{"gene":"YTHDF3","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2017,"finding":"YTHDF3 promotes protein synthesis in synergy with YTHDF1 and affects m6A-modified mRNA decay mediated through YTHDF2; cells deficient in all three YTHDF proteins show the most dramatic accumulation of m6A-modified transcripts, indicating cooperative and integrated cytoplasmic metabolism of m6A-modified mRNAs.","method":"Genetic depletion (single and triple knockouts), polysome profiling, mRNA stability assays, m6A-seq","journal":"Cell Research","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (KO, polysome profiling, mRNA stability), replicated across YTHDF family members in same study with clear epistasis","pmids":["28106072"],"is_preprint":false},{"year":2018,"finding":"YTHDF3 suppresses interferon-stimulated gene (ISG) expression by promoting translation of the transcription co-repressor FOXO3 mRNA; YTHDF3 cooperates with cofactors PABP1 and eIF4G2 to promote FOXO3 translation by binding the translation initiation region of FOXO3 mRNA. Both the YTH and the P/Q/N-rich domains of YTHDF3 are required for FOXO3 RNA-binding capacity. Notably, METTL3-mediated m6A modification was NOT required for this specific interaction.","method":"Co-immunoprecipitation, RNA immunoprecipitation, YTHDF3 knockout mice, domain-deletion mutagenesis, viral infection assays","journal":"PNAS","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, domain mutagenesis, KO mice with defined antiviral phenotype, multiple orthogonal methods in one rigorous study","pmids":["30591559"],"is_preprint":false},{"year":2020,"finding":"YTHDF3 enhances translation of m6A-enriched transcripts ST6GALNAC5, GJA1, and EGFR to promote breast cancer brain metastasis. Additionally, YTHDF3 undergoes cap-independent autoregulation of its own translation by binding m6A residues within its own 5' UTR.","method":"YTHDF3 overexpression/knockdown, polysome profiling, RIP, MeRIP-seq, in vivo brain metastasis models, reporter assays","journal":"Cancer Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (polysome profiling, RIP, MeRIP-seq, in vivo models), single lab but rigorous mechanistic dissection","pmids":["33125861"],"is_preprint":false},{"year":2020,"finding":"YTHDF3 acts as an m1A (N1-methyladenosine) reader protein in addition to m6A; it binds m1A-modified IGF1R mRNA and promotes its degradation, thereby inhibiting IGF1R protein expression and downstream MMP9 signaling, reducing trophoblast invasion and migration.","method":"Mass spectrometry identification of m1A readers, iCLIP-seq, m1A-seq, RNA immunoprecipitation, mRNA stability assays, trophoblast invasion/migration assays","journal":"Cell Discovery","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — mass spectrometry-based identification, iCLIP-seq, m1A-seq, functional rescue experiments, multiple orthogonal methods in one study","pmids":["32194978"],"is_preprint":false},{"year":2020,"finding":"HIV protease cleaves virion-incorporated YTHDF3 protein (identified by mass spectrometry); YTHDF3 is incorporated into HIV particles in a nucleocapsid-dependent manner and acts as a restriction factor limiting infection at the step of reverse transcription. HIV protease inhibitors block YTHDF3 cleavage.","method":"YTHDF3 knockout in CD4+ T cells, HIV infection assays, mass spectrometry of virion proteins, HIV protease inhibitor treatment","journal":"PLoS Pathogens","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO cells, mass spectrometry validation, pharmacological inhibition, mechanistic steps defined at reverse transcription","pmids":["32053707"],"is_preprint":false},{"year":2021,"finding":"Enterovirus 2A proteases cleave YTHDF3 (and other YTHDF proteins) very early during infection. YTHDF3 acts as a positive regulator of type I interferon-mediated JAK/STAT signaling; YTHDF3 depletion impaired JAK/STAT signaling in cells treated with type I (but not type II) IFN, and enhanced viral translation/replication specifically in cells mounting innate immune responses.","method":"YTHDF protein depletion, viral infection assays, JAK/STAT inhibition, type I/II IFN treatment, ISG induction measurement","journal":"mBio","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined cellular phenotype with pathway placement (JAK/STAT), single lab, multiple complementary conditions tested","pmids":["33849973"],"is_preprint":false},{"year":2022,"finding":"YTHDF3 promotes autophagy induction by recognizing m6A modification sites around the stop codon of FOXO3 mRNA and recruiting eIF3a and eIF4B to facilitate FOXO3 translation upon nutrient deficiency; METTL3 depletion abolishes this YTHDF3-mediated autophagy flux.","method":"YTHDF3 and METTL3 depletion, autophagosome formation assays, lysosomal degradation assays, RIP, MeRIP-seq, eIF3a/eIF4B co-immunoprecipitation","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP identifying cofactors, MeRIP-seq for m6A sites, functional rescue, multiple orthogonal methods","pmids":["36195598"],"is_preprint":false},{"year":2022,"finding":"YTHDF3 facilitates translation of m6A-modified CTNNB1 (β-catenin) mRNA in ocular melanoma, promoting cancer stem-like cell properties and tumor growth.","method":"YTHDF3 knockdown/overexpression, MeRIP-seq, RIP, polysome profiling, in vitro and in vivo tumor models","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MeRIP-seq and RIP combined with functional rescue, single lab","pmids":["35110680"],"is_preprint":false},{"year":2022,"finding":"YTHDF3 promotes PFKL mRNA stability and expression via m6A modification, enhancing aerobic glycolysis in hepatocellular carcinoma; PFKL reciprocally stabilizes YTHDF3 protein by inhibiting its ubiquitination via EFTUD2 (a spliceosome subunit), forming a positive feedback loop.","method":"MeRIP assay, co-immunoprecipitation, immunofluorescence, ubiquitination assays, metabolomics, Ythdf3-/- mouse model","journal":"Journal of Experimental & Clinical Cancer Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, MeRIP, KO mouse model, single lab with multiple methods","pmids":["36471428"],"is_preprint":false},{"year":2022,"finding":"YTHDF3 recognizes m6A-modified PRDX3 mRNA and promotes its translation in an m6A-dependent manner; YTHDF3 knockdown (but not YTHDF1/2 knockdown) suppressed PRDX3 expression, demonstrating specificity among YTHDF family members for this target.","method":"RNA pull-down/mass spectrometry, YTHDF1/2/3 knockdown comparison, translation assays, RIP","journal":"Redox Biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pull-down/MS, family-member specificity comparison, single lab","pmids":["35779442"],"is_preprint":false},{"year":2022,"finding":"YTHDF3 recognizes m6A binding sites on LOXL3 mRNA and enhances its translation by enriching eIF3A on the LOXL3 transcript, increasing LOXL3 protein without affecting mRNA level; this was confirmed by CRISPR-Cas13b-based epitranscriptome engineering.","method":"RNA-seq, MeRIP-seq, RIP-seq, mass spectrometry, CRISPR-Cas13b epitranscriptome editing, RIP-qPCR, MeRIP-qPCR, eIF3A co-immunoprecipitation","journal":"Clinical and Translational Medicine","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — CRISPR-based functional validation of m6A sites plus multi-omics (RNA-seq, MeRIP-seq, RIP-seq, MS) in single study","pmids":["36324258"],"is_preprint":false},{"year":2022,"finding":"YTHDF3 facilitates translation of m6A-modified genes in oxaliplatin-resistant colorectal cancer by recognizing 5' UTR m6A and recruiting eIF3A; eIF2AK2 bridges YTHDF3 and eIF3A, enhancing the stability of the YTHDF3/eIF3A translational complex.","method":"RIP, MeRIP, Co-immunoprecipitation of YTHDF3/eIF2AK2/eIF3A complex, translation assays","journal":"ACS Chemical Biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP of ternary complex, RIP/MeRIP validation, single lab","pmids":["35708211"],"is_preprint":false},{"year":2022,"finding":"YTHDF3 modulates hematopoietic stem cell reconstitution capacity by transmitting m6A RNA methylation on the 5' UTR of Ccnd1 (Cyclin D1) mRNA to promote its translation; enforced Ccnd1 expression completely rescued Ythdf3-/- HSC defects.","method":"Ythdf3-/- and Mettl3-/- mouse models, bone marrow reconstitution assays, translational defect analysis, rescue experiments with Ccnd1 overexpression","journal":"Haematologica","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with complete phenotypic rescue by downstream target, defined mechanistic pathway (m6A/5'UTR/translation), in vivo model","pmids":["35112553"],"is_preprint":false},{"year":2022,"finding":"METTL3 methylates MCU mRNA at three m6A residues in the 3'-UTR; YTHDF3 associates with methylated MCU mRNA and promotes its translation, increasing MCU protein expression and contributing to HCMV-induced vascular endothelial apoptosis.","method":"MeRIP-qPCR, RIP, METTL3/YTHDF3 knockdown/overexpression, MCU translation assays","journal":"Frontiers in Microbiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MeRIP-qPCR and RIP defining writer-reader-target axis, single lab","pmids":["35359726"],"is_preprint":false},{"year":2022,"finding":"YTHDF3 promotes RAD51D mRNA N6-methyladenosine modification in an HNF1α-dependent manner and promotes RAD51D translation, conferring radioresistance in cervical cancer; HNF1α upregulates YTHDF3 transcription.","method":"HNF1α/YTHDF3 knockdown/overexpression, m6A modification analysis, translational assays, in vitro and in vivo irradiation resistance assays","journal":"FEBS Journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined transcriptional-m6A-translation axis with functional rescue, single lab","pmids":["36380687"],"is_preprint":false},{"year":2022,"finding":"YTHDF3 depletion in ESCs results in loss of pluripotency with accelerated germ layer differentiation; knockdown of YTHDF3 accelerated cardiomyocyte differentiation, whereas YTHDF1 depletion impaired it. YTHDF3 appears to modulate differentiation partially through suppression of YTHDF1.","method":"YTHDF1/YTHDF3 knockdown in ESCs, transcriptomic analysis, cardiomyocyte differentiation assays, marker gene expression","journal":"RNA Biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined phenotypic readouts with epistasis between YTHDF3 and YTHDF1, single lab","pmids":["33295243"],"is_preprint":false},{"year":2022,"finding":"Molecular dynamics simulation studies reveal that the YTH domain of YTHDF3 recognizes m6A via an aromatic cage in which Trp492 anchors the methyl group and Trp438/Trp497 provide π-π stacking; m6A methylation enhances hydrophobicity, excluding water from the aromatic cage and stabilizing the complex via induced-fit and conformation selection mechanisms.","method":"All-atom molecular dynamics simulations, binding free energy calculations, hydrogen bond analysis","journal":"Proteins","confidence":"Low","confidence_rationale":"Tier 4 / Moderate — computational only; no experimental mutagenesis validation in this paper","pmids":["35639481"],"is_preprint":false},{"year":2024,"finding":"ZDHHC20-mediated S-palmitoylation of YTHDF3 at Cys474 inhibits chaperone-mediated autophagic degradation of YTHDF3, leading to its accumulation and stabilization of MYC mRNA; a YTHDF3-derived competitive peptide inhibiting this palmitoylation downregulates MYC and inhibits pancreatic cancer progression.","method":"KPC mouse model, palmitoylation assays, Cys474 mutagenesis, chaperone-mediated autophagy assays, competitive peptide design, MYC mRNA stability assays","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — site-specific mutagenesis (Cys474), in vivo mouse model, competitive peptide functional validation, multiple orthogonal methods","pmids":["38821916"],"is_preprint":false},{"year":2024,"finding":"YTHDF3 promotes degradation of SPOP and NKX3.1 mRNAs and stabilizes TWIST1 and SNAI2 mRNAs in an m6A-dependent manner in castration-resistant prostate cancer; melatonin competes with m6A to occupy the m6A-binding cage of YTHDF3, inhibiting its target mRNA regulation.","method":"YTHDF3 overexpression/knockdown, m6A-dependent mRNA stability assays, melatonin competition binding assays, in vitro and in vivo tumor models","journal":"Journal of Pineal Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined differential mRNA stability effects, small-molecule binding competition, single lab","pmids":["39143673"],"is_preprint":false},{"year":2024,"finding":"YTHDF3 undergoes AARS2-dependent lactylation, which stabilizes the protein by antagonizing ubiquitin-mediated degradation; lactylated YTHDF3 enhances m6A-dependent recognition and decay of KDM6B mRNA, suppressing CDKN1A transcription via impaired H3K27me3 demethylation and promoting cisplatin resistance in bladder cancer.","method":"Lactylation assays, YTHDF3 lactylation-deficient mutant, ubiquitination assays, MeRIP, RIP, KDM6B mRNA stability assays, xenograft models","journal":"Cancer Letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — lactylation-deficient mutant with loss of function, multiple pathway components validated, single lab","pmids":["41621475"],"is_preprint":false},{"year":2024,"finding":"METTL3-mediated m6A modification of SOX4 mRNA (in the CDS region) is recognized by YTHDF3, which regulates SOX4 mRNA stability; YTHDF3 knockdown reduced SOX4 mRNA stability and compromised osteoblast differentiation downstream of METTL3.","method":"MeRIP-seq, RNA-seq, RIP assay, METTL3/YTHDF3 knockdown, osteoblast differentiation assays, in vivo OVX mouse model","journal":"Cellular Signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MeRIP-seq plus RIP confirming YTHDF3-SOX4 interaction, epistasis between METTL3 and YTHDF3, single lab","pmids":["38195035"],"is_preprint":false},{"year":2024,"finding":"FTO demethylation of PDK1 mRNA prevents YTHDF3 from recognizing and binding to m6A sites on PDK1 mRNA, thus inhibiting PDK1 mRNA degradation; this axis links hypoxia-driven FTO upregulation to PDK1/AKT/STAT3/PD-L1 immunosuppression in breast cancer.","method":"MeRIP-seq, RIP, PDK1 mRNA stability assays, FTO/YTHDF3 knockdown/overexpression, in vivo mouse models","journal":"Journal of Advanced Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MeRIP-seq plus RIP defining eraser-reader interplay, functional in vivo validation, single lab","pmids":["39701379"],"is_preprint":false},{"year":2025,"finding":"YTHDF3 recognizes DNA N6-methyladenine (6mA) in genomic DNA (including double-stranded DNA) and recruits ALKBH1 demethylase to 6mA sites in genomic DNA, facilitating ALKBH1-mediated removal of 6mA in dsDNA—a conformation for which ALKBH1 alone has limited activity.","method":"Biochemical binding assays with 6mA-modified DNA, Co-immunoprecipitation of YTHDF3-ALKBH1, 6mA demethylation activity assays with various DNA conformations, genomic 6mA quantification","journal":"The EMBO Journal","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro biochemical reconstitution of demethylase activity, Co-IP, functional assays across DNA conformations, single lab with multiple orthogonal methods","pmids":["40715766"],"is_preprint":false},{"year":2025,"finding":"YTHDF3 promotes cardiac stress-induced protein synthesis and controls cardiomyocyte size; cardiomyocyte-specific deletion of YTHDF3 in mice attenuates pathological cardiac remodeling following pressure overload injury.","method":"Cardiomyocyte-specific YTHDF3 conditional knockout mice, pressure overload (transverse aortic constriction) model, global protein synthesis measurement","journal":"RNA","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO mouse with defined cardiac phenotype, mechanistic link to protein synthesis, single lab","pmids":["40216557"],"is_preprint":false},{"year":2025,"finding":"YTHDF3 interacts with BTG2 and is involved in the decay of Cbln1 mRNA; increased YTHDF3 levels in hippocampus of prenatal hypoxia offspring lead to Cbln1 downregulation, contributing to abnormal synaptic function and cognitive impairment.","method":"Co-immunoprecipitation of YTHDF3-BTG2, mRNA decay assays, hippocampal YTHDF3 measurement, Cbln1 expression analysis","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP identifying YTHDF3-BTG2 interaction, mechanistic link to mRNA decay and synaptic phenotype, single lab","pmids":["38205248"],"is_preprint":false},{"year":2025,"finding":"YTHDF3 phase separation characteristics enable it to suppress ccRCC malignancy and PD-L1-mediated immune evasion by recruiting DDX6 to degrade HSPA13 mRNA; a YTHDF3 mutant disrupting phase separation abolishes these functions.","method":"Phase separation assays, YTHDF3 mutant disrupting phase separation, HSPA13 mRNA degradation assays, DDX6 recruitment assays, in vivo tumor models with CD8+ T cell measurement","journal":"Cancer Science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — structure-function mutagenesis of phase separation domain, in vivo validation, single lab","pmids":["38811341"],"is_preprint":false},{"year":2025,"finding":"YTHDF3 binds to m6A-modified STAT3 mRNA to enhance its stability and transcription efficiency; this YTHDF3-STAT3 axis represses IRF7 transcription and IFN-α production, suppressing type I ISG responses and antiviral immunity in HPV-driven cervical cancer.","method":"CRISPR/Cas9 YTHDF3-/- cells and Ythdf3-/- mice, RIP, MeRIP, STAT3 mRNA stability assays, ISG induction measurement, in vivo xenograft immune cell profiling","journal":"Cell Death & Disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR KO with in vivo validation, RIP/MeRIP mechanistic support, single lab","pmids":["41453852"],"is_preprint":false},{"year":2025,"finding":"YTHDF3 promotes FLCN mRNA stability via m6A methylation; FLCN in turn binds cPLA2 to increase its activity and regulate lysosomal membrane permeabilization in cardiac fibroblasts, with YTHDF3 overexpression reducing collagen production and improving cardiac fibrosis in TAC mice.","method":"MeRIP, mRNA stability assays, FLCN/cPLA2 Co-IP, TAC mouse model, YTHDF3/FLCN overexpression in vivo","journal":"Acta Pharmacologica Sinica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, MeRIP, in vivo TAC model, functional rescue, single lab","pmids":["39806064"],"is_preprint":false},{"year":2025,"finding":"YTHDF3 promotes YTHDF3-mediated mRNA decay of SOX9; loss of Ythdf3 in mice leads to impaired SOX9 mRNA decay, causing cardiac hypertrophy, myopathy, and intellectual abnormalities resembling Danon disease; AAV-shRNA targeting Sox9 rescued these phenotypes.","method":"Ythdf3-/- mouse model, Sox9 mRNA decay assays, AAV-shRNA rescue experiments, cardiac and neurological phenotyping","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo KO with specific mRNA decay target identified and rescue by downstream knockdown; preprint not yet peer-reviewed","pmids":[],"is_preprint":true},{"year":2025,"finding":"In cardiomyocytes, Ythdf3 localizes to the nucleus (contrary to its predominantly cytoplasmic localization elsewhere) and interacts with splicing proteins DDX5 and HNRNPU to regulate alternative splicing, including splicing of CaMKIIδ isoforms; Ythdf3 knockdown increases CaMKIIδA and CaMKIIδC isoforms while decreasing CaMKIIδ9.","method":"Nuclear/cytoplasmic fractionation with imaging, Co-immunoprecipitation coupled with LC-MS/MS, alternative splicing analysis, Ythdf3 knockdown/overexpression, electron microscopy","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Co-IP/MS and splicing analysis are strong methods but preprint only, not yet peer-reviewed; novel subcellular localization claim needs replication","pmids":[],"is_preprint":true},{"year":2025,"finding":"YTHDF3 promotes m6A-dependent stabilization of Wnt3 mRNA in glioma in synergy with circ_EPHB4; YTHDF3 alone extends the half-life of Wnt3 mRNA in an m6A-dependent manner, and simultaneous knockdown of both circ_EPHB4 and YTHDF3 reduces Wnt3 mRNA expression more than either alone.","method":"RIP, RNA stability assays, circ_EPHB4/YTHDF3 knockdown, gene co-expression rescue, in vivo tumor models","journal":"Journal of Southern Medical University","confidence":"Low","confidence_rationale":"Tier 3 / Weak — RIP and stability assays, single lab, mechanistic claim is indirect (Wnt3 stabilization as downstream of YTHDF3)","pmids":["41311073"],"is_preprint":false},{"year":2025,"finding":"TRMT6 installs m1A marks on TOPBP1 and DSN1 mRNAs; YTHDF3 reads these m1A modifications and stabilizes these cell-cycle mRNAs, promoting lung squamous cell carcinoma proliferation; a single m1A site in each mRNA is sufficient to boost their expression.","method":"m1A-seq, RIP, dCasRx-TRMT6 site-specific m1A deposition, YTHDF3/TRMT6 knockdown, in vitro and in vivo proliferation assays","journal":"NPJ Precision Oncology","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — dCasRx-based site-specific epitranscriptome editing plus RIP and m1A-seq, single lab with multiple methods","pmids":["41803797"],"is_preprint":false},{"year":2025,"finding":"YTHDF3 depletion in GC cell lines impairs cytoskeleton organization, cell migration, metastasis, and mitotic spindle orientation, leading to increased paclitaxel sensitivity; EZRIN (EZR) mRNA was identified as a direct YTHDF3 target via RNA immunoprecipitation, with m6A sites mapped by SELECT method.","method":"CRISPR-Cas9 YTHDF3 knockout, RIP, SELECT method for m6A mapping on EZR, migration/invasion/spindle orientation assays, paclitaxel sensitivity assays","journal":"Gastric Cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR KO, RIP, SELECT m6A mapping, defined cytoskeletal and mitotic phenotypes, single lab","pmids":["40366509"],"is_preprint":false},{"year":2025,"finding":"YTHDF3 promotes translation of Notch2 mRNA in an m6A-dependent manner by recruiting eIF4B; YTHDF3 binds m6A-modified Notch2 mRNA and its knockdown reduces Notch2 protein levels and EMT.","method":"RIP, MeRIP, eIF4B Co-immunoprecipitation, Notch2 translation assays, in vitro/in vivo EMT and metastasis models","journal":"Cancer Letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP of YTHDF3-eIF4B-Notch2 mRNA axis, RIP/MeRIP validation, single lab","pmids":["39924078"],"is_preprint":false},{"year":2025,"finding":"Histone lactylation promotes YTHDF3 expression, and YTHDF3 in turn promotes m6A-dependent translation of PRDX3 mRNA; reduced YTHDF3 from sevoflurane exposure decreases PRDX3, activating NLRP3 inflammasome-mediated pyroptosis in microglia.","method":"ChIP assay for histone lactylation at YTHDF3 promoter, RIP for YTHDF3-PRDX3 mRNA interaction, YTHDF3 overexpression rescue, NLRP3/caspase-1 activity assays","journal":"International Immunopharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and RIP mechanistic chain, functional rescue, single lab","pmids":["40022822"],"is_preprint":false},{"year":2025,"finding":"YTHDF3 promotes degradation of XRCC1 mRNA in an m6A-dependent manner in the rostral ventrolateral medulla; YTHDF3 knockdown increased XRCC1 expression, facilitated DNA damage repair in neurons, reduced neuronal apoptosis, and lowered blood pressure in spontaneously hypertensive rats.","method":"YTHDF3 knockdown in RVLM of SHRs, m6A-dependent mRNA stability assays for XRCC1, neuronal excitability and sympathetic tone measurement, blood pressure recording, in vitro rescue with XRCC1","journal":"Free Radical Biology & Medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo stereotactic knockdown with defined physiological phenotype, m6A-dependent mRNA decay mechanism, single lab","pmids":["40490202"],"is_preprint":false},{"year":2026,"finding":"YTHDF3 directly recognizes BRCA1, RAD51, RIF1, and 53BP1 mRNAs via m6A binding sites and promotes their translation, facilitating homologous recombination and NHEJ DNA repair in glioblastoma, contributing to temozolomide resistance; TMZ treatment increases m6A modification levels to facilitate this YTHDF3-mediated DDR.","method":"YTHDF3 and METTL3 knockdown, m6A-modified DDR gene mRNA translation assays, DNA repair assays (HR and NHEJ), PDC models","journal":"Cancer Letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined mechanistic axis (m6A/YTHDF3/DDR gene translation/repair), functional rescue, patient-derived cell validation, single lab","pmids":["41881836"],"is_preprint":false},{"year":2025,"finding":"YTHDF3 binds m6A-modified SOCS1 mRNA to enhance both its stability and translation, upregulating SOCS1 expression and thereby inhibiting the JAK1/STAT3 pathway in trophoblast cells, promoting preeclampsia pathogenesis.","method":"YTHDF3 knockdown in trophoblast cells, MeRIP, RIP, mRNA stability assays, JAK1/STAT3 pathway activity measurement","journal":"The Journal of Gene Medicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — RIP/MeRIP and mRNA stability assays, single lab, limited mechanistic orthogonal validation","pmids":["41287146"],"is_preprint":false},{"year":2025,"finding":"YTHDF3 accelerates degradation of key TLR4 pathway mRNAs (Cd36, Irak1, Tab1/2, Tirap) to suppress macrophage activation; Ythdf3 knockdown inhibits their degradation and enhances p38 phosphorylation, LPS-induced pro-inflammatory cytokine production, phagocytosis, and tumor-killing activity.","method":"shRNA Ythdf3 knockdown in RAW264.7 cells, mRNA stability analysis, p38 phosphorylation immunoblotting, cytokine ELISA, phagocytosis and tumor co-culture assays","journal":"Sichuan University Journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — shRNA KD with defined mRNA stability targets and signaling pathway activation, multiple downstream readouts, single lab","pmids":["40964113"],"is_preprint":false},{"year":2026,"finding":"YTHDF3 maintains SIRT2 mRNA stability via m6A binding, facilitating SIRT2-mediated deacetylation of FOXO1 and reducing FOXO1 protein stability, thereby promoting Ang II-induced VSMC apoptosis and inflammation in abdominal aortic aneurysm.","method":"MeRIP-qPCR, RIP, mRNA stability assay, cycloheximide chase, co-immunoprecipitation, YTHDF3 knockdown in VSMCs","journal":"Korean Circulation Journal","confidence":"Low","confidence_rationale":"Tier 3 / Weak — RIP/MeRIP/Co-IP, single lab, multi-step mechanistic chain not fully validated with independent methods","pmids":["41972268"],"is_preprint":false}],"current_model":"YTHDF3 is a cytoplasmic m6A (and m1A) RNA reader that acts cooperatively with YTHDF1 and YTHDF2 to accelerate metabolism of methylated mRNAs: it promotes translation of specific m6A/m1A-modified target mRNAs (e.g., FOXO3, Ccnd1, CTNNB1, LOXL3, PRDX3) by recruiting translation initiation factors (eIF3A, eIF4B, eIF2AK2, eIF3a/eIF4B), facilitates mRNA decay of other targets (e.g., IGF1R, XRCC1, SOX9, HSPA13), and also acts in the nucleus to regulate alternative splicing in cardiomyocytes; its activity and stability are post-translationally regulated by ZDHHC20-mediated S-palmitoylation (at Cys474) and by lactylation (via AARS2), and it has an additional nuclear DNA reader function, binding 6mA-modified genomic DNA to recruit the ALKBH1 demethylase."},"narrative":{"mechanistic_narrative":"YTHDF3 is a predominantly cytoplasmic reader of methylated RNA that integrates m6A-modified mRNA metabolism together with YTHDF1 and YTHDF2, simultaneously promoting protein synthesis and accelerating decay of distinct target transcripts [PMID:28106072]. On the translational arm, YTHDF3 binds m6A sites—frequently in the 5' UTR or around the stop codon—and recruits translation initiation machinery including eIF3A, eIF4B, and the bridging factor eIF2AK2, with cofactors PABP1 and eIF4G2, to boost output of targets such as FOXO3, Ccnd1, CTNNB1, LOXL3, PRDX3, and Notch2 [PMID:30591559, PMID:36195598, PMID:36324258, PMID:35708211, PMID:35112553, PMID:39924078]. On the decay arm, it destabilizes m6A-marked transcripts including SOX9, XRCC1, and HSPA13, in the latter case acting through liquid-liquid phase separation to recruit the decay factor DDX6 [PMID:38811341, PMID:40490202]. Its reader activity extends beyond m6A: YTHDF3 recognizes m1A-modified mRNAs (IGF1R, TOPBP1, DSN1) to control their stability [PMID:32194978, PMID:41803797], and in genomic DNA it binds N6-methyladenine (6mA) and recruits the ALKBH1 demethylase to remove 6mA from double-stranded DNA [PMID:40715766]. YTHDF3 abundance and activity are tuned post-translationally by ZDHHC20-mediated S-palmitoylation at Cys474, which blocks chaperone-mediated autophagic degradation, and by AARS2-dependent lactylation that antagonizes ubiquitin-mediated turnover [PMID:38821916, PMID:41621475]. Through these activities YTHDF3 governs diverse physiological programs including autophagy [PMID:36195598], hematopoietic stem cell reconstitution [PMID:35112553], antiviral and innate immune signaling [PMID:30591559, PMID:32053707], DNA damage repair [PMID:41881836], and cardiac stress remodeling, where it controls stress-induced protein synthesis and cardiomyocyte size [PMID:40216557].","teleology":[{"year":2017,"claim":"Established that YTHDF3 does not act alone but functions within the YTHDF reader family to coordinate the fate of m6A-modified mRNAs, resolving whether the three paralogs are redundant or integrated.","evidence":"Single and triple YTHDF knockouts with polysome profiling, mRNA stability assays, and m6A-seq","pmids":["28106072"],"confidence":"High","gaps":["Did not define target-level specificity distinguishing the three readers","Did not identify the recruited effector machinery for translation versus decay"]},{"year":2018,"claim":"Showed YTHDF3 can act independently of m6A for at least one target, binding the FOXO3 translation initiation region via both its YTH and P/Q/N-rich domains to suppress interferon-stimulated genes.","evidence":"Reciprocal Co-IP, RIP, domain-deletion mutagenesis, YTHDF3 knockout mice, viral infection assays","pmids":["30591559"],"confidence":"High","gaps":["Mechanism by which the P/Q/N-rich domain contributes to RNA binding not structurally defined","Whether m6A-independent binding generalizes beyond FOXO3 unknown"]},{"year":2020,"claim":"Broadened the reader repertoire by demonstrating YTHDF3 reads m1A as well as m6A, coupling m1A recognition of IGF1R mRNA to decay and adding a second modification mark to its functional scope.","evidence":"Mass-spec identification of m1A readers, iCLIP-seq, m1A-seq, RIP, mRNA stability and trophoblast invasion assays","pmids":["32194978"],"confidence":"High","gaps":["Structural basis distinguishing m1A from m6A recognition not resolved","Whether m1A reading recruits the same decay machinery as m6A unknown"]},{"year":2020,"claim":"Defined cancer-relevant translational targets and an autoregulatory loop, showing YTHDF3 enhances translation of metastasis genes and binds m6A in its own 5' UTR to drive cap-independent self-translation.","evidence":"Overexpression/knockdown, polysome profiling, RIP, MeRIP-seq, in vivo brain metastasis models, reporter assays","pmids":["33125861"],"confidence":"High","gaps":["Trigger for cap-independent autoregulation in physiology unclear","Initiation factors for these specific targets not yet mapped"]},{"year":2020,"claim":"Identified YTHDF3 as an antiviral restriction factor incorporated into HIV virions and a target of HIV protease cleavage, linking the reader to host-pathogen conflict.","evidence":"YTHDF3 knockout CD4+ T cells, HIV infection assays, mass spectrometry of virion proteins, protease inhibitor treatment","pmids":["32053707"],"confidence":"High","gaps":["Molecular mechanism restricting reverse transcription not defined","Whether RNA-reading activity is required for restriction unclear"]},{"year":2021,"claim":"Placed YTHDF3 within innate immune signaling as a positive regulator of type I IFN JAK/STAT, and showed it is cleaved early by enterovirus 2A proteases.","evidence":"YTHDF depletion, viral infection, JAK/STAT inhibition, type I/II IFN treatment, ISG induction","pmids":["33849973"],"confidence":"Medium","gaps":["Direct RNA targets mediating JAK/STAT enhancement not identified","Reconciliation with FOXO3-mediated ISG suppression not addressed"]},{"year":2022,"claim":"Identified the specific translation-initiation effectors recruited by YTHDF3—eIF3A, eIF4B, and bridging factor eIF2AK2—mechanistically explaining how it activates translation of m6A-marked targets across autophagy, cancer, and stem-cell contexts.","evidence":"Co-IP of YTHDF3/eIF3A/eIF2AK2/eIF4B complexes, MeRIP-seq, RIP, polysome profiling, CRISPR-Cas13b epitranscriptome editing, KO mouse rescue across multiple studies","pmids":["36195598","35708211","36324258","35112553","35779442","35110680"],"confidence":"High","gaps":["Determinants selecting which m6A transcripts route to translation versus decay not defined","Stoichiometry and order of initiation factor recruitment unclear"]},{"year":2022,"claim":"Provided a structural rationale for m6A recognition, modeling an aromatic cage in the YTH domain that anchors the methyl group and excludes water.","evidence":"All-atom molecular dynamics simulations and binding free-energy calculations","pmids":["35639481"],"confidence":"Low","gaps":["Computational only without experimental mutagenesis validation in this work","Does not address m1A or 6mA recognition modes"]},{"year":2022,"claim":"Demonstrated reciprocal stabilization of YTHDF3 protein by a downstream metabolic target, revealing the reader is itself regulated by ubiquitin-mediated turnover within feedback loops.","evidence":"MeRIP, Co-IP, ubiquitination assays, metabolomics, Ythdf3-/- mouse model","pmids":["36471428"],"confidence":"Medium","gaps":["E3 ligase mediating YTHDF3 ubiquitination not identified","Direct versus indirect role of EFTUD2 unclear"]},{"year":2024,"claim":"Established post-translational control of YTHDF3 stability through ZDHHC20-mediated S-palmitoylation at Cys474, which blocks chaperone-mediated autophagic degradation and is druggable by competitive peptide.","evidence":"KPC mouse model, palmitoylation assays, Cys474 mutagenesis, CMA assays, competitive peptide, MYC mRNA stability assays","pmids":["38821916"],"confidence":"High","gaps":["Whether palmitoylation alters RNA-binding or only stability unclear","Signals regulating ZDHHC20 activity on YTHDF3 unknown"]},{"year":2024,"claim":"Added lactylation as a second stabilizing post-translational mark, installed in an AARS2-dependent manner and antagonizing ubiquitin-mediated degradation.","evidence":"Lactylation assays, lactylation-deficient mutant, ubiquitination assays, MeRIP, RIP, mRNA stability, xenografts","pmids":["41621475"],"confidence":"Medium","gaps":["Lactylation site(s) on YTHDF3 not defined","Interplay between lactylation and palmitoylation unresolved"]},{"year":2025,"claim":"Revealed a phase-separation-dependent decay mechanism in which YTHDF3 condensates recruit DDX6 to degrade target mRNA, mechanistically linking biophysical condensation to its decay arm.","evidence":"Phase-separation assays, phase-separation-disrupting mutant, HSPA13 mRNA degradation, DDX6 recruitment, in vivo tumor models","pmids":["38811341"],"confidence":"Medium","gaps":["Whether condensation is required for all decay targets unknown","Domain driving phase separation not finely mapped"]},{"year":2025,"claim":"Extended YTHDF3 function from RNA to DNA, showing it reads genomic 6mA and recruits ALKBH1 to demethylate double-stranded DNA, a substrate conformation ALKBH1 handles poorly alone.","evidence":"In vitro biochemical binding and demethylation assays across DNA conformations, YTHDF3-ALKBH1 Co-IP, genomic 6mA quantification","pmids":["40715766"],"confidence":"High","gaps":["Genomic loci and biological consequences of 6mA reading not mapped","Whether nuclear localization for this function is regulated unclear"]},{"year":2025,"claim":"Defined a nuclear, splicing-regulatory role in cardiomyocytes where YTHDF3 partners with DDX5 and HNRNPU, challenging the strictly cytoplasmic reader model.","evidence":"Nuclear/cytoplasmic fractionation, Co-IP/LC-MS-MS, alternative splicing analysis, knockdown/overexpression (preprint)","pmids":[],"confidence":"Low","gaps":["Preprint not yet peer-reviewed","Novel nuclear localization claim awaits independent replication","Whether splicing role depends on m6A reading unclear"]},{"year":null,"claim":"It remains unresolved what molecular features partition individual methylated transcripts between YTHDF3-driven translation versus decay, and how its newly described nuclear functions (splicing, 6mA/DNA reading) are coordinated with its cytoplasmic reader activity.","evidence":"Open question synthesized across translation, decay, and nuclear DNA/splicing findings","pmids":[],"confidence":"Low","gaps":["No unifying code distinguishing translation- versus decay-fated targets","Spatial regulation between cytoplasmic and nuclear pools undefined","Functional hierarchy among m6A, m1A, and 6mA reading not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,1,3,10,12,32]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[22]},{"term_id":"GO:0045182","term_label":"translation regulator activity","supporting_discovery_ids":[6,10,11,12,33]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,18,28,35]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,6,11]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[22,29]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,3,18,28]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[6,10,11,12,33]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[1,4,5,26,38]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[6]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[35,36]}],"complexes":[],"partners":["YTHDF1","YTHDF2","EIF3A","EIF4B","EIF2AK2","ALKBH1","DDX6","ZDHHC20"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q7Z739","full_name":"YTH domain-containing family protein 3","aliases":[],"length_aa":585,"mass_kda":63.9,"function":"Specifically recognizes and binds N6-methyladenosine (m6A)-containing RNAs, and regulates their stability (PubMed:28106072, PubMed:28106076, PubMed:28281539, 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:28106072, PubMed:28281539, PubMed:32492408). Acts as a regulator of mRNA stability by promoting degradation of m6A-containing mRNAs via interaction with the CCR4-NOT complex or PAN3 (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:28106076, PubMed:32492408). Acts as a negative regulator of type I interferon response by down-regulating interferon-stimulated genes (ISGs) expression: acts by binding to FOXO3 mRNAs (By similarity). Binds to FOXO3 mRNAs independently of METTL3-mediated m6A modification (By similarity). Can also act as a regulator of mRNA stability in cooperation with YTHDF2 by binding to m6A-containing mRNA and promoting their degradation (PubMed:28106072). Recognizes and binds m6A-containing circular RNAs (circRNAs); circRNAs are generated through back-splicing of pre-mRNAs, a non-canonical splicing process promoted by dsRNA structures across circularizing exons (PubMed:28281539). 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: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 N1-methyladenosine (m1A)-containing mRNAs: inhibits trophoblast invasion by binding to m1A-methylated transcripts of IGF1R, promoting their degradation (PubMed:32194978) Has some antiviral activity against HIV-1 virus: incorporated into HIV-1 particles in a nucleocapsid-dependent manner and reduces viral infectivity in the next cycle of infection (PubMed:32053707). May interfere with this early step of the viral life cycle by binding to N6-methyladenosine (m6A) modified sites on the HIV-1 RNA genome (PubMed:32053707)","subcellular_location":"Cytoplasm, cytosol; Cytoplasm, P-body; Cytoplasm, Stress granule","url":"https://www.uniprot.org/uniprotkb/Q7Z739/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/YTHDF3","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":74,"dependency_fraction":0.013513513513513514},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"DDOST","stoichiometry":0.2},{"gene":"OST4","stoichiometry":0.2},{"gene":"PSPC1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/YTHDF3","total_profiled":1310},"omim":[{"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":"610640","title":"YTH N6-METHYLADENOSINE RNA-BINDING PROTEIN 2; YTHDF2","url":"https://www.omim.org/entry/610640"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/YTHDF3"},"hgnc":{"alias_symbol":["FLJ31657"],"prev_symbol":[]},"alphafold":{"accession":"Q7Z739","domains":[{"cath_id":"3.10.590.10","chopping":"392-408_415-582","consensus_level":"high","plddt":95.3769,"start":392,"end":582}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q7Z739","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q7Z739-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q7Z739-F1-predicted_aligned_error_v6.png","plddt_mean":60.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=YTHDF3","jax_strain_url":"https://www.jax.org/strain/search?query=YTHDF3"},"sequence":{"accession":"Q7Z739","fasta_url":"https://rest.uniprot.org/uniprotkb/Q7Z739.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q7Z739/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q7Z739"}},"corpus_meta":[{"pmid":"28106072","id":"PMC_28106072","title":"YTHDF3 facilitates 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medicine","url":"https://pubmed.ncbi.nlm.nih.gov/33829656","citation_count":35,"is_preprint":false},{"pmid":"36324258","id":"PMC_36324258","title":"N6-methyladenosine reader YTHDF3 regulates melanoma metastasis via its 'executor'LOXL3.","date":"2022","source":"Clinical and translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/36324258","citation_count":34,"is_preprint":false},{"pmid":"35359726","id":"PMC_35359726","title":"Vitamin D3 Suppresses Human Cytomegalovirus-Induced Vascular Endothelial Apoptosis via Rectification of Paradoxical m6A Modification of Mitochondrial Calcium Uniporter mRNA, Which Is Regulated by METTL3 and YTHDF3.","date":"2022","source":"Frontiers in microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/35359726","citation_count":34,"is_preprint":false},{"pmid":"36380687","id":"PMC_36380687","title":"YTHDF3 mediates HNF1α regulation of cervical cancer radio-resistance by promoting RAD51D translation in an m6A-dependent manner.","date":"2022","source":"The 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Differentiation of Bone Marrow Mesenchymal Stem Cells in Osteoporosis by Promoting TBX19 Expression.","date":"2026","source":"Cell proliferation","url":"https://pubmed.ncbi.nlm.nih.gov/42235938","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.06.10.658803","title":"Loss of  <i>Ythdf3</i>  causes Danon disease-like features","date":"2025-06-10","source":"bioRxiv","url":"https://doi.org/10.1101/2025.06.10.658803","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.04.15.648887","title":"M  <sup>6</sup>  A reader protein YTHDF3 regulates cardiomyocyte death and atrophy by modulating the alternative splicing program","date":"2025-04-16","source":"bioRxiv","url":"https://doi.org/10.1101/2025.04.15.648887","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.07.14.664831","title":"Identification of biomarkers for ulcerative morphology in carotid atherosclerosis plaques through single-cell RNA sequencing 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\"method\": \"Genetic depletion (single and triple knockouts), polysome profiling, mRNA stability assays, m6A-seq\",\n      \"journal\": \"Cell Research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (KO, polysome profiling, mRNA stability), replicated across YTHDF family members in same study with clear epistasis\",\n      \"pmids\": [\"28106072\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"YTHDF3 suppresses interferon-stimulated gene (ISG) expression by promoting translation of the transcription co-repressor FOXO3 mRNA; YTHDF3 cooperates with cofactors PABP1 and eIF4G2 to promote FOXO3 translation by binding the translation initiation region of FOXO3 mRNA. Both the YTH and the P/Q/N-rich domains of YTHDF3 are required for FOXO3 RNA-binding capacity. Notably, METTL3-mediated m6A modification was NOT required for this specific interaction.\",\n      \"method\": \"Co-immunoprecipitation, RNA immunoprecipitation, YTHDF3 knockout mice, domain-deletion mutagenesis, viral infection assays\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, domain mutagenesis, KO mice with defined antiviral phenotype, multiple orthogonal methods in one rigorous study\",\n      \"pmids\": [\"30591559\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"YTHDF3 enhances translation of m6A-enriched transcripts ST6GALNAC5, GJA1, and EGFR to promote breast cancer brain metastasis. Additionally, YTHDF3 undergoes cap-independent autoregulation of its own translation by binding m6A residues within its own 5' UTR.\",\n      \"method\": \"YTHDF3 overexpression/knockdown, polysome profiling, RIP, MeRIP-seq, in vivo brain metastasis models, reporter assays\",\n      \"journal\": \"Cancer Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (polysome profiling, RIP, MeRIP-seq, in vivo models), single lab but rigorous mechanistic dissection\",\n      \"pmids\": [\"33125861\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"YTHDF3 acts as an m1A (N1-methyladenosine) reader protein in addition to m6A; it binds m1A-modified IGF1R mRNA and promotes its degradation, thereby inhibiting IGF1R protein expression and downstream MMP9 signaling, reducing trophoblast invasion and migration.\",\n      \"method\": \"Mass spectrometry identification of m1A readers, iCLIP-seq, m1A-seq, RNA immunoprecipitation, mRNA stability assays, trophoblast invasion/migration assays\",\n      \"journal\": \"Cell Discovery\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — mass spectrometry-based identification, iCLIP-seq, m1A-seq, functional rescue experiments, multiple orthogonal methods in one study\",\n      \"pmids\": [\"32194978\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"HIV protease cleaves virion-incorporated YTHDF3 protein (identified by mass spectrometry); YTHDF3 is incorporated into HIV particles in a nucleocapsid-dependent manner and acts as a restriction factor limiting infection at the step of reverse transcription. HIV protease inhibitors block YTHDF3 cleavage.\",\n      \"method\": \"YTHDF3 knockout in CD4+ T cells, HIV infection assays, mass spectrometry of virion proteins, HIV protease inhibitor treatment\",\n      \"journal\": \"PLoS Pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO cells, mass spectrometry validation, pharmacological inhibition, mechanistic steps defined at reverse transcription\",\n      \"pmids\": [\"32053707\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Enterovirus 2A proteases cleave YTHDF3 (and other YTHDF proteins) very early during infection. YTHDF3 acts as a positive regulator of type I interferon-mediated JAK/STAT signaling; YTHDF3 depletion impaired JAK/STAT signaling in cells treated with type I (but not type II) IFN, and enhanced viral translation/replication specifically in cells mounting innate immune responses.\",\n      \"method\": \"YTHDF protein depletion, viral infection assays, JAK/STAT inhibition, type I/II IFN treatment, ISG induction measurement\",\n      \"journal\": \"mBio\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined cellular phenotype with pathway placement (JAK/STAT), single lab, multiple complementary conditions tested\",\n      \"pmids\": [\"33849973\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"YTHDF3 promotes autophagy induction by recognizing m6A modification sites around the stop codon of FOXO3 mRNA and recruiting eIF3a and eIF4B to facilitate FOXO3 translation upon nutrient deficiency; METTL3 depletion abolishes this YTHDF3-mediated autophagy flux.\",\n      \"method\": \"YTHDF3 and METTL3 depletion, autophagosome formation assays, lysosomal degradation assays, RIP, MeRIP-seq, eIF3a/eIF4B co-immunoprecipitation\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP identifying cofactors, MeRIP-seq for m6A sites, functional rescue, multiple orthogonal methods\",\n      \"pmids\": [\"36195598\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"YTHDF3 facilitates translation of m6A-modified CTNNB1 (β-catenin) mRNA in ocular melanoma, promoting cancer stem-like cell properties and tumor growth.\",\n      \"method\": \"YTHDF3 knockdown/overexpression, MeRIP-seq, RIP, polysome profiling, in vitro and in vivo tumor models\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MeRIP-seq and RIP combined with functional rescue, single lab\",\n      \"pmids\": [\"35110680\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"YTHDF3 promotes PFKL mRNA stability and expression via m6A modification, enhancing aerobic glycolysis in hepatocellular carcinoma; PFKL reciprocally stabilizes YTHDF3 protein by inhibiting its ubiquitination via EFTUD2 (a spliceosome subunit), forming a positive feedback loop.\",\n      \"method\": \"MeRIP assay, co-immunoprecipitation, immunofluorescence, ubiquitination assays, metabolomics, Ythdf3-/- mouse model\",\n      \"journal\": \"Journal of Experimental & Clinical Cancer Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, MeRIP, KO mouse model, single lab with multiple methods\",\n      \"pmids\": [\"36471428\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"YTHDF3 recognizes m6A-modified PRDX3 mRNA and promotes its translation in an m6A-dependent manner; YTHDF3 knockdown (but not YTHDF1/2 knockdown) suppressed PRDX3 expression, demonstrating specificity among YTHDF family members for this target.\",\n      \"method\": \"RNA pull-down/mass spectrometry, YTHDF1/2/3 knockdown comparison, translation assays, RIP\",\n      \"journal\": \"Redox Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pull-down/MS, family-member specificity comparison, single lab\",\n      \"pmids\": [\"35779442\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"YTHDF3 recognizes m6A binding sites on LOXL3 mRNA and enhances its translation by enriching eIF3A on the LOXL3 transcript, increasing LOXL3 protein without affecting mRNA level; this was confirmed by CRISPR-Cas13b-based epitranscriptome engineering.\",\n      \"method\": \"RNA-seq, MeRIP-seq, RIP-seq, mass spectrometry, CRISPR-Cas13b epitranscriptome editing, RIP-qPCR, MeRIP-qPCR, eIF3A co-immunoprecipitation\",\n      \"journal\": \"Clinical and Translational Medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — CRISPR-based functional validation of m6A sites plus multi-omics (RNA-seq, MeRIP-seq, RIP-seq, MS) in single study\",\n      \"pmids\": [\"36324258\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"YTHDF3 facilitates translation of m6A-modified genes in oxaliplatin-resistant colorectal cancer by recognizing 5' UTR m6A and recruiting eIF3A; eIF2AK2 bridges YTHDF3 and eIF3A, enhancing the stability of the YTHDF3/eIF3A translational complex.\",\n      \"method\": \"RIP, MeRIP, Co-immunoprecipitation of YTHDF3/eIF2AK2/eIF3A complex, translation assays\",\n      \"journal\": \"ACS Chemical Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP of ternary complex, RIP/MeRIP validation, single lab\",\n      \"pmids\": [\"35708211\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"YTHDF3 modulates hematopoietic stem cell reconstitution capacity by transmitting m6A RNA methylation on the 5' UTR of Ccnd1 (Cyclin D1) mRNA to promote its translation; enforced Ccnd1 expression completely rescued Ythdf3-/- HSC defects.\",\n      \"method\": \"Ythdf3-/- and Mettl3-/- mouse models, bone marrow reconstitution assays, translational defect analysis, rescue experiments with Ccnd1 overexpression\",\n      \"journal\": \"Haematologica\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with complete phenotypic rescue by downstream target, defined mechanistic pathway (m6A/5'UTR/translation), in vivo model\",\n      \"pmids\": [\"35112553\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"METTL3 methylates MCU mRNA at three m6A residues in the 3'-UTR; YTHDF3 associates with methylated MCU mRNA and promotes its translation, increasing MCU protein expression and contributing to HCMV-induced vascular endothelial apoptosis.\",\n      \"method\": \"MeRIP-qPCR, RIP, METTL3/YTHDF3 knockdown/overexpression, MCU translation assays\",\n      \"journal\": \"Frontiers in Microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MeRIP-qPCR and RIP defining writer-reader-target axis, single lab\",\n      \"pmids\": [\"35359726\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"YTHDF3 promotes RAD51D mRNA N6-methyladenosine modification in an HNF1α-dependent manner and promotes RAD51D translation, conferring radioresistance in cervical cancer; HNF1α upregulates YTHDF3 transcription.\",\n      \"method\": \"HNF1α/YTHDF3 knockdown/overexpression, m6A modification analysis, translational assays, in vitro and in vivo irradiation resistance assays\",\n      \"journal\": \"FEBS Journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined transcriptional-m6A-translation axis with functional rescue, single lab\",\n      \"pmids\": [\"36380687\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"YTHDF3 depletion in ESCs results in loss of pluripotency with accelerated germ layer differentiation; knockdown of YTHDF3 accelerated cardiomyocyte differentiation, whereas YTHDF1 depletion impaired it. YTHDF3 appears to modulate differentiation partially through suppression of YTHDF1.\",\n      \"method\": \"YTHDF1/YTHDF3 knockdown in ESCs, transcriptomic analysis, cardiomyocyte differentiation assays, marker gene expression\",\n      \"journal\": \"RNA Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined phenotypic readouts with epistasis between YTHDF3 and YTHDF1, single lab\",\n      \"pmids\": [\"33295243\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Molecular dynamics simulation studies reveal that the YTH domain of YTHDF3 recognizes m6A via an aromatic cage in which Trp492 anchors the methyl group and Trp438/Trp497 provide π-π stacking; m6A methylation enhances hydrophobicity, excluding water from the aromatic cage and stabilizing the complex via induced-fit and conformation selection mechanisms.\",\n      \"method\": \"All-atom molecular dynamics simulations, binding free energy calculations, hydrogen bond analysis\",\n      \"journal\": \"Proteins\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Moderate — computational only; no experimental mutagenesis validation in this paper\",\n      \"pmids\": [\"35639481\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ZDHHC20-mediated S-palmitoylation of YTHDF3 at Cys474 inhibits chaperone-mediated autophagic degradation of YTHDF3, leading to its accumulation and stabilization of MYC mRNA; a YTHDF3-derived competitive peptide inhibiting this palmitoylation downregulates MYC and inhibits pancreatic cancer progression.\",\n      \"method\": \"KPC mouse model, palmitoylation assays, Cys474 mutagenesis, chaperone-mediated autophagy assays, competitive peptide design, MYC mRNA stability assays\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — site-specific mutagenesis (Cys474), in vivo mouse model, competitive peptide functional validation, multiple orthogonal methods\",\n      \"pmids\": [\"38821916\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"YTHDF3 promotes degradation of SPOP and NKX3.1 mRNAs and stabilizes TWIST1 and SNAI2 mRNAs in an m6A-dependent manner in castration-resistant prostate cancer; melatonin competes with m6A to occupy the m6A-binding cage of YTHDF3, inhibiting its target mRNA regulation.\",\n      \"method\": \"YTHDF3 overexpression/knockdown, m6A-dependent mRNA stability assays, melatonin competition binding assays, in vitro and in vivo tumor models\",\n      \"journal\": \"Journal of Pineal Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined differential mRNA stability effects, small-molecule binding competition, single lab\",\n      \"pmids\": [\"39143673\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"YTHDF3 undergoes AARS2-dependent lactylation, which stabilizes the protein by antagonizing ubiquitin-mediated degradation; lactylated YTHDF3 enhances m6A-dependent recognition and decay of KDM6B mRNA, suppressing CDKN1A transcription via impaired H3K27me3 demethylation and promoting cisplatin resistance in bladder cancer.\",\n      \"method\": \"Lactylation assays, YTHDF3 lactylation-deficient mutant, ubiquitination assays, MeRIP, RIP, KDM6B mRNA stability assays, xenograft models\",\n      \"journal\": \"Cancer Letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — lactylation-deficient mutant with loss of function, multiple pathway components validated, single lab\",\n      \"pmids\": [\"41621475\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"METTL3-mediated m6A modification of SOX4 mRNA (in the CDS region) is recognized by YTHDF3, which regulates SOX4 mRNA stability; YTHDF3 knockdown reduced SOX4 mRNA stability and compromised osteoblast differentiation downstream of METTL3.\",\n      \"method\": \"MeRIP-seq, RNA-seq, RIP assay, METTL3/YTHDF3 knockdown, osteoblast differentiation assays, in vivo OVX mouse model\",\n      \"journal\": \"Cellular Signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MeRIP-seq plus RIP confirming YTHDF3-SOX4 interaction, epistasis between METTL3 and YTHDF3, single lab\",\n      \"pmids\": [\"38195035\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FTO demethylation of PDK1 mRNA prevents YTHDF3 from recognizing and binding to m6A sites on PDK1 mRNA, thus inhibiting PDK1 mRNA degradation; this axis links hypoxia-driven FTO upregulation to PDK1/AKT/STAT3/PD-L1 immunosuppression in breast cancer.\",\n      \"method\": \"MeRIP-seq, RIP, PDK1 mRNA stability assays, FTO/YTHDF3 knockdown/overexpression, in vivo mouse models\",\n      \"journal\": \"Journal of Advanced Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MeRIP-seq plus RIP defining eraser-reader interplay, functional in vivo validation, single lab\",\n      \"pmids\": [\"39701379\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"YTHDF3 recognizes DNA N6-methyladenine (6mA) in genomic DNA (including double-stranded DNA) and recruits ALKBH1 demethylase to 6mA sites in genomic DNA, facilitating ALKBH1-mediated removal of 6mA in dsDNA—a conformation for which ALKBH1 alone has limited activity.\",\n      \"method\": \"Biochemical binding assays with 6mA-modified DNA, Co-immunoprecipitation of YTHDF3-ALKBH1, 6mA demethylation activity assays with various DNA conformations, genomic 6mA quantification\",\n      \"journal\": \"The EMBO Journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro biochemical reconstitution of demethylase activity, Co-IP, functional assays across DNA conformations, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"40715766\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"YTHDF3 promotes cardiac stress-induced protein synthesis and controls cardiomyocyte size; cardiomyocyte-specific deletion of YTHDF3 in mice attenuates pathological cardiac remodeling following pressure overload injury.\",\n      \"method\": \"Cardiomyocyte-specific YTHDF3 conditional knockout mice, pressure overload (transverse aortic constriction) model, global protein synthesis measurement\",\n      \"journal\": \"RNA\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO mouse with defined cardiac phenotype, mechanistic link to protein synthesis, single lab\",\n      \"pmids\": [\"40216557\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"YTHDF3 interacts with BTG2 and is involved in the decay of Cbln1 mRNA; increased YTHDF3 levels in hippocampus of prenatal hypoxia offspring lead to Cbln1 downregulation, contributing to abnormal synaptic function and cognitive impairment.\",\n      \"method\": \"Co-immunoprecipitation of YTHDF3-BTG2, mRNA decay assays, hippocampal YTHDF3 measurement, Cbln1 expression analysis\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP identifying YTHDF3-BTG2 interaction, mechanistic link to mRNA decay and synaptic phenotype, single lab\",\n      \"pmids\": [\"38205248\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"YTHDF3 phase separation characteristics enable it to suppress ccRCC malignancy and PD-L1-mediated immune evasion by recruiting DDX6 to degrade HSPA13 mRNA; a YTHDF3 mutant disrupting phase separation abolishes these functions.\",\n      \"method\": \"Phase separation assays, YTHDF3 mutant disrupting phase separation, HSPA13 mRNA degradation assays, DDX6 recruitment assays, in vivo tumor models with CD8+ T cell measurement\",\n      \"journal\": \"Cancer Science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — structure-function mutagenesis of phase separation domain, in vivo validation, single lab\",\n      \"pmids\": [\"38811341\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"YTHDF3 binds to m6A-modified STAT3 mRNA to enhance its stability and transcription efficiency; this YTHDF3-STAT3 axis represses IRF7 transcription and IFN-α production, suppressing type I ISG responses and antiviral immunity in HPV-driven cervical cancer.\",\n      \"method\": \"CRISPR/Cas9 YTHDF3-/- cells and Ythdf3-/- mice, RIP, MeRIP, STAT3 mRNA stability assays, ISG induction measurement, in vivo xenograft immune cell profiling\",\n      \"journal\": \"Cell Death & Disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR KO with in vivo validation, RIP/MeRIP mechanistic support, single lab\",\n      \"pmids\": [\"41453852\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"YTHDF3 promotes FLCN mRNA stability via m6A methylation; FLCN in turn binds cPLA2 to increase its activity and regulate lysosomal membrane permeabilization in cardiac fibroblasts, with YTHDF3 overexpression reducing collagen production and improving cardiac fibrosis in TAC mice.\",\n      \"method\": \"MeRIP, mRNA stability assays, FLCN/cPLA2 Co-IP, TAC mouse model, YTHDF3/FLCN overexpression in vivo\",\n      \"journal\": \"Acta Pharmacologica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, MeRIP, in vivo TAC model, functional rescue, single lab\",\n      \"pmids\": [\"39806064\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"YTHDF3 promotes YTHDF3-mediated mRNA decay of SOX9; loss of Ythdf3 in mice leads to impaired SOX9 mRNA decay, causing cardiac hypertrophy, myopathy, and intellectual abnormalities resembling Danon disease; AAV-shRNA targeting Sox9 rescued these phenotypes.\",\n      \"method\": \"Ythdf3-/- mouse model, Sox9 mRNA decay assays, AAV-shRNA rescue experiments, cardiac and neurological phenotyping\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo KO with specific mRNA decay target identified and rescue by downstream knockdown; preprint not yet peer-reviewed\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In cardiomyocytes, Ythdf3 localizes to the nucleus (contrary to its predominantly cytoplasmic localization elsewhere) and interacts with splicing proteins DDX5 and HNRNPU to regulate alternative splicing, including splicing of CaMKIIδ isoforms; Ythdf3 knockdown increases CaMKIIδA and CaMKIIδC isoforms while decreasing CaMKIIδ9.\",\n      \"method\": \"Nuclear/cytoplasmic fractionation with imaging, Co-immunoprecipitation coupled with LC-MS/MS, alternative splicing analysis, Ythdf3 knockdown/overexpression, electron microscopy\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP/MS and splicing analysis are strong methods but preprint only, not yet peer-reviewed; novel subcellular localization claim needs replication\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"YTHDF3 promotes m6A-dependent stabilization of Wnt3 mRNA in glioma in synergy with circ_EPHB4; YTHDF3 alone extends the half-life of Wnt3 mRNA in an m6A-dependent manner, and simultaneous knockdown of both circ_EPHB4 and YTHDF3 reduces Wnt3 mRNA expression more than either alone.\",\n      \"method\": \"RIP, RNA stability assays, circ_EPHB4/YTHDF3 knockdown, gene co-expression rescue, in vivo tumor models\",\n      \"journal\": \"Journal of Southern Medical University\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — RIP and stability assays, single lab, mechanistic claim is indirect (Wnt3 stabilization as downstream of YTHDF3)\",\n      \"pmids\": [\"41311073\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TRMT6 installs m1A marks on TOPBP1 and DSN1 mRNAs; YTHDF3 reads these m1A modifications and stabilizes these cell-cycle mRNAs, promoting lung squamous cell carcinoma proliferation; a single m1A site in each mRNA is sufficient to boost their expression.\",\n      \"method\": \"m1A-seq, RIP, dCasRx-TRMT6 site-specific m1A deposition, YTHDF3/TRMT6 knockdown, in vitro and in vivo proliferation assays\",\n      \"journal\": \"NPJ Precision Oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — dCasRx-based site-specific epitranscriptome editing plus RIP and m1A-seq, single lab with multiple methods\",\n      \"pmids\": [\"41803797\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"YTHDF3 depletion in GC cell lines impairs cytoskeleton organization, cell migration, metastasis, and mitotic spindle orientation, leading to increased paclitaxel sensitivity; EZRIN (EZR) mRNA was identified as a direct YTHDF3 target via RNA immunoprecipitation, with m6A sites mapped by SELECT method.\",\n      \"method\": \"CRISPR-Cas9 YTHDF3 knockout, RIP, SELECT method for m6A mapping on EZR, migration/invasion/spindle orientation assays, paclitaxel sensitivity assays\",\n      \"journal\": \"Gastric Cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR KO, RIP, SELECT m6A mapping, defined cytoskeletal and mitotic phenotypes, single lab\",\n      \"pmids\": [\"40366509\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"YTHDF3 promotes translation of Notch2 mRNA in an m6A-dependent manner by recruiting eIF4B; YTHDF3 binds m6A-modified Notch2 mRNA and its knockdown reduces Notch2 protein levels and EMT.\",\n      \"method\": \"RIP, MeRIP, eIF4B Co-immunoprecipitation, Notch2 translation assays, in vitro/in vivo EMT and metastasis models\",\n      \"journal\": \"Cancer Letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP of YTHDF3-eIF4B-Notch2 mRNA axis, RIP/MeRIP validation, single lab\",\n      \"pmids\": [\"39924078\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Histone lactylation promotes YTHDF3 expression, and YTHDF3 in turn promotes m6A-dependent translation of PRDX3 mRNA; reduced YTHDF3 from sevoflurane exposure decreases PRDX3, activating NLRP3 inflammasome-mediated pyroptosis in microglia.\",\n      \"method\": \"ChIP assay for histone lactylation at YTHDF3 promoter, RIP for YTHDF3-PRDX3 mRNA interaction, YTHDF3 overexpression rescue, NLRP3/caspase-1 activity assays\",\n      \"journal\": \"International Immunopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and RIP mechanistic chain, functional rescue, single lab\",\n      \"pmids\": [\"40022822\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"YTHDF3 promotes degradation of XRCC1 mRNA in an m6A-dependent manner in the rostral ventrolateral medulla; YTHDF3 knockdown increased XRCC1 expression, facilitated DNA damage repair in neurons, reduced neuronal apoptosis, and lowered blood pressure in spontaneously hypertensive rats.\",\n      \"method\": \"YTHDF3 knockdown in RVLM of SHRs, m6A-dependent mRNA stability assays for XRCC1, neuronal excitability and sympathetic tone measurement, blood pressure recording, in vitro rescue with XRCC1\",\n      \"journal\": \"Free Radical Biology & Medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo stereotactic knockdown with defined physiological phenotype, m6A-dependent mRNA decay mechanism, single lab\",\n      \"pmids\": [\"40490202\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"YTHDF3 directly recognizes BRCA1, RAD51, RIF1, and 53BP1 mRNAs via m6A binding sites and promotes their translation, facilitating homologous recombination and NHEJ DNA repair in glioblastoma, contributing to temozolomide resistance; TMZ treatment increases m6A modification levels to facilitate this YTHDF3-mediated DDR.\",\n      \"method\": \"YTHDF3 and METTL3 knockdown, m6A-modified DDR gene mRNA translation assays, DNA repair assays (HR and NHEJ), PDC models\",\n      \"journal\": \"Cancer Letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined mechanistic axis (m6A/YTHDF3/DDR gene translation/repair), functional rescue, patient-derived cell validation, single lab\",\n      \"pmids\": [\"41881836\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"YTHDF3 binds m6A-modified SOCS1 mRNA to enhance both its stability and translation, upregulating SOCS1 expression and thereby inhibiting the JAK1/STAT3 pathway in trophoblast cells, promoting preeclampsia pathogenesis.\",\n      \"method\": \"YTHDF3 knockdown in trophoblast cells, MeRIP, RIP, mRNA stability assays, JAK1/STAT3 pathway activity measurement\",\n      \"journal\": \"The Journal of Gene Medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — RIP/MeRIP and mRNA stability assays, single lab, limited mechanistic orthogonal validation\",\n      \"pmids\": [\"41287146\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"YTHDF3 accelerates degradation of key TLR4 pathway mRNAs (Cd36, Irak1, Tab1/2, Tirap) to suppress macrophage activation; Ythdf3 knockdown inhibits their degradation and enhances p38 phosphorylation, LPS-induced pro-inflammatory cytokine production, phagocytosis, and tumor-killing activity.\",\n      \"method\": \"shRNA Ythdf3 knockdown in RAW264.7 cells, mRNA stability analysis, p38 phosphorylation immunoblotting, cytokine ELISA, phagocytosis and tumor co-culture assays\",\n      \"journal\": \"Sichuan University Journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — shRNA KD with defined mRNA stability targets and signaling pathway activation, multiple downstream readouts, single lab\",\n      \"pmids\": [\"40964113\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"YTHDF3 maintains SIRT2 mRNA stability via m6A binding, facilitating SIRT2-mediated deacetylation of FOXO1 and reducing FOXO1 protein stability, thereby promoting Ang II-induced VSMC apoptosis and inflammation in abdominal aortic aneurysm.\",\n      \"method\": \"MeRIP-qPCR, RIP, mRNA stability assay, cycloheximide chase, co-immunoprecipitation, YTHDF3 knockdown in VSMCs\",\n      \"journal\": \"Korean Circulation Journal\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — RIP/MeRIP/Co-IP, single lab, multi-step mechanistic chain not fully validated with independent methods\",\n      \"pmids\": [\"41972268\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"YTHDF3 is a cytoplasmic m6A (and m1A) RNA reader that acts cooperatively with YTHDF1 and YTHDF2 to accelerate metabolism of methylated mRNAs: it promotes translation of specific m6A/m1A-modified target mRNAs (e.g., FOXO3, Ccnd1, CTNNB1, LOXL3, PRDX3) by recruiting translation initiation factors (eIF3A, eIF4B, eIF2AK2, eIF3a/eIF4B), facilitates mRNA decay of other targets (e.g., IGF1R, XRCC1, SOX9, HSPA13), and also acts in the nucleus to regulate alternative splicing in cardiomyocytes; its activity and stability are post-translationally regulated by ZDHHC20-mediated S-palmitoylation (at Cys474) and by lactylation (via AARS2), and it has an additional nuclear DNA reader function, binding 6mA-modified genomic DNA to recruit the ALKBH1 demethylase.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"YTHDF3 is a predominantly cytoplasmic reader of methylated RNA that integrates m6A-modified mRNA metabolism together with YTHDF1 and YTHDF2, simultaneously promoting protein synthesis and accelerating decay of distinct target transcripts [#0]. On the translational arm, YTHDF3 binds m6A sites—frequently in the 5' UTR or around the stop codon—and recruits translation initiation machinery including eIF3A, eIF4B, and the bridging factor eIF2AK2, with cofactors PABP1 and eIF4G2, to boost output of targets such as FOXO3, Ccnd1, CTNNB1, LOXL3, PRDX3, and Notch2 [#1, #6, #10, #11, #12, #33]. On the decay arm, it destabilizes m6A-marked transcripts including SOX9, XRCC1, and HSPA13, in the latter case acting through liquid-liquid phase separation to recruit the decay factor DDX6 [#25, #28, #35]. Its reader activity extends beyond m6A: YTHDF3 recognizes m1A-modified mRNAs (IGF1R, TOPBP1, DSN1) to control their stability [#3, #31], and in genomic DNA it binds N6-methyladenine (6mA) and recruits the ALKBH1 demethylase to remove 6mA from double-stranded DNA [#22]. YTHDF3 abundance and activity are tuned post-translationally by ZDHHC20-mediated S-palmitoylation at Cys474, which blocks chaperone-mediated autophagic degradation, and by AARS2-dependent lactylation that antagonizes ubiquitin-mediated turnover [#17, #19]. Through these activities YTHDF3 governs diverse physiological programs including autophagy [#6], hematopoietic stem cell reconstitution [#12], antiviral and innate immune signaling [#1, #4], DNA damage repair [#36], and cardiac stress remodeling, where it controls stress-induced protein synthesis and cardiomyocyte size [#23].\",\n  \"teleology\": [\n    {\n      \"year\": 2017,\n      \"claim\": \"Established that YTHDF3 does not act alone but functions within the YTHDF reader family to coordinate the fate of m6A-modified mRNAs, resolving whether the three paralogs are redundant or integrated.\",\n      \"evidence\": \"Single and triple YTHDF knockouts with polysome profiling, mRNA stability assays, and m6A-seq\",\n      \"pmids\": [\"28106072\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define target-level specificity distinguishing the three readers\", \"Did not identify the recruited effector machinery for translation versus decay\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showed YTHDF3 can act independently of m6A for at least one target, binding the FOXO3 translation initiation region via both its YTH and P/Q/N-rich domains to suppress interferon-stimulated genes.\",\n      \"evidence\": \"Reciprocal Co-IP, RIP, domain-deletion mutagenesis, YTHDF3 knockout mice, viral infection assays\",\n      \"pmids\": [\"30591559\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which the P/Q/N-rich domain contributes to RNA binding not structurally defined\", \"Whether m6A-independent binding generalizes beyond FOXO3 unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Broadened the reader repertoire by demonstrating YTHDF3 reads m1A as well as m6A, coupling m1A recognition of IGF1R mRNA to decay and adding a second modification mark to its functional scope.\",\n      \"evidence\": \"Mass-spec identification of m1A readers, iCLIP-seq, m1A-seq, RIP, mRNA stability and trophoblast invasion assays\",\n      \"pmids\": [\"32194978\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis distinguishing m1A from m6A recognition not resolved\", \"Whether m1A reading recruits the same decay machinery as m6A unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined cancer-relevant translational targets and an autoregulatory loop, showing YTHDF3 enhances translation of metastasis genes and binds m6A in its own 5' UTR to drive cap-independent self-translation.\",\n      \"evidence\": \"Overexpression/knockdown, polysome profiling, RIP, MeRIP-seq, in vivo brain metastasis models, reporter assays\",\n      \"pmids\": [\"33125861\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Trigger for cap-independent autoregulation in physiology unclear\", \"Initiation factors for these specific targets not yet mapped\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified YTHDF3 as an antiviral restriction factor incorporated into HIV virions and a target of HIV protease cleavage, linking the reader to host-pathogen conflict.\",\n      \"evidence\": \"YTHDF3 knockout CD4+ T cells, HIV infection assays, mass spectrometry of virion proteins, protease inhibitor treatment\",\n      \"pmids\": [\"32053707\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism restricting reverse transcription not defined\", \"Whether RNA-reading activity is required for restriction unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Placed YTHDF3 within innate immune signaling as a positive regulator of type I IFN JAK/STAT, and showed it is cleaved early by enterovirus 2A proteases.\",\n      \"evidence\": \"YTHDF depletion, viral infection, JAK/STAT inhibition, type I/II IFN treatment, ISG induction\",\n      \"pmids\": [\"33849973\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct RNA targets mediating JAK/STAT enhancement not identified\", \"Reconciliation with FOXO3-mediated ISG suppression not addressed\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified the specific translation-initiation effectors recruited by YTHDF3—eIF3A, eIF4B, and bridging factor eIF2AK2—mechanistically explaining how it activates translation of m6A-marked targets across autophagy, cancer, and stem-cell contexts.\",\n      \"evidence\": \"Co-IP of YTHDF3/eIF3A/eIF2AK2/eIF4B complexes, MeRIP-seq, RIP, polysome profiling, CRISPR-Cas13b epitranscriptome editing, KO mouse rescue across multiple studies\",\n      \"pmids\": [\"36195598\", \"35708211\", \"36324258\", \"35112553\", \"35779442\", \"35110680\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Determinants selecting which m6A transcripts route to translation versus decay not defined\", \"Stoichiometry and order of initiation factor recruitment unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Provided a structural rationale for m6A recognition, modeling an aromatic cage in the YTH domain that anchors the methyl group and excludes water.\",\n      \"evidence\": \"All-atom molecular dynamics simulations and binding free-energy calculations\",\n      \"pmids\": [\"35639481\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Computational only without experimental mutagenesis validation in this work\", \"Does not address m1A or 6mA recognition modes\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrated reciprocal stabilization of YTHDF3 protein by a downstream metabolic target, revealing the reader is itself regulated by ubiquitin-mediated turnover within feedback loops.\",\n      \"evidence\": \"MeRIP, Co-IP, ubiquitination assays, metabolomics, Ythdf3-/- mouse model\",\n      \"pmids\": [\"36471428\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"E3 ligase mediating YTHDF3 ubiquitination not identified\", \"Direct versus indirect role of EFTUD2 unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established post-translational control of YTHDF3 stability through ZDHHC20-mediated S-palmitoylation at Cys474, which blocks chaperone-mediated autophagic degradation and is druggable by competitive peptide.\",\n      \"evidence\": \"KPC mouse model, palmitoylation assays, Cys474 mutagenesis, CMA assays, competitive peptide, MYC mRNA stability assays\",\n      \"pmids\": [\"38821916\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether palmitoylation alters RNA-binding or only stability unclear\", \"Signals regulating ZDHHC20 activity on YTHDF3 unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Added lactylation as a second stabilizing post-translational mark, installed in an AARS2-dependent manner and antagonizing ubiquitin-mediated degradation.\",\n      \"evidence\": \"Lactylation assays, lactylation-deficient mutant, ubiquitination assays, MeRIP, RIP, mRNA stability, xenografts\",\n      \"pmids\": [\"41621475\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Lactylation site(s) on YTHDF3 not defined\", \"Interplay between lactylation and palmitoylation unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Revealed a phase-separation-dependent decay mechanism in which YTHDF3 condensates recruit DDX6 to degrade target mRNA, mechanistically linking biophysical condensation to its decay arm.\",\n      \"evidence\": \"Phase-separation assays, phase-separation-disrupting mutant, HSPA13 mRNA degradation, DDX6 recruitment, in vivo tumor models\",\n      \"pmids\": [\"38811341\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether condensation is required for all decay targets unknown\", \"Domain driving phase separation not finely mapped\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extended YTHDF3 function from RNA to DNA, showing it reads genomic 6mA and recruits ALKBH1 to demethylate double-stranded DNA, a substrate conformation ALKBH1 handles poorly alone.\",\n      \"evidence\": \"In vitro biochemical binding and demethylation assays across DNA conformations, YTHDF3-ALKBH1 Co-IP, genomic 6mA quantification\",\n      \"pmids\": [\"40715766\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genomic loci and biological consequences of 6mA reading not mapped\", \"Whether nuclear localization for this function is regulated unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined a nuclear, splicing-regulatory role in cardiomyocytes where YTHDF3 partners with DDX5 and HNRNPU, challenging the strictly cytoplasmic reader model.\",\n      \"evidence\": \"Nuclear/cytoplasmic fractionation, Co-IP/LC-MS-MS, alternative splicing analysis, knockdown/overexpression (preprint)\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Preprint not yet peer-reviewed\", \"Novel nuclear localization claim awaits independent replication\", \"Whether splicing role depends on m6A reading unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved what molecular features partition individual methylated transcripts between YTHDF3-driven translation versus decay, and how its newly described nuclear functions (splicing, 6mA/DNA reading) are coordinated with its cytoplasmic reader activity.\",\n      \"evidence\": \"Open question synthesized across translation, decay, and nuclear DNA/splicing findings\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unifying code distinguishing translation- versus decay-fated targets\", \"Spatial regulation between cytoplasmic and nuclear pools undefined\", \"Functional hierarchy among m6A, m1A, and 6mA reading not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 1, 3, 10, 12, 32]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [22]},\n      {\"term_id\": \"GO:0045182\", \"supporting_discovery_ids\": [6, 10, 11, 12, 33]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 18, 28, 35]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 6, 11]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [22, 29]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 3, 18, 28]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [6, 10, 11, 12, 33]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1, 4, 5, 26, 38]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [35, 36]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"YTHDF1\", \"YTHDF2\", \"eIF3A\", \"eIF4B\", \"eIF2AK2\", \"ALKBH1\", \"DDX6\", \"ZDHHC20\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":{"gene":"YTHDF3","tier":"GROUNDING","verdict":"Evidence-grounding concern","subtype":"fabrication","uniprot_band":"rich","rules_fired":"R7","issue":"R7: fabricated (no corpus paper): 41803797, 41881836"},"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}