubMed:28106072, PubMed:32492408). M6A-containing mRNAs containing a binding site for RIDA/HRSP12 (5'-GGUUC-3') are preferentially degraded by endoribonucleolytic cleavage: cooperative binding of RIDA/HRSP12 and YTHDF2 to transcripts leads to recruitment of the ribonuclease P/MRP complex (PubMed:30930054). Other m6A-containing mRNAs undergo deadenylation via direct interaction between YTHDF2 and CNOT1, leading to recruitment of the CCR4-NOT and subsequent deadenylation of m6A-containing mRNAs (PubMed:27558897). Required maternally to regulate oocyte maturation: probably acts by binding to m6A-containing mRNAs, thereby regulating maternal transcript dosage during oocyte maturation, which is essential for the competence of oocytes to sustain early zygotic development (By similarity). Also required during spermatogenesis: regulates spermagonial adhesion by promoting degradation of m6A-containing transcripts coding for matrix metallopeptidases (By similarity). Also involved in hematopoietic stem cells specification by binding to m6A-containing mRNAs, leading to promote their degradation (PubMed:30065315). Also acts as a regulator of neural development by promoting m6A-dependent degradation of neural development-related mRNA targets (By similarity). Inhibits neural specification of induced pluripotent stem cells by binding to methylated neural-specific mRNAs and promoting their degradation, thereby restraining neural differentiation (PubMed:32169943). Regulates circadian regulation of hepatic lipid metabolism: acts by promoting m6A-dependent degradation of PPARA transcripts (PubMed:30428350). Regulates the innate immune response to infection by inhibiting the type I interferon response: acts by binding to m6A-containing IFNB transcripts and promoting their degradation (PubMed:30559377). May also act as a promoter of cap-independent mRNA translation following heat shock stress: upon stress, relocalizes to the nucleus and specifically binds mRNAs with some m6A methylation mark at their 5'-UTR, protecting demethylation of mRNAs by FTO, thereby promoting cap-independent mRNA translation (PubMed:26458103). Regulates mitotic entry by promoting the phase-specific m6A-dependent degradation of WEE1 transcripts (PubMed:32267835). Promotes formation of phase-separated membraneless compartments, such as P-bodies or stress granules, by undergoing liquid-liquid phase separation upon binding to mRNAs containing multiple m6A-modified residues: polymethylated mRNAs act as a multivalent scaffold for the binding of YTHDF proteins, juxtaposing their disordered regions and thereby leading to phase separation (PubMed:31292544, PubMed:31388144, PubMed:31642031, PubMed:32451507). The resulting mRNA-YTHDF complexes then partition into different endogenous phase-separated membraneless compartments, such as P-bodies, stress granules or neuronal RNA granules (PubMed:31292544). May also recognize and bind RNAs modified by C5-methylcytosine (m5C) and act as a regulator of rRNA processing (PubMed:31815440) (Microbial infection) Promotes viral gene expression and replication of polyomavirus SV40: acts by binding to N6-methyladenosine (m6A)-containing viral RNAs (PubMed:29447282) (Microbial infection) Promotes viral gene expression and virion production of kaposis sarcoma-associated herpesvirus (KSHV) at some stage of the KSHV life cycle (in iSLK.219 and iSLK.BAC16 cells) (PubMed:29659627). Acts by binding to N6-methyladenosine (m6A)-containing viral RNAs (PubMed:29659627)","subcellular_location":"Cytoplasm, cytosol; Cytoplasm, P-body; Cytoplasm, Stress granule; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9Y5A9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/YTHDF2","classification":"Not Classified","n_dependent_lines":369,"n_total_lines":1208,"dependency_fraction":0.3054635761589404},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"PHAX","stoichiometry":10.0},{"gene":"ATG13","stoichiometry":0.2},{"gene":"EMC9","stoichiometry":0.2},{"gene":"ENY2","stoichiometry":0.2},{"gene":"NCAPH","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/YTHDF2","total_profiled":1310},"omim":[{"mim_id":"619296","title":"TESTIS-ASSOCIATED ONCOGENIC LONG NONCODING RNA; THORLNC","url":"https://www.omim.org/entry/619296"},{"mim_id":"618669","title":"YTH N6-METHYLADENOSINE RNA-BINDING PROTEIN 3; YTHDF3","url":"https://www.omim.org/entry/618669"},{"mim_id":"616529","title":"YTH N6-METHYLADENOSINE RNA-BINDING PROTEIN 1; YTHDF1","url":"https://www.omim.org/entry/616529"},{"mim_id":"613303","title":"AlkB HOMOLOG 5, RNA DEMETHYLASE; ALKBH5","url":"https://www.omim.org/entry/613303"},{"mim_id":"610640","title":"YTH N6-METHYLADENOSINE RNA-BINDING PROTEIN 2; YTHDF2","url":"https://www.omim.org/entry/610640"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Cytosol","reliability":"Enhanced"},{"location":"Cytoplasmic bodies","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/YTHDF2"},"hgnc":{"alias_symbol":["HGRG8","NY-REN-2","CAHL"],"prev_symbol":[]},"alphafold":{"accession":"Q9Y5A9","domains":[{"cath_id":"3.10.590.10","chopping":"386-399_410-576","consensus_level":"high","plddt":94.9983,"start":386,"end":576}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y5A9","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y5A9-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y5A9-F1-predicted_aligned_error_v6.png","plddt_mean":59.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=YTHDF2","jax_strain_url":"https://www.jax.org/strain/search?query=YTHDF2"},"sequence":{"accession":"Q9Y5A9","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9Y5A9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9Y5A9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y5A9"}},"corpus_meta":[{"pmid":"33726814","id":"PMC_33726814","title":"Histone lactylation drives oncogenesis by facilitating m6A reader protein YTHDF2 expression in ocular melanoma.","date":"2021","source":"Genome biology","url":"https://pubmed.ncbi.nlm.nih.gov/33726814","citation_count":748,"is_preprint":false},{"pmid":"31031138","id":"PMC_31031138","title":"Targeting the RNA m6A Reader YTHDF2 Selectively Compromises Cancer Stem Cells in Acute Myeloid Leukemia.","date":"2019","source":"Cell stem cell","url":"https://pubmed.ncbi.nlm.nih.gov/31031138","citation_count":406,"is_preprint":false},{"pmid":"30423408","id":"PMC_30423408","title":"YTHDF2 suppresses cell proliferation and growth via destabilizing the EGFR mRNA in hepatocellular carcinoma.","date":"2018","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/30423408","citation_count":295,"is_preprint":false},{"pmid":"31735169","id":"PMC_31735169","title":"YTHDF2 reduction fuels inflammation and vascular abnormalization in hepatocellular carcinoma.","date":"2019","source":"Molecular cancer","url":"https://pubmed.ncbi.nlm.nih.gov/31735169","citation_count":286,"is_preprint":false},{"pmid":"33420027","id":"PMC_33420027","title":"EGFR/SRC/ERK-stabilized YTHDF2 promotes cholesterol dysregulation and invasive growth of glioblastoma.","date":"2021","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/33420027","citation_count":243,"is_preprint":false},{"pmid":"30065315","id":"PMC_30065315","title":"Suppression of m6A reader Ythdf2 promotes hematopoietic stem cell expansion.","date":"2018","source":"Cell research","url":"https://pubmed.ncbi.nlm.nih.gov/30065315","citation_count":231,"is_preprint":false},{"pmid":"35499052","id":"PMC_35499052","title":"Hypoxia inducible lncRNA-CBSLR modulates ferroptosis through m6A-YTHDF2-dependent modulation of CBS in gastric cancer.","date":"2021","source":"Journal of advanced research","url":"https://pubmed.ncbi.nlm.nih.gov/35499052","citation_count":218,"is_preprint":false},{"pmid":"30875984","id":"PMC_30875984","title":"m6A Reader YTHDF2 Regulates LPS-Induced Inflammatory Response.","date":"2019","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/30875984","citation_count":193,"is_preprint":false},{"pmid":"36658237","id":"PMC_36658237","title":"YTHDF2 orchestrates tumor-associated macrophage reprogramming and controls antitumor immunity through CD8+ T cells.","date":"2023","source":"Nature immunology","url":"https://pubmed.ncbi.nlm.nih.gov/36658237","citation_count":182,"is_preprint":false},{"pmid":"37236197","id":"PMC_37236197","title":"YTHDF2 inhibition potentiates radiotherapy antitumor efficacy.","date":"2023","source":"Cancer cell","url":"https://pubmed.ncbi.nlm.nih.gov/37236197","citation_count":174,"is_preprint":false},{"pmid":"33577677","id":"PMC_33577677","title":"SUMOylation of YTHDF2 promotes mRNA degradation and cancer progression by increasing its binding affinity with m6A-modified mRNAs.","date":"2021","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/33577677","citation_count":155,"is_preprint":false},{"pmid":"34216543","id":"PMC_34216543","title":"Inhibition of YTHDF2 triggers proteotoxic cell death in MYC-driven breast cancer.","date":"2021","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/34216543","citation_count":148,"is_preprint":false},{"pmid":"36765030","id":"PMC_36765030","title":"O-GlcNAcylation of YTHDF2 promotes HBV-related hepatocellular carcinoma progression in an N6-methyladenosine-dependent manner.","date":"2023","source":"Signal transduction and targeted therapy","url":"https://pubmed.ncbi.nlm.nih.gov/36765030","citation_count":135,"is_preprint":false},{"pmid":"32126149","id":"PMC_32126149","title":"METTL3/YTHDF2 m6 A axis promotes tumorigenesis by degrading SETD7 and KLF4 mRNAs in bladder cancer.","date":"2020","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/32126149","citation_count":125,"is_preprint":false},{"pmid":"33156926","id":"PMC_33156926","title":"The mRNA m6A reader YTHDF2 suppresses proinflammatory pathways and sustains hematopoietic stem cell function.","date":"2021","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/33156926","citation_count":117,"is_preprint":false},{"pmid":"29795461","id":"PMC_29795461","title":"Epigallocatechin gallate targets FTO and inhibits adipogenesis in an mRNA m6A-YTHDF2-dependent manner.","date":"2018","source":"International journal of obesity (2005)","url":"https://pubmed.ncbi.nlm.nih.gov/29795461","citation_count":110,"is_preprint":false},{"pmid":"33658012","id":"PMC_33658012","title":"FBW7 suppresses ovarian cancer development by targeting the N6-methyladenosine binding protein YTHDF2.","date":"2021","source":"Molecular cancer","url":"https://pubmed.ncbi.nlm.nih.gov/33658012","citation_count":106,"is_preprint":false},{"pmid":"33593354","id":"PMC_33593354","title":"The biological function of m6A reader YTHDF2 and its role in human disease.","date":"2021","source":"Cancer cell international","url":"https://pubmed.ncbi.nlm.nih.gov/33593354","citation_count":105,"is_preprint":false},{"pmid":"31815430","id":"PMC_31815430","title":"YTHDF2 Recognition of N1-Methyladenosine (m1A)-Modified RNA Is Associated with Transcript Destabilization.","date":"2019","source":"ACS chemical biology","url":"https://pubmed.ncbi.nlm.nih.gov/31815430","citation_count":93,"is_preprint":false},{"pmid":"33087165","id":"PMC_33087165","title":"Activation of the KDM5A/miRNA-495/YTHDF2/m6A-MOB3B axis facilitates prostate cancer progression.","date":"2020","source":"Journal of experimental & clinical cancer research : 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\"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (m6A-seq, KO mouse, xenograft), independent functional validation of target\",\n      \"pmids\": [\"31031138\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"YTHDF2 directly binds m6A modification sites in the EGFR 3'-UTR and promotes EGFR mRNA degradation, suppressing MEK/ERK activation in hepatocellular carcinoma cells.\",\n      \"method\": \"m6A-RIP, RNA stability assay, overexpression/knockdown with downstream signaling readouts\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — single lab, multiple complementary assays (m6A-RIP + stability + signaling)\",\n      \"pmids\": [\"30423408\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"YTHDF2 promotes decay of m6A-containing IL11 and SERPINE2 mRNAs in hepatocytes, and its transcription is repressed by HIF-2α; administration of a HIF-2α antagonist restores YTHDF2-dependent mRNA decay.\",\n      \"method\": \"m6A-IP with high-throughput sequencing, RNA stability assay, conditional hepatocyte knockout, HIF-2α antagonist (PT2385) treatment\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multi-omic m6A profiling plus in vivo KO plus pharmacological epistasis\",\n      \"pmids\": [\"31735169\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"EGFR/SRC/ERK signaling phosphorylates YTHDF2 at serine 39 and threonine 381, stabilizing YTHDF2 protein; stabilized YTHDF2 promotes m6A-dependent decay of LXRA and HIVEP2 mRNAs in glioblastoma.\",\n      \"method\": \"Phosphorylation mapping by mass spectrometry, site-directed mutagenesis, RIP, m6A sequencing, in vivo tumorigenesis assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — MS-identified phosphosites validated by mutagenesis, multiple downstream functional assays\",\n      \"pmids\": [\"33420027\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Conditional knockout of mouse Ythdf2 increases HSC numbers; knockdown of human YTHDF2 expands cord blood HSCs ex vivo by stabilizing m6A-marked mRNAs encoding transcription factors (e.g., Tal1) critical for self-renewal.\",\n      \"method\": \"Conditional KO mouse, limiting dilution transplantation, m6A-seq in HSPCs, siRNA knockdown rescue\",\n      \"journal\": \"Cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo KO plus human ex vivo expansion plus m6A-seq plus epistasis rescue\",\n      \"pmids\": [\"30065315\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"YTHDF2 is SUMOylated in vivo and in vitro at K571; SUMOylation (induced by hypoxia) increases YTHDF2 binding affinity for m6A-modified mRNAs without affecting ubiquitination or localization, leading to enhanced mRNA degradation.\",\n      \"method\": \"In vitro SUMOylation assay, in vivo SUMOylation, site-directed mutagenesis (K571), m6A-RIP, mRNA stability assay\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution of SUMOylation, mutagenesis of SUMOylation site, functional binding assay\",\n      \"pmids\": [\"33577677\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FBW7 E3 ubiquitin ligase directly interacts with YTHDF2, inducing its proteasomal degradation and thereby reducing YTHDF2-mediated BMF mRNA decay in ovarian cancer.\",\n      \"method\": \"IP-mass spectrometry, co-IP, western blot, in vitro and in vivo tumorigenesis assays, m6A-RIP-seq, RNA-seq\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — MS identification of interaction, co-IP validation, functional rescue experiments\",\n      \"pmids\": [\"33658012\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"YTHDF2 recognizes N1-methyladenosine (m1A)-modified sequences in addition to m6A; YTHDF2 depletion increases abundance of endogenously m1A-modified transcripts, indicating YTHDF2-dependent destabilization of m1A-containing mRNAs.\",\n      \"method\": \"Chemical proteomics pulldown, recombinant protein binding assay, YTHDF2 knockdown with transcript-level quantification\",\n      \"journal\": \"ACS chemical biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — biochemical binding characterization plus cellular loss-of-function, but single lab\",\n      \"pmids\": [\"31815430\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"YTHDF2 promotes mRNA decay of WEE1 (a negative cell cycle regulator containing m6A) to accelerate mitotic entry; CDK1 activity stabilizes YTHDF2 protein, forming a CDK1–YTHDF2–WEE1 feedforward loop; CUL1, CUL4A, DDB1, and SKP2 E3 ligase components mediate YTHDF2 proteolysis.\",\n      \"method\": \"YTHDF2 siRNA depletion, m6A-seq, RNA stability assay, CDK1 inhibitor treatment, co-IP with E3 components\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods, pharmacological and genetic epistasis, E3 complex identification by co-IP\",\n      \"pmids\": [\"32267835\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"YTHDF2 and YTHDF3 are both required for somatic cell reprogramming; YTHDF2 recruits the CCR4-NOT deadenylase complex to promote deadenylation and mRNA clearance of somatic genes (e.g., Tead2, Tgfb1), facilitating mesenchymal-to-epithelial transition during iPSC generation.\",\n      \"method\": \"CRISPR/siRNA KD of Ythdf2/3 in reprogramming assay, scRNA-seq, co-IP with CCR4-NOT, mRNA stability assay\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic requirement shown, CCR4-NOT interaction validated by co-IP, target mRNAs identified by sequencing\",\n      \"pmids\": [\"32905781\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"YTHDF2 recognizes m6A-modified PER1 and TP53 mRNAs and promotes their degradation, contributing to ocular melanoma tumorigenesis driven by elevated histone lactylation.\",\n      \"method\": \"m6A-RIP, RNA stability assay, overexpression/knockdown in vitro and in vivo\",\n      \"journal\": \"Genome biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct m6A-RIP on specific targets plus functional rescue, single lab\",\n      \"pmids\": [\"33726814\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"YTHDF2 is required for TNBC cell survival; disrupting YTHDF2-dependent mRNA degradation stabilizes MAPK pathway mRNAs, inducing EMT and increasing global translation, ultimately causing ER stress-induced apoptosis.\",\n      \"method\": \"Pooled CRISPR-Cas9 screen, eCLIP, m6A-seq, scRibo-STAMP, in vivo tumor models\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — CRISPR screen plus eCLIP mapping plus ribosome profiling at single-cell resolution\",\n      \"pmids\": [\"34216543\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"O-GlcNAcylation of YTHDF2 at serine 263 (by OGT) enhances its protein stability by inhibiting ubiquitination; O-GlcNAcylated YTHDF2 stabilizes MCM2 and MCM5 mRNAs in an m6A-dependent manner to promote cell cycle progression.\",\n      \"method\": \"Co-IP, mass spectrometry, site-directed mutagenesis (S263), OGT inhibitor treatment, MeRIP, RNA stability assay\",\n      \"journal\": \"Signal transduction and targeted therapy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — MS identification, mutagenesis, pharmacological inhibition of OGT, multi-omic validation\",\n      \"pmids\": [\"36765030\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Ythdf2-deficient HSCs chronically upregulate multiple m6A-modified inflammation-related transcripts, activating proinflammatory pathways; YTHDF2 is required to protect HSCs from inflammation-induced dysfunction and experimentally induced inflammation increases YTHDF2 expression.\",\n      \"method\": \"Conditional Ythdf2 KO mouse, serial transplantation, transcriptomic profiling, experimental inflammation induction\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo KO with functional HSC readout, serial transplant, multi-condition epistasis\",\n      \"pmids\": [\"33156926\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"YTHDF2 deficiency in tumor-associated macrophages (TAMs) reprograms them toward an antitumoral phenotype by targeting IFN-γ–STAT1 signaling; YTHDF2 expression in TAMs is regulated by IL-10–STAT3 signaling.\",\n      \"method\": \"Myeloid-specific Ythdf2 KO, flow cytometry, in vivo tumor models, STAT1/STAT3 signaling pathway analyses, TLR9-siRNA targeting\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — cell-type-specific KO with defined signaling pathway, in vivo rescue, pharmacological targeting\",\n      \"pmids\": [\"36658237\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Ionizing radiation induces YTHDF2 expression in MDSCs via NF-κB signaling; YTHDF2 in turn directly binds and degrades transcripts encoding negative regulators of NF-κB, creating an IR–YTHDF2–NF-κB feedforward circuit.\",\n      \"method\": \"Myeloid-specific Ythdf2 KO, RNA-seq, m6A-RIP, in vivo tumor irradiation models, NF-κB inhibitor treatment\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO, m6A-RIP identification of targets, in vivo epistasis with pharmacological NF-κB inhibition\",\n      \"pmids\": [\"37236197\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"YTHDF2 knockdown in LPS-stimulated macrophages increases mRNA stability of MAP2K4 and MAP4K4, activating MAPK and NF-κB signaling to enhance proinflammatory cytokine expression.\",\n      \"method\": \"siRNA knockdown, mRNA stability assay, signaling pathway inhibitors, cytokine measurement\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single lab, siRNA KD with mRNA stability measurements and pathway inhibitor rescue\",\n      \"pmids\": [\"30875984\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"X-ray crystallography of small-molecule fragment ligands bound to the YTH domain of YTHDF2 revealed the m6A-binding pocket; fragment ligands compete with m6A-RNA for binding.\",\n      \"method\": \"X-ray crystallography, fluorescence-based competitive binding assay\",\n      \"journal\": \"ACS medicinal chemistry letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structures at high resolution with quantified binding affinities\",\n      \"pmids\": [\"36110386\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"YTHDF2 mediates decay of m6A-modified CBS mRNA by binding within its CDS; in gastric cancer under hypoxia, lncRNA CBSLR interacts with YTHDF2 to enhance its binding to CBS mRNA, reducing CBS protein levels and leading to ferroptosis resistance.\",\n      \"method\": \"RIP, m6A-RIP, RNA stability assay, lncRNA pulldown, in vitro and in vivo cancer models\",\n      \"journal\": \"Journal of advanced research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — direct YTHDF2-RIP on CBS mRNA, lncRNA interaction identified, single lab\",\n      \"pmids\": [\"35499052\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Mouse Ythdf2 knockout in spermatogonia leads to downregulated matrix metallopeptidase expression (Mmp3, Mmp13, Adamts1, Adamts9); m6A-IP-PCR and RIP-PCR confirm YTHDF2 binds and promotes degradation of these m6A-marked mRNAs, regulating cell adhesion and proliferation.\",\n      \"method\": \"CRISPR/Cas9 KO in spermatogonia, m6A-IP-PCR, RIP-PCR, rescue with Mmp13 inhibition\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO, m6A-RIP target validation, partial rescue experiment\",\n      \"pmids\": [\"31959747\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"YTHDF2 directly binds the m6A-modified CDS of DDX58 (RIG-I) mRNA and promotes its degradation; YTHDF2 depletion in bladder cancer stabilizes RIG-I, activating innate immune signaling and recruiting CD8+ T cells.\",\n      \"method\": \"MeRIP-seq, RNA-seq, RIP, RNA stability assay, in vivo orthotopic tumor model\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multi-omic target identification, direct RIP on RIG-I mRNA, in vivo immune phenotyping\",\n      \"pmids\": [\"36939388\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"YTHDF2 facilitates translation of m6A-modified ETV5 mRNA by recognizing its 5'-UTR m6A and recruiting eIF3B, elevating ETV5 expression which transcriptionally induces PD-L1 and VEGFA in HCC.\",\n      \"method\": \"MeRIP-seq, RIP, co-IP with eIF3B, polysome profiling, in vivo HCC models\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct binding in 5'-UTR shown by RIP, eIF3B interaction by co-IP, translational output measured\",\n      \"pmids\": [\"38247171\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"YTHDF2 acts as a B cell-intrinsic factor required for GC B cell fate commitment; Ythdf2-deficient B cells fail to enter GCs because they cannot attenuate the plasmablast genetic program; YTHDF2 targets m6A-methylated plasmablast-regulating transcripts for decay.\",\n      \"method\": \"Conditional B-cell Ythdf2 KO, scRNA-seq, YTHDF2 binding site analysis, in vivo GC response\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo B cell KO, scRNA-seq-based target identification, clear differentiation phenotype\",\n      \"pmids\": [\"35508130\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"YTHDF2 promotes miR-126 maturation from pre-miR-126 by recognizing m6A modification within pre-miR-126 and recruiting AGO2, a regulator of pre-miRNA processing, in AML cells.\",\n      \"method\": \"RIP, m6A-RIP on pre-miRNA, AGO2 co-IP, rescue with miR-126 overexpression\",\n      \"journal\": \"Genes & diseases\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — novel mechanism of pre-miRNA processing, but single lab; AGO2 interaction validated by co-IP\",\n      \"pmids\": [\"37588203\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Germ cell-specific Ythdf2 knockout mice are male sterile; YTHDF2 mediates timely clearance of phase-specific m6A-marked transcripts during spermatogenesis (differentiated spermatogonia to pachytene spermatocyte transition); loss of YTHDF2 leads to persistence of mRNAs mainly enriched in transcription regulation.\",\n      \"method\": \"Conditional KO (Vasa-Cre, Stra8-Cre), RNA-seq, YTHDF2-RIP-seq, MeRIP-qPCR, sperm functional assays\",\n      \"journal\": \"Cell proliferation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple Cre drivers, RIP-seq genome-wide target identification, functional fertility phenotype\",\n      \"pmids\": [\"34850470\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"HSP90β physically interacts with both YTHDF2 and the E3 ligase STUB1 in the cytoplasm, competitively inhibiting STUB1-mediated ubiquitination and degradation of YTHDF2, thereby stabilizing YTHDF2 protein in HCC.\",\n      \"method\": \"Co-IP, domain-mapping co-IP, ubiquitination assay, HSP90 inhibitor treatment\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP, domain mapping, ubiquitination assay, single lab\",\n      \"pmids\": [\"37515378\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PBRM1 (SWI/SNF component) interacts with YTHDF2 and is required for YTHDF2 binding to m6A-modified HIF-1α mRNA; YTHDF2 promotes HIF-1α mRNA translation rather than decay, and YTHDF2 depletion reduces HIF-1α protein.\",\n      \"method\": \"Co-IP, polysome/translation assay, m6A-RIP, siRNA depletion\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — co-IP of PBRM1-YTHDF2 validated, translational role shown by polysome assay, single lab\",\n      \"pmids\": [\"34200988\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"YTHDF2 promotes nuclear nascent RNA synthesis in CD8+ T cells in an m6A-recognition-dependent manner and interacts with IKZF1/3 to sustain transcription of their target genes; nuclear YTHDF2 also orchestrates chromatin changes promoting T cell polyfunctionality.\",\n      \"method\": \"T cell-specific KO, ChIP-seq, m6A-seq, YTHDF2 co-IP with IKZF1/3, nascent RNA assays, in vivo tumor models with lenalidomide rescue\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO, multi-omic profiling, direct protein interaction by co-IP, pharmacological rescue in vivo\",\n      \"pmids\": [\"39500904\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"YTHDF2 functions as a dual reader: it destabilizes m6A-modified mRNAs (canonical) while stabilizing m5C-modified mRNAs by recruiting PABPC1, thereby enhancing expression and ATP synthesis in B cell malignancies.\",\n      \"method\": \"RIP-seq, m5C-seq, co-IP with PABPC1, mRNA stability assays, YTHDF2 overexpression/KO in B cell transformation models\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — genome-wide sequencing for both m5C and m6A targets, PABPC1 interaction by co-IP, overexpression-induced transformation is a strong functional readout\",\n      \"pmids\": [\"39694037\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"YTHDF2 promotes degradation of Hmox1 (heme oxygenase 1) mRNA in an m6A-dependent manner in alveolar macrophages, and myeloid-specific Ythdf2 KO elevates Hmox1, attenuating alternative macrophage activation and protecting from pulmonary hypertension.\",\n      \"method\": \"Myeloid-specific Ythdf2 KO (Lyz2-Cre), m6A-RIP, mRNA stability assay, Hmox1 inhibitor rescue, in vivo PH model\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — cell-type-specific in vivo KO, direct m6A-RIP on Hmox1, pharmacological epistasis\",\n      \"pmids\": [\"36801705\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"YTHDF2 promotes m6A-dependent decay of TGF-β signaling pathway component mRNAs (ligands, receptors, transcription regulators) in hippocampal NSCs; Ythdf2 deletion elevates TGF-β signaling and increases quiescence acquisition.\",\n      \"method\": \"Conditional Ythdf2 KO in NSCs, m6A-seq, YTHDF2-RIP-seq, mRNA decay profiling, TGF-β pathway inhibitor rescue\",\n      \"journal\": \"Cell stem cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO, multi-modal sequencing, pathway epistasis with inhibitor rescue\",\n      \"pmids\": [\"39476834\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"YTHDF2 forms a complex with eIF3F and DDX1 to enhance translation of m6A-modified mRNAs encoding microtubule-associated proteins, driving cancer progression and paclitaxel resistance independently of RNA decay.\",\n      \"method\": \"Co-IP (YTHDF2-eIF3F, YTHDF2-DDX1), polysome profiling, m6A-seq, RNA stability assay (ruling out decay), in vivo tumor models, virtual screening for inhibitor\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — co-IP of translation complex, polysome profiling, m6A-seq, stability assay controls, in vivo validation\",\n      \"pmids\": [\"40480228\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"YTHDF2 stabilizes Cx3cl1 (CX3CL1) mRNA in an m6A-dependent manner in peritumoral hepatocytes, facilitating CD8+ T cell recruitment; oxaliplatin upregulates YTHDF2 expression via cGAS-STING signaling.\",\n      \"method\": \"Liver-specific Ythdf2 KO mouse, tumor-bearing model, m6A-RIP, RNA stability assay, cGAS-STING pathway analysis\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — cell-type-specific KO, m6A-RIP target validation, upstream pathway epistasis, single lab\",\n      \"pmids\": [\"39237909\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Smooth muscle cell-specific Ythdf2 deficiency ameliorates pulmonary vascular remodeling; Ythdf2 paradoxically stabilizes Myadm mRNA in an m6A-dependent manner in PASMCs, promoting cell proliferation via suppression of the cell cycle inhibitor p21.\",\n      \"method\": \"SM-specific Ythdf2 KO (SM22α-Cre), proteomics, m6A-seq, RIP, mRNA stability assay, in vivo PH model\",\n      \"journal\": \"Hypertension\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — cell-type-specific in vivo KO, proteomics + m6A-seq + RIP for target identification, mechanistic chain to p21\",\n      \"pmids\": [\"38832511\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"YTHDF2 controls mRNA stability of the ubiquitin ligase ASB2 in skeletal muscle; muscle-specific YTHDF2 deletion impairs postnatal muscle growth and hypertrophic response by activating SMAD3-dependent TGF-β anti-growth program.\",\n      \"method\": \"Muscle-specific Ythdf2 KO, m6A-RIP, mRNA stability assay, SMAD3 readout, hypertrophy stimulus model\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo KO with clear growth phenotype, direct m6A-RIP on ASB2 mRNA, signaling pathway linkage\",\n      \"pmids\": [\"38467649\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"YTHDF2 promotes degradation of m6A-modified DAPK3 mRNA by binding its 3'-UTR, driving gallbladder cancer progression and gemcitabine resistance.\",\n      \"method\": \"RIP-seq, MeRIP-seq, RNA-seq integration, RNA stability assay, in vitro/in vivo functional assays\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multi-omic target identification, direct RIP validation, in vivo xenograft, single lab\",\n      \"pmids\": [\"37700438\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"YTHDF2 binds m6A-modified Ythdf2/YTHDF2 mRNA as part of an autoregulatory loop in CD8+ T cells, reinforcing its own expression; this nuclear function requires m6A recognition by the YTH domain.\",\n      \"method\": \"m6A-seq, YTHDF2 nuclear localization demonstrated, domain mutagenesis, T cell-specific KO\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic and domain-mutagenesis evidence, but autoregulation is a secondary finding within a larger study\",\n      \"pmids\": [\"39500904\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Ythdf2 binds m6A sites in STK11 mRNA and recruits AGO2 to form a silencing complex promoting STK11 mRNA degradation; loss of Ythdf2 stabilizes STK11, activates AMPK/mTOR, and impairs myoblast differentiation.\",\n      \"method\": \"Co-IP of Ythdf2-Ago2, RIP, m6A-RIP, RNA stability assay, AMPK/mTOR pathway readouts\",\n      \"journal\": \"International journal of biological macromolecules\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — Ago2 interaction validated by co-IP, m6A-RIP target confirmation, pathway epistasis, single lab\",\n      \"pmids\": [\"37884231\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"YTHDF2 mediates m6A-dependent degradation of SLC7A11 mRNA in Sertoli cells, as shown by RIP experiments demonstrating direct binding; this is exploited by BPF toxin to disrupt blood-testis barrier integrity.\",\n      \"method\": \"MeRIP, RIP, FTO overexpression/KD, in vivo/in vitro models\",\n      \"journal\": \"Environmental pollution\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — RIP showing binding, mechanistic context is toxicology model, single lab\",\n      \"pmids\": [\"38996995\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"YTHDF2 promotes degradation of CDKN1B mRNA in an m6A-dependent manner in intrahepatic cholangiocarcinoma, identified by integration of RNA-seq, MeRIP-seq, and anti-YTHDF2 RIP-seq.\",\n      \"method\": \"MeRIP-seq, RNA-seq, anti-YTHDF2 RIP-seq integration, RNA stability assay, PDX model\",\n      \"journal\": \"Clinical and translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multi-omic triple sequencing approach plus PDX validation, single lab\",\n      \"pmids\": [\"35696608\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"YBX2 interacts with YTHDF2 through its cold-shock domain and recruits YTHDF2 to cytoplasmic granules; YTHDF2 knockdown ameliorates YBX2-induced HSPA6 mRNA destabilization in endometrial cancer cells.\",\n      \"method\": \"Co-IP, RNA pulldown, YTHDF2 KD rescue, mRNA stability assay\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — co-IP of YBX2-YTHDF2, stability rescue, but single lab, single method per finding\",\n      \"pmids\": [\"37030331\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"YTHDF2 cardiomyocyte-specific knockout drives cardiac dysfunction; YTHDF2 normally binds m6A-modified Myzap mRNA and controls its stability, and loss of YTHDF2 leads to upregulation of MYZAP, causing adverse cardiac remodeling.\",\n      \"method\": \"Cardiomyocyte-specific Ythdf2 KO, proteomics, m6A-RIP on Myzap mRNA, in vivo cardiac function measurements\",\n      \"journal\": \"JACC. Basic to translational science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo KO with cardiac phenotype, proteomics target identification, m6A-RIP validation, single lab\",\n      \"pmids\": [\"37791304\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Lactylation of YTHDF2 (mediated by elevated lactate) increases its protein levels in cardiomyocytes; the intrinsically disordered region of YTHDF2 (not its m6A-binding activity) is required for its role in upregulating G3BP1 to control cardiomyocyte size and OGD/R-induced apoptosis.\",\n      \"method\": \"Lactylation detection, domain-deletion mutants lacking m6A binding, G3BP1 pathway readout, OGD/R cardiomyocyte model\",\n      \"journal\": \"Basic research in cardiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — domain mutants dissecting m6A-dependent vs -independent functions, lactylation assay, single lab\",\n      \"pmids\": [\"38563985\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IFN-γ induces autophagic degradation of tumoral YTHDF2, sensitizing tumor cells to CD8+ T cell-mediated cytotoxicity; tumoral YTHDF2 deficiency promotes macrophage recruitment via CX3CL1 and enhances mitochondrial respiration in CD8+ T cells by impairing tumor glycolysis.\",\n      \"method\": \"Tumoral Ythdf2 KO, co-culture assays, autophagy inhibitors, metabolic assays, in vivo immunocompetent tumor models\",\n      \"journal\": \"Science immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo tumoral KO, mechanistic autophagy pathway for YTHDF2 degradation, metabolic consequence measured\",\n      \"pmids\": [\"38820140\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"YTHDF2 is a cytoplasmic (and, in certain contexts, nuclear) m6A reader that primarily recruits the CCR4-NOT deadenylase complex to promote decay of m6A-modified mRNAs, but can also stabilize mRNAs bearing m5C modifications via PABPC1 recruitment or enhance translation of m6A-modified mRNAs by interacting with eIF3F/DDX1; its activity and stability are regulated by multiple post-translational modifications including SUMOylation at K571 (increasing m6A-RNA binding affinity), O-GlcNAcylation at S263 (blocking ubiquitination), phosphorylation at S39/T381 by EGFR/SRC/ERK (stabilizing the protein), CDK1-dependent stabilization during mitosis, and proteasomal degradation mediated by FBW7 and CUL1/CUL4A–DDB1–SKP2 E3 complexes, placing YTHDF2 at the intersection of cell-cycle control, stem cell self-renewal, immune regulation, and oncogenesis through coordinated post-transcriptional gene expression programs.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"YTHDF2 is a cytoplasmic m6A reader protein that serves as a central post-transcriptional regulator, primarily accelerating mRNA decay but also modulating translation and miRNA maturation in a context-dependent manner. Its canonical function involves binding m6A-modified mRNAs through its YTH domain and recruiting the CCR4-NOT deadenylase complex to promote deadenylation and degradation of target transcripts — a mechanism demonstrated across hematopoietic stem cells, immune cells, germ cells, and multiple cancer types [PMID:32905781, PMID:31031138, PMID:34850470]. Beyond decay, YTHDF2 enhances translation of specific m6A-modified mRNAs by recruiting eIF3B or forming a complex with eIF3F and DDX1 [PMID:38247171, PMID:40480228], stabilizes m5C-modified mRNAs through PABPC1 recruitment [PMID:39694037], and operates in the nucleus to sustain transcription via interaction with IKZF1/3 in CD8+ T cells [PMID:39500904]. YTHDF2 protein stability and activity are extensively regulated by post-translational modifications — including EGFR/SRC/ERK-mediated phosphorylation at S39/T381 [PMID:33420027], SUMOylation at K571 that enhances m6A-RNA binding under hypoxia [PMID:33577677], O-GlcNAcylation at S263 that blocks ubiquitination [PMID:36765030], CDK1-dependent stabilization during mitosis [PMID:32267835], and proteasomal degradation directed by FBW7, CUL1/CUL4A–DDB1–SKP2, and STUB1 E3 ligase complexes [PMID:33658012, PMID:32267835, PMID:37515378].\",\n  \"teleology\": [\n    {\n      \"year\": 2018,\n      \"claim\": \"Establishing YTHDF2 as a physiological regulator of HSC self-renewal resolved how m6A-dependent mRNA turnover controls stem cell pool size — YTHDF2 loss stabilized m6A-marked transcription factor mRNAs (e.g., Tal1), expanding functional HSCs ex vivo and in vivo.\",\n      \"evidence\": \"Conditional Ythdf2 KO mouse with limiting-dilution transplantation and m6A-seq in HSPCs\",\n      \"pmids\": [\"30065315\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of all HSC-relevant YTHDF2 target mRNAs not fully catalogued\", \"Whether YTHDF2 acts exclusively through decay in HSCs or also through translational regulation was not addressed\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrating that YTHDF2 binds m6A sites in EGFR 3′-UTR and accelerates EGFR mRNA degradation linked YTHDF2-mediated decay to oncogenic signaling suppression in hepatocellular carcinoma.\",\n      \"evidence\": \"m6A-RIP, RNA stability assay, and downstream MEK/ERK signaling readouts in HCC cells\",\n      \"pmids\": [\"30423408\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab study without independent replication\", \"Structural basis of YTHDF2 selectivity for EGFR mRNA over other m6A targets not determined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identification of Tnfrsf2 as a YTHDF2-degraded target in AML established that YTHDF2 suppresses apoptotic priming in leukemic stem cells, providing a disease-specific mechanistic rationale for targeting YTHDF2 in AML.\",\n      \"evidence\": \"m6A-seq, RNA stability assays, conditional KO mouse models, human AML xenograft transplantation\",\n      \"pmids\": [\"31031138\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether all AML subtypes depend on YTHDF2 equally was not tested\", \"Redundancy with YTHDF1/3 in AML context not resolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Discovery that YTHDF2 recognizes m1A in addition to m6A broadened the epitranscriptomic reader specificity of the YTH domain beyond a single modification.\",\n      \"evidence\": \"Chemical proteomics pulldown and recombinant protein binding assay with m1A probes, followed by cellular knockdown\",\n      \"pmids\": [\"31815430\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis for m1A recognition not resolved\", \"Physiological relevance of m1A reading in vivo not established\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showing that YTHDF2 knockdown in macrophages stabilizes MAP2K4/MAP4K4 mRNAs and hyperactivates MAPK/NF-κB signaling revealed YTHDF2 as a tonic suppressor of inflammatory gene expression programs.\",\n      \"evidence\": \"siRNA knockdown, mRNA stability assay, signaling pathway inhibitors in LPS-stimulated macrophages\",\n      \"pmids\": [\"30875984\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Macrophage-specific YTHDF2 KO was not used\", \"Direct m6A-RIP on MAP2K4/MAP4K4 not performed in this study\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"The CDK1–YTHDF2–WEE1 feedforward loop established that YTHDF2-mediated mRNA decay is integrated into cell cycle control: CDK1 stabilizes YTHDF2, which degrades WEE1 mRNA to accelerate mitotic entry, while CUL1/CUL4A–DDB1–SKP2 E3 complexes degrade YTHDF2 to reset the cycle.\",\n      \"evidence\": \"siRNA depletion, m6A-seq, RNA stability assay, CDK1 inhibitor treatment, co-IP with E3 ligase components\",\n      \"pmids\": [\"32267835\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct phosphorylation of YTHDF2 by CDK1 not demonstrated\", \"Relative contributions of CUL1 vs CUL4A complexes not disentangled\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Establishing that YTHDF2 recruits the CCR4-NOT deadenylase complex to degrade somatic gene mRNAs during iPSC reprogramming defined the effector mechanism for YTHDF2-mediated mRNA clearance.\",\n      \"evidence\": \"CRISPR/siRNA KD in reprogramming, scRNA-seq, co-IP with CCR4-NOT subunits, mRNA stability assay\",\n      \"pmids\": [\"32905781\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CCR4-NOT is the universal YTHDF2 decay effector or context-specific was not resolved\", \"Contribution of YTHDF3 versus YTHDF2 to CCR4-NOT recruitment not fully separated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Mapping EGFR/SRC/ERK-dependent phosphorylation of YTHDF2 at S39 and T381 revealed how oncogenic signaling stabilizes the reader protein, amplifying m6A-dependent mRNA decay in glioblastoma.\",\n      \"evidence\": \"Phosphorylation mapping by mass spectrometry, site-directed mutagenesis, RIP, m6A-seq, in vivo tumorigenesis\",\n      \"pmids\": [\"33420027\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether phosphorylation alters YTHDF2 substrate specificity or just abundance was not clarified\", \"Kinase-dead rescue experiments not performed\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identification of K571 SUMOylation as a hypoxia-induced modification that increases YTHDF2's m6A-binding affinity without affecting stability established a distinct post-translational control axis that tunes reader activity rather than abundance.\",\n      \"evidence\": \"In vitro and in vivo SUMOylation assays, K571 mutagenesis, m6A-RIP, mRNA stability assay\",\n      \"pmids\": [\"33577677\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"SUMO E3 ligase identity not determined\", \"Whether SUMOylation affects YTHDF2 interactome (e.g., CCR4-NOT recruitment) not tested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrating that FBW7 targets YTHDF2 for proteasomal degradation added a tumor-suppressive E3 ligase axis to YTHDF2 regulation, connecting FBW7 loss in ovarian cancer to aberrant m6A-reader accumulation.\",\n      \"evidence\": \"IP-mass spectrometry, co-IP, ubiquitination assays, in vitro/in vivo tumorigenesis, m6A-RIP-seq\",\n      \"pmids\": [\"33658012\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"FBW7 degron motif on YTHDF2 not mapped\", \"Whether FBW7-mediated regulation is phosphodegron-dependent (as for canonical FBW7 substrates) not determined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Ythdf2 conditional KO in HSCs revealed chronic upregulation of m6A-modified inflammation transcripts, establishing YTHDF2 as a guardian that dampens inflammatory signaling to preserve HSC fitness during stress.\",\n      \"evidence\": \"Conditional Ythdf2 KO mouse, serial transplantation, transcriptomic profiling, experimental inflammation\",\n      \"pmids\": [\"33156926\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether anti-inflammatory function of YTHDF2 in HSCs is separable from its role in self-renewal not tested\", \"Direct demonstration that specific inflammation transcripts are m6A-marked and YTHDF2-bound was limited\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Germ cell-specific Ythdf2 KO demonstrated male infertility from failure to clear phase-specific transcripts during spermatogenesis, establishing a non-redundant developmental role for YTHDF2 in germ cell differentiation.\",\n      \"evidence\": \"Multiple Cre drivers (Vasa-Cre, Stra8-Cre), RIP-seq, MeRIP-qPCR, fertility assays\",\n      \"pmids\": [\"34850470\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Redundancy with YTHDF1/3 in spermatogenesis not systematically addressed\", \"Whether YTHDF2 acts solely through decay or also translation in spermatocytes not resolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"A CRISPR screen in TNBC revealed that YTHDF2 is essential for cancer cell viability: its loss stabilizes MAPK pathway mRNAs, induces EMT, increases global translation, and triggers lethal ER stress — demonstrating that YTHDF2 buffers translational homeostasis.\",\n      \"evidence\": \"Pooled CRISPR screen, eCLIP, m6A-seq, scRibo-STAMP, in vivo tumor models\",\n      \"pmids\": [\"34216543\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ER stress is a universal consequence of YTHDF2 loss or TNBC-specific not established\", \"Mechanism linking stabilized mRNAs to increased global translation not fully resolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Structural determination of small-molecule fragments bound to the YTHDF2 YTH domain m6A pocket enabled pharmacological targeting, providing the first atomic-resolution view of druggable YTHDF2 interfaces.\",\n      \"evidence\": \"X-ray crystallography and fluorescence-based competitive binding assay\",\n      \"pmids\": [\"36110386\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No cell-active inhibitor demonstrated\", \"Fragment affinity was modest; drug-like optimization not achieved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"B cell-specific Ythdf2 KO showed failure of GC B cell commitment because plasmablast-program transcripts were not cleared, revealing YTHDF2 as a fate switch in humoral immunity.\",\n      \"evidence\": \"Conditional B-cell Ythdf2 KO, scRNA-seq, YTHDF2 binding-site analysis, in vivo GC response\",\n      \"pmids\": [\"35508130\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether YTHDF2 also functions at later GC stages (e.g., affinity maturation) not investigated\", \"Specific m6A sites on plasmablast transcripts not mapped at nucleotide resolution\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"O-GlcNAcylation of YTHDF2 at S263 by OGT was shown to stabilize YTHDF2 by blocking ubiquitination, linking nutrient sensing to m6A-reader abundance and cell cycle progression via MCM2/MCM5 mRNA stabilization.\",\n      \"evidence\": \"MS identification of S263 O-GlcNAcylation, site-directed mutagenesis, OGT inhibitor, MeRIP, RNA stability assay\",\n      \"pmids\": [\"36765030\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which E3 ligase is blocked by O-GlcNAcylation at S263 not identified\", \"Whether S263 O-GlcNAcylation affects YTHDF2 RNA-binding specificity not tested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Myeloid-specific Ythdf2 KO reprogrammed tumor-associated macrophages toward antitumoral phenotypes via IFN-γ–STAT1 signaling, and YTHDF2 expression was regulated by IL-10–STAT3, establishing a macrophage-intrinsic m6A-dependent immune checkpoint.\",\n      \"evidence\": \"Myeloid-specific Ythdf2 KO, flow cytometry, in vivo tumor models, STAT1/STAT3 signaling analysis\",\n      \"pmids\": [\"36658237\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific m6A-modified STAT1 pathway mRNAs targeted by YTHDF2 not comprehensively identified\", \"Whether this mechanism operates across all tumor types not tested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"An IR–YTHDF2–NF-κB feedforward circuit in MDSCs demonstrated that ionizing radiation induces YTHDF2 via NF-κB, and YTHDF2 then degrades negative regulators of NF-κB, amplifying immunosuppression.\",\n      \"evidence\": \"Myeloid-specific Ythdf2 KO, RNA-seq, m6A-RIP, in vivo tumor irradiation, NF-κB inhibitor\",\n      \"pmids\": [\"37236197\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identities of all NF-κB negative regulators targeted by YTHDF2 not exhaustively mapped\", \"Therapeutic window for combining YTHDF2 inhibition with radiotherapy not defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"HSP90β was shown to competitively block STUB1-mediated ubiquitination of YTHDF2, adding a chaperone-dependent stabilization mechanism to the growing repertoire of YTHDF2 post-translational regulation.\",\n      \"evidence\": \"Reciprocal co-IP, domain mapping, ubiquitination assay, HSP90 inhibitor treatment in HCC\",\n      \"pmids\": [\"37515378\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether HSP90β stabilization of YTHDF2 is constitutive or signal-regulated not determined\", \"Interaction interface on YTHDF2 not mapped\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Discovery that YTHDF2 recognizes m5C-modified mRNAs and stabilizes them by recruiting PABPC1 — opposite to its canonical m6A-mediated decay — established YTHDF2 as a dual-modification reader with modification-dependent functional polarity, driving B cell malignancy.\",\n      \"evidence\": \"RIP-seq, m5C-seq, co-IP with PABPC1, mRNA stability assays, YTHDF2 OE/KO in B cell transformation models\",\n      \"pmids\": [\"39694037\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for m5C recognition by the YTH domain not determined\", \"Whether m5C reading by YTHDF2 operates broadly or is restricted to B cell lineage not tested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identification of a YTHDF2–eIF3F–DDX1 translation complex demonstrated a decay-independent translational enhancement function for YTHDF2 on m6A-modified mRNAs encoding microtubule-associated proteins, explaining paclitaxel resistance.\",\n      \"evidence\": \"Co-IP of complex components, polysome profiling, m6A-seq, RNA stability assay ruling out decay, in vivo tumor models\",\n      \"pmids\": [\"40480228\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether eIF3F/DDX1 complex is the same as the eIF3B-dependent translation pathway reported in HCC not clarified\", \"Structural basis of YTHDF2–eIF3F interaction unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Nuclear YTHDF2 in CD8+ T cells was shown to promote nascent RNA synthesis by interacting with IKZF1/3 and sustaining their transcriptional programs, expanding YTHDF2's functional repertoire beyond cytoplasmic mRNA fate determination.\",\n      \"evidence\": \"T cell-specific KO, ChIP-seq, m6A-seq, YTHDF2 co-IP with IKZF1/3, nascent RNA assays, in vivo lenalidomide rescue\",\n      \"pmids\": [\"39500904\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether nuclear YTHDF2 directly contacts chromatin or acts through IKZF1/3 intermediaries not resolved\", \"How YTHDF2 nuclear import is regulated remains unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"IFN-γ-induced autophagic degradation of tumoral YTHDF2 was shown to sensitize tumors to CD8+ T cell killing, revealing a non-proteasomal degradation pathway that connects immune cytokine signaling to m6A reader abundance in the tumor microenvironment.\",\n      \"evidence\": \"Tumoral Ythdf2 KO, co-culture assays, autophagy inhibitors, metabolic assays, in vivo immunocompetent models\",\n      \"pmids\": [\"38820140\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Selective autophagy receptor mediating YTHDF2 degradation not identified\", \"Whether autophagic degradation of YTHDF2 operates in non-tumor cell types not tested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"YTHDF2-dependent decay of TGF-β pathway mRNAs in hippocampal neural stem cells demonstrated that YTHDF2 controls the balance between NSC activation and quiescence, extending its stem cell regulatory role beyond the hematopoietic system.\",\n      \"evidence\": \"Conditional Ythdf2 KO in NSCs, m6A-seq, YTHDF2-RIP-seq, mRNA decay profiling, TGF-β inhibitor rescue\",\n      \"pmids\": [\"39476834\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether YTHDF2 regulates NSC quiescence in aging or disease contexts not tested\", \"Redundancy with YTHDF1/3 in NSCs not addressed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include: (1) the structural basis for YTHDF2's dual recognition of m6A and m5C and how modification identity switches its output from decay to stabilization; (2) how nuclear versus cytoplasmic YTHDF2 pools are partitioned and whether translational, transcriptional, and decay functions are mutually exclusive or co-occurring; (3) whether the multiple E3 ligase systems (FBW7, SKP2, STUB1) and post-translational modifications act hierarchically or in parallel across tissues.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model for m5C recognition by YTH domain\", \"Nuclear import/export mechanism undetermined\", \"Integrated model of PTM crosstalk on YTHDF2 lacking\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 1, 4, 5, 7, 28]},\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [0, 9, 11, 20]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [21, 31]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [27]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 9, 25, 31]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [27, 36]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 9, 11, 20, 28, 30]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [8, 12]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [14, 15, 22, 27]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 3, 16]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [6, 8, 25]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [11, 43]}\n    ],\n    \"complexes\": [\n      \"CCR4-NOT deadenylase complex\",\n      \"YTHDF2–eIF3F–DDX1 translation complex\"\n    ],\n    \"partners\": [\n      \"CNOT1\",\n      \"eIF3F\",\n      \"eIF3B\",\n      \"DDX1\",\n      \"PABPC1\",\n      \"IKZF1\",\n      \"FBW7\",\n      \"HSP90AB1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}