{"gene":"YTHDF2","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2018,"finding":"YTHDF2 directly binds the m6A modification site in the 3'-UTR of EGFR mRNA and promotes its degradation, suppressing cell proliferation in hepatocellular carcinoma cells.","method":"RIP assay, mRNA stability assay, loss-of-function/gain-of-function in HCC cells","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal binding shown by RIP, mRNA stability assay, functional rescue; single lab, two orthogonal methods","pmids":["30423408"],"is_preprint":false},{"year":2019,"finding":"YTHDF2 decreases the half-life of diverse m6A-modified transcripts in leukemic stem cells (LSCs), including Tnfrsf2, whose upregulation upon YTHDF2 deficiency primes LSCs for apoptosis; YTHDF2 is required for AML disease initiation and propagation but is not essential for normal HSC function.","method":"Mouse/human AML models, conditional KO, mRNA half-life assay, m6A sequencing","journal":"Cell stem cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (KO mouse model, human AML, mRNA half-life, m6A-seq), replicated across mouse and human systems","pmids":["31031138"],"is_preprint":false},{"year":2019,"finding":"YTHDF2 promotes decay of m6A-containing IL11 and SERPINE2 mRNAs; its transcription is suppressed by HIF-2α, creating a feedback loop whereby HIF-2α reduction of YTHDF2 leads to inflammation and vascular abnormalization in hepatocellular carcinoma.","method":"m6A-IP sequencing, mRNA stability assay, HIF-2α antagonist treatment, KO mouse model","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — m6A-IP-seq and mRNA stability assay in single lab, KO mouse corroborates","pmids":["31735169"],"is_preprint":false},{"year":2019,"finding":"YTHDF2 binds 5-methylcytosine (m5C) in RNA via Trp432 (the same conserved hydrophobic pocket residue required for m6A recognition), albeit with lower affinity than m6A; YTHDF2 knockout increases m5C levels at the majority of rRNA sites and impairs pre-rRNA processing.","method":"Quantitative proteomics pull-down, in vitro binding assay with Trp432 mutagenesis, CRISPR-Cas9 KO, RNA bisulfite sequencing","journal":"Analytical chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro binding assay with active-site mutagenesis (Trp432), CRISPR KO + bisulfite sequencing; multiple orthogonal methods in single rigorous study","pmids":["31815440"],"is_preprint":false},{"year":2019,"finding":"YTHDF2 depletion in LPS-stimulated macrophages increases the stability of MAP2K4 and MAP4K4 mRNAs, activating MAPK and NF-κB signaling and promoting proinflammatory cytokine expression.","method":"YTHDF2 knockdown in RAW264.7 cells, mRNA stability assay, inhibitor rescue experiments","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mRNA stability assay plus signaling inhibitor rescue; single lab, two orthogonal methods","pmids":["30875984"],"is_preprint":false},{"year":2020,"finding":"YTHDF2 promotes mitotic entry by facilitating m6A-dependent decay of WEE1 mRNA; CDK1 activity stabilizes YTHDF2 protein, forming a CDK1-YTHDF2-WEE1 feedforward loop. YTHDF2 proteolysis is mediated by CUL1, CUL4A, DDB1, and SKP2 E3 ubiquitin ligase complexes.","method":"YTHDF2 depletion in HeLa cells, mRNA stability assay, CDK1 inhibitor treatment, identification of E3 ubiquitin ligase components by co-IP","journal":"PLoS biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (KD, mRNA stability, CDK1 inhibitor, co-IP for E3 ligases), mechanistic loop experimentally established","pmids":["32267835"],"is_preprint":false},{"year":2020,"finding":"YTHDF2 recruits the CCR4-NOT deadenylase complex to mediate mRNA deadenylation and clearance of m6A-modified somatic gene transcripts (including Tead2 and Tgfb1) during somatic reprogramming to iPSCs; YTHDF3 independently recruits PAN2-PAN3 deadenylase complex for the same purpose.","method":"Ythdf2/3 knockout, mRNA clearance assays, co-IP of CCR4-NOT and PAN2-PAN3, rescue experiments","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP identifying deadenylase partners, KO with functional rescue, multiple orthogonal methods","pmids":["32905781"],"is_preprint":false},{"year":2020,"finding":"YTHDF2 knockdown in mouse spermatogonia causes decreased expression of MMP3, MMP13, ADAMTS1, and ADAMTS9, affecting cell-matrix adhesion and proliferation; m6A-IP-PCR and RIP-PCR confirmed these transcripts are m6A-modified and directly bound by YTHDF2.","method":"CRISPR/Cas9 KO, m6A-IP-PCR, RIP-PCR, mRNA stability assay, inhibitor rescue","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP-PCR and m6A-IP confirming direct binding, KO phenotype; single lab","pmids":["31959747"],"is_preprint":false},{"year":2021,"finding":"EGFR/SRC/ERK signaling phosphorylates YTHDF2 at serine 39 and threonine 381, stabilizing the YTHDF2 protein; YTHDF2 in turn facilitates m6A-dependent mRNA decay of LXRA and HIVEP2 to promote GBM tumorigenesis and inhibits LXRα-dependent cholesterol homeostasis.","method":"Phosphorylation site identification by mutagenesis, mRNA decay assay, co-IP, YTHDF2 KD/OE in GBM cells and xenografts","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — active-site mutagenesis (S39/T381) plus mRNA decay assay plus co-IP; multiple orthogonal methods in one study","pmids":["33420027"],"is_preprint":false},{"year":2021,"finding":"Histone lactylation drives YTHDF2 expression; YTHDF2 then recognizes m6A-modified PER1 and TP53 mRNAs and promotes their degradation to accelerate tumorigenesis in ocular melanoma.","method":"Histone lactylation profiling, RIP assay, mRNA stability assay, in vitro and in vivo KD/OE","journal":"Genome biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP assay and mRNA stability assay confirming binding/decay; single lab, two methods","pmids":["33726814"],"is_preprint":false},{"year":2021,"finding":"Conditional depletion of Ythdf2 in mice causes embryonic lethality with compromised neural development; Ythdf2 loss impairs NSPC self-renewal and differentiation, and delays degradation of m6A-containing neural development-related mRNAs including JAK-STAT cascade inhibitory genes.","method":"Conditional KO mice, m6A methylome profiling of KO NSPCs, mRNA stability assay in vivo/in vitro","journal":"Genome biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO mice with defined developmental phenotype, m6A methylome, and mRNA stability assay; multiple orthogonal methods","pmids":["29855337"],"is_preprint":false},{"year":2021,"finding":"YTHDF2 disruption in triple-negative breast cancer stabilizes MAPK pathway mRNAs (identified by eCLIP and m6A sequencing), increasing global translation rates and inducing EMT; in MYC-driven tumors, YTHDF2-dependent mRNA degradation counteracts the global increase in mRNA synthesis, and YTHDF2 loss triggers ER stress-induced apoptosis.","method":"Pooled CRISPR-Cas9 screen, eCLIP, m6A-seq, scRibo-STAMP, xenograft tumors","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — eCLIP + m6A-seq + scRibo-STAMP; multiple orthogonal methods, rigorous mechanistic dissection","pmids":["34216543"],"is_preprint":false},{"year":2021,"finding":"YTHDF2 recognizes m6A modification and promotes mRNA decay of AXIN1 (a negative regulator of Wnt/β-catenin), thereby activating Wnt/β-catenin signaling to promote lung adenocarcinoma cell proliferation and migration; AXIN1 KO rescues the inhibitory effect of YTHDF2 depletion.","method":"Integrative RNA-seq, m6A-seq, CLIP-seq, RIP-seq, mRNA stability assay, epistasis rescue experiments","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 2 / Moderate — four orthogonal sequencing datasets plus mRNA stability plus genetic epistasis; single lab but multiple methods","pmids":["33980824"],"is_preprint":false},{"year":2021,"finding":"YTHDF2 recognizes m6A-modified Notch1 mRNA in the cytoplasm and promotes its decay, suppressing Notch signaling (HES1, HES5); under heat shock, YTHDF2 translocates to the nucleus via its YTH domain, reducing Notch1 mRNA decay and restoring Notch signaling. YTH domain deletion mutants confirm the domain is critical for both m6A binding and nuclear translocation.","method":"YTHDF2 deletion mutant analysis, mRNA stability assay, nuclear translocation imaging, heat shock treatment","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — deletion mutant analysis plus mRNA stability plus localization imaging; single lab","pmids":["34671198"],"is_preprint":false},{"year":2021,"finding":"YTHDF2 is required for NK cell terminal maturation and effector function in antitumor/antiviral immunity; YTHDF2 forms a STAT5-YTHDF2 positive feedback loop upon IL-15 stimulation and targets Tardbp mRNA (involved in cell survival/proliferation) for degradation in NK cells.","method":"Ythdf2 conditional KO in NK cells, transcriptome-wide YTHDF2 binding screening, in vivo tumor/viral infection models","journal":"The Journal of experimental medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with defined in vivo phenotype, transcriptome-wide binding screen; single lab","pmids":["34160549"],"is_preprint":false},{"year":2021,"finding":"Ythdf2-deficient hematopoietic stem cells chronically upregulate multiple m6A-modified inflammation-related transcripts, activating proinflammatory pathways; YTHDF2 expression is induced by inflammation and is required to protect HSCs from inflammatory insult.","method":"Hematopoiesis-specific Ythdf2 KO mice, serial transplantation, m6A-mRNA abundance profiling","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with serial transplantation and long-term in vivo characterization, replicated across two papers from independent labs","pmids":["33156926"],"is_preprint":false},{"year":2021,"finding":"YTHDF2 recognizes m6A-modified LncRNA FENDRR and promotes its degradation in endometrial cancer cells, thereby elevating SOX4 protein and promoting cell proliferation.","method":"RIP assay, mRNA stability assay, knockdown rescue experiments, xenograft model","journal":"Laboratory investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP and mRNA stability assay; single lab, two methods","pmids":["33692441"],"is_preprint":false},{"year":2021,"finding":"YTHDF2 promotes AXIN1 mRNA stability and expression in cervical cancer (opposite to its canonical decay function), and AXIN1 knockdown reverses the effects of YTHDF2 depletion on migration, invasion, EMT, and cisplatin sensitivity.","method":"MeRIP-seq, actinomycin D mRNA stability assay, epistasis KD rescue experiments","journal":"Drug development research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MeRIP-seq plus stability assay plus genetic epistasis; single lab","pmids":["35489084"],"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; this interaction promotes HIF-1α mRNA translation, as PBRM1 or YTHDF2 loss reduces HIF-1α protein but not mRNA levels.","method":"Co-IP (PBRM1-YTHDF2 interaction), RIP (HIF-1α mRNA binding), polysome profiling, KD experiments","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus RIP plus polysome profiling; single lab, multiple orthogonal methods","pmids":["34200988"],"is_preprint":false},{"year":2021,"finding":"YTHDF2 depletion in LPS-stimulated osteoclast precursors stabilizes Tnfrsf11a, Traf6, Map4k4, Map2k3, Map2k4, and Nfatc1 mRNAs, enhancing NF-κB and MAPK signaling and promoting inflammatory osteoclastogenesis.","method":"Ythdf2 KD in RAW264.7 and BMMs, mRNA stability assay, TRAP/pit formation assays, NF-κB/MAPK inhibitor rescue","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mRNA stability assay plus signaling inhibitor rescue; single lab","pmids":["34089814"],"is_preprint":false},{"year":2021,"finding":"O-GlcNAc transferase (OGT)-mediated O-GlcNAcylation of YTHDF2 at serine 263 enhances its protein stability by inhibiting its ubiquitination; O-GlcNAcylated YTHDF2 stabilizes MCM2 and MCM5 mRNAs in an m6A-dependent manner to promote cell cycle progression in HBV-related HCC.","method":"Mass spectrometry identification of S263 modification, mutagenesis, ubiquitination assay, RIP, m6A-dependent mRNA stability assay","journal":"Signal transduction and targeted therapy","confidence":"High","confidence_rationale":"Tier 1 / Moderate — modification site identified by MS and confirmed by mutagenesis (S263), plus ubiquitination assay and RIP; multiple orthogonal methods in one study","pmids":["36765030"],"is_preprint":false},{"year":2022,"finding":"YTHDF2 requires B cell activation to be upregulated; YTHDF2 enhances decay of methylated transcripts encoding key plasmablast-regulating genes to suppress the plasmablast genetic program and promote germinal center B cell fate commitment.","method":"Ythdf2 conditional KO in B cells, single-cell RNA-seq, m6A-mRNA decay assay","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO plus scRNA-seq; single lab","pmids":["35508130"],"is_preprint":false},{"year":2022,"finding":"YTHDF2 promotes CDKN1B mRNA degradation in an m6A-dependent manner in intrahepatic cholangiocarcinoma, driving cell cycle progression and cisplatin resistance.","method":"RNA-seq, MeRIP-seq, anti-YTHDF2 RIP-seq, RNA stability assay, PDX model","journal":"Clinical and translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — three orthogonal sequencing methods plus stability assay; single lab","pmids":["35696608"],"is_preprint":false},{"year":2022,"finding":"YTHDF2 facilitates m6A-dependent mRNA decay of LXRA and promotes YTHDF2/APC and GSK3β mRNA degradation via Wnt-β-catenin pathway activation in glioblastoma; PRMT6 and CDK9 co-regulate YTHDF2 transcription, with PRMT6 acting upstream.","method":"Dual-luciferase reporter assay, ChIP-qPCR, mRNA stability assay, in situ tumor model","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-qPCR, luciferase assay, mRNA stability assay; single lab","pmids":["38637831"],"is_preprint":false},{"year":2022,"finding":"HSP90β physically interacts with YTHDF2 and STUB1 (an E3 ubiquitin ligase) in the cytoplasm; HSP90β inhibits STUB1-induced ubiquitination and degradation of YTHDF2, stabilizing YTHDF2 protein and promoting HCC proliferation and sorafenib resistance.","method":"Co-IP, domain mapping (HSP90β large and small middle domain required for interaction), ubiquitination assay, KD/OE experiments","journal":"Advanced science","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP, domain mapping, in vitro ubiquitination assay; multiple orthogonal methods establishing the regulatory mechanism","pmids":["37515378"],"is_preprint":false},{"year":2022,"finding":"YTHDF2 binds to m6A sites on ACER2 mRNA and stabilizes (rather than degrades) it, enhancing ACER2 expression; increased ACER2 hydrolyzes ceramides and activates ERK and PI3K/AKT pathways in diffuse large B-cell lymphoma.","method":"RNA-seq, lipidomics, MeRIP-seq, RIP-qPCR, RNA stability assay, luciferase assay, CRISPR KO","journal":"Journal of advanced research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple sequencing methods plus stability assay; single lab; notably shows stabilization rather than decay","pmids":["37865189"],"is_preprint":false},{"year":2022,"finding":"YTHDF2 accelerates EGR1 mRNA degradation in an m6A-dependent manner in multiple myeloma; EGR1 suppresses proliferation by activating p21cip1/waf1 transcription and inhibiting CDK2-cyclinE1.","method":"RIP-PCR, MeRIP-qPCR, mRNA stability assay, EGR1 KD rescue, in vivo xenograft","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP plus MeRIP plus mRNA stability plus genetic epistasis; single lab","pmids":["37012388"],"is_preprint":false},{"year":2022,"finding":"YTHDF2 degrades STAT5A mRNA at its m6A modification site; reduced STAT5A relieves suppression of MAP2K2 transcription (ChIP-seq), thereby increasing p-ERK and promoting multiple myeloma cell proliferation.","method":"m6A-RIP-seq, RIP-PCR, ChIP-seq, mRNA stability assay, YTHDF2 KD/OE","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — m6A-RIP-seq plus ChIP-seq plus mRNA stability; single lab, multiple orthogonal methods","pmids":["35075244"],"is_preprint":false},{"year":2022,"finding":"YBX2 physically interacts with YTHDF2 via its cold-shock domain within YBX2-containing cytoplasmic granules; YTHDF2 knockdown ameliorates YBX2-induced HSPA6 mRNA destabilization, demonstrating synergistic effects of YBX2 and YTHDF2 on mRNA stability.","method":"Co-IP, transcriptomic analysis, mRNA stability assay, YTHDF2 KD rescue","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus mRNA stability rescue; single lab","pmids":["37030331"],"is_preprint":false},{"year":2023,"finding":"YTHDF2 deficiency in tumor-associated macrophages (TAMs) suppresses tumor growth by reprogramming TAMs toward antitumoral phenotype via targeting IFN-γ-STAT1 signaling; YTHDF2 expression in TAMs is regulated by IL-10-STAT3 signaling.","method":"Conditional Ythdf2 KO in macrophages, in vivo tumor models, signaling pathway analysis, siRNA-TLR9 agonist conjugate targeting","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with defined in vivo phenotype, upstream/downstream signaling established, multiple cell and in vivo models","pmids":["36658237"],"is_preprint":false},{"year":2023,"finding":"Ionizing radiation induces YTHDF2 expression via NF-κB signaling; YTHDF2 in turn activates NF-κB by degrading m6A-modified transcripts encoding NF-κB negative regulators, creating an IR-YTHDF2-NF-κB positive feedback circuit that promotes MDSC immunosuppression.","method":"Conditional Ythdf2 KO in myeloid cells, mRNA binding/degradation assay, NF-κB signaling analysis, in vivo irradiation tumor models","journal":"Cancer cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO mice, m6A-dependent mRNA decay mechanistically established, NF-κB circuit confirmed by multiple methods","pmids":["37236197"],"is_preprint":false},{"year":2023,"finding":"YTHDF2 directly binds and degrades BAMBI transcripts in an m6A-dependent and NF-κB-signaling-dependent manner in MDSCs after ionizing radiation, reducing BAMBI-mediated suppression of TGF-β signaling and extrinsic radioresistance.","method":"YTHDF2 RIP assay, m6A-dependent mRNA stability assay, NF-κB signaling inhibition, AAV-BAMBI rescue in tumor models","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP plus mRNA stability plus in vivo rescue; single lab","pmids":["38099498"],"is_preprint":false},{"year":2023,"finding":"Loss of YTHDF2 in regulatory T cells (Tregs) leads to increased apoptosis and impaired suppressive function in the tumor microenvironment; elevated TNF signaling in the TME promotes YTHDF2 expression, which then accelerates degradation of m6A-modified NF-κB negative regulator transcripts to activate NF-κB signaling in Tregs.","method":"Treg-specific Ythdf2 KO mice, in vivo tumor models, m6A mRNA decay analysis, TNF/NF-κB pathway analysis","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with defined cellular phenotype, signaling pathway dissected, multiple in vivo and in vitro methods","pmids":["37345898"],"is_preprint":false},{"year":2023,"finding":"YTHDF2 recognizes m6A modification in the 5'-UTR of ETV5 mRNA and recruits eukaryotic translation initiation factor 3 subunit B (eIF3B) to facilitate ETV5 translation (rather than decay), which then induces transcription of PD-L1 and VEGFA to promote HCC immune evasion and angiogenesis.","method":"RIP assay, m6A modification mapping (5'-UTR), co-IP for eIF3B recruitment, ETV5 ChIP, KD/OE experiments in vitro and in vivo","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP + co-IP + ChIP; identifies a translation-promoting (not decay) function at 5'-UTR m6A; single lab, multiple orthogonal methods","pmids":["38247171"],"is_preprint":false},{"year":2023,"finding":"YTHDF2 directly binds RIG-I (DDX58) mRNA at its coding sequence and mediates its degradation in an m6A-dependent manner in bladder cancer, suppressing RIG-I-mediated innate immune signaling and promoting immune evasion.","method":"Integrative RNA-seq and m6A-seq, RIP assay, mRNA stability assay, epistasis rescue, orthotopic mouse model","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP + RNA-seq + m6A-seq + mRNA stability + genetic rescue; single lab","pmids":["36939388"],"is_preprint":false},{"year":2023,"finding":"YTHDF2 promotes pre-miR-126 maturation by recognizing m6A modifications in pre-miR-126 and recruiting AGO2, facilitating processing of pre-miR-126 into mature miR-126 to promote AML progression.","method":"RIP assay (YTHDF2-pre-miR-126 binding), AGO2 co-IP, forced expression of miR-126 rescue, KD/OE in AML cells and mouse models","journal":"Genes & diseases","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP plus co-IP identifying AGO2 recruitment plus genetic rescue; single lab, two orthogonal methods","pmids":["37588203"],"is_preprint":false},{"year":2023,"finding":"YTHDF2 binds m6A sites on DAPK3 mRNA 3'-UTR and facilitates its degradation in gallbladder cancer; DAPK3 inhibition rescues tumor-suppressive phenotypes from YTHDF2 deficiency and drives gemcitabine resistance.","method":"RIP-seq, MeRIP-seq, RNA-seq integration, mRNA stability assay, epistasis rescue, in vivo xenograft","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — three orthogonal sequencing methods plus stability assay; single lab","pmids":["37700438"],"is_preprint":false},{"year":2023,"finding":"KRT17 causes YTHDF2 degradation through the ubiquitin-proteasome system; YTHDF2 targets CXCL10 mRNA (identified by RIP sequencing) for m6A-dependent decay, thus suppressing CXCL10-mediated T-lymphocyte recruitment in colorectal cancer.","method":"Mass spectrometry, co-IP, ubiquitin-proteasome inhibition, high-throughput RIP sequencing, YTHDF2 KD rescue","journal":"Cancer immunology research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS + co-IP + RIP-seq; single lab, multiple methods","pmids":["37129929"],"is_preprint":false},{"year":2023,"finding":"Ythdf2 promotes degradation of Hmox1 mRNA in an m6A-dependent manner in alveolar macrophages; myeloid-specific Ythdf2 KO mice are protected from pulmonary hypertension with elevated Hmox1, and Hmox1 inhibition reverses this protection.","method":"Myeloid-specific KO mice, mRNA stability assay, Hmox1 inhibitor epistasis, in vivo PH model","journal":"Redox biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO mouse model, mRNA stability, pharmacological epistasis; multiple orthogonal methods","pmids":["36801705"],"is_preprint":false},{"year":2023,"finding":"YTHDF2 promotes aggresome formation in an m6A-independent manner by interacting with UPF1 within a misfolded polypeptide-associated complex (containing UPF1, CTIF, eEF1A1, and DCTN1); YTHDF2 increases dynein motor protein interaction with this complex, facilitating movement of misfolded polypeptides toward aggresomes.","method":"YTHDF2 KD in HeLa cells, co-IP of protein complex, dynein interaction assay, aggresome circularity/movement analysis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — co-IP identifying complex components, motor protein interaction assay, functional live-cell imaging; multiple orthogonal methods establishing m6A-independent mechanism","pmids":["37803021"],"is_preprint":false},{"year":2023,"finding":"YTHDF2 directly binds RXRα mRNA via RIP-qPCR and promotes its degradation, reducing RXRα expression in myeloid cells; Ythdf2 conditional KO mice show elevated MDSCs with enhanced suppressive function in autoimmune hepatitis.","method":"m6A RIP, RIP-qPCR, conditional KO mice, flow cytometry, multi-omic m6A-seq + mRNA-seq","journal":"Journal of autoimmunity","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP-qPCR plus conditional KO plus m6A-seq; single lab","pmids":["36642058"],"is_preprint":false},{"year":2023,"finding":"YTHDF2 mediates decay of Ythdf2 mRNA itself (autoregulation) in an m6A-dependent manner in CD8 T cells; additionally, YTHDF2 translocates to the nucleus where it facilitates nascent RNA synthesis and interacts with IKZF1/3 to sustain transcription of their target genes, reinforcing T cell polyfunctionality.","method":"Conditional KO in T cells, m6A recognition mutant analysis, nuclear localization imaging, co-IP (YTHDF2-IKZF1/3), chromatin assays, in vivo tumor models","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO, co-IP, nuclear function established, m6A recognition mutagenesis; multiple orthogonal methods","pmids":["39500904"],"is_preprint":false},{"year":2023,"finding":"Ythdf2 directly regulates mRNA stability of eukaryotic elongation factor 2 (eEF2) in cardiomyocytes (identified by cell-type specific Ribo-seq); cardiomyocyte-specific Ythdf2 deletion leads to cardiac hypertrophy, reduced function, and increased fibrosis during pressure overload and aging.","method":"Cardiomyocyte-specific Ythdf2 KO mice, Ribo-seq, mRNA stability analysis, cardiac phenotyping","journal":"Journal of molecular and cellular cardiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with cardiac phenotype, Ribo-seq identifying eEF2 as target; single lab","pmids":["37315764"],"is_preprint":false},{"year":2023,"finding":"YTHDF2 binds m6A-modified Myzap mRNA and controls its stability; cardiomyocyte-specific YTHDF2 KO leads to cardiac dysfunction and upregulation of MYZAP protein, demonstrating YTHDF2 maintains cardiac homeostasis by suppressing this hypertrophic protein.","method":"Cardiomyocyte-specific KO mice, proteomics, RIP assay for YTHDF2-Myzap mRNA binding, mRNA stability assay","journal":"JACC. Basic to translational science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO, proteomics, RIP; single lab, multiple methods","pmids":["37791304"],"is_preprint":false},{"year":2023,"finding":"YTHDF2-mediated m6A-dependent mRNA decay of Pyk2 in macrophages attenuates LPS-induced proinflammatory signaling (MAPKs, AKT) and ROS generation; Mettl3 depletion stabilizes Pyk2 mRNA via Ythdf2, and RIP-PCR confirmed direct YTHDF2-Pyk2 mRNA binding.","method":"RNA-seq, m6A mapping, RIP-PCR, Mettl3/Ythdf2 KD, Pyk2 inhibitor rescue","journal":"Immunology letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP-PCR plus mRNA stability plus pharmacological rescue; single lab","pmids":["37952687"],"is_preprint":false},{"year":2024,"finding":"YTHDF2 functions as a dual m6A/m5C reader: it stabilizes m5C-modified mRNAs by recruiting PABPC1, enhancing their translation and ATP synthesis (pro-tumorigenic), while simultaneously destabilizing other m6A-modified mRNAs to promote immune evasion in B cell malignancies; YTHDF2 overexpression alone is sufficient to cause B cell transformation.","method":"m5C/m6A reader assay, co-IP (YTHDF2-PABPC1), mRNA stability and translation assay, YTHDF2 OE-driven transformation model, small-molecule inhibitor","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro binding assay, co-IP, translation assay, transformation model; multiple orthogonal methods establishing dual-reader mechanism","pmids":["39694037"],"is_preprint":false},{"year":2024,"finding":"FMDV structural protein VP1 promotes autophagy (AKT-MTOR-dependent) and degrades YTHDF2 through the autophagy pathway, leading to increased GTPBP4 mRNA/protein levels; elevated GTPBP4 inhibits IRF3 binding to the Ifnb promoter, suppressing type I interferon production.","method":"Co-IP (VP1-YTHDF2 interaction), autophagy inhibitor/activator treatment, IRF3 ChIP assay, YTHDF2 KD rescue of IFN-β, in vivo GTPBP4-deficient mice","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus ChIP plus autophagy pathway dissection; single lab, multiple methods","pmids":["38516932"],"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 CX3CL1-mediated macrophage recruitment and enhances mitochondrial respiration of CD8+ T cells by impairing tumor glycolysis.","method":"Conditional KO tumor models, CX3CL1 mRNA stabilization assay, autophagy inhibitor experiments, metabolic assays in CD8+ T cells","journal":"Science immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with multiple mechanistic readouts; single lab","pmids":["38820140"],"is_preprint":false},{"year":2024,"finding":"Protein lactylation elevates YTHDF2 expression in cardiomyocytes; the intrinsic disorder region (not the m6A-binding domain) of YTHDF2 is required for its regulation of cardiomyocyte size and apoptosis via upregulating G3BP1; exercise-induced downregulation of YTHDF2 is required for physiological cardiac hypertrophy.","method":"Lactylation inhibition, YTHDF2 domain deletion mutant analysis, OGD/R model, YTHDF2 KD/OE in cardiomyocytes, in vivo ischemia/reperfusion model","journal":"Basic research in cardiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain mutant analysis identifying disorder region as functional, in vivo cardiac model; single lab","pmids":["38563985"],"is_preprint":false},{"year":2024,"finding":"YTHDF2 stabilizes Cx3cl1 transcripts in an m6A-dependent manner in hepatocytes (identified by liver-specific KO model), regulating CD8+ T cell recruitment and antitumor immunity; OXA upregulates YTHDF2 expression via the cGAS-STING signaling pathway.","method":"Liver-specific Ythdf2 KO mice, mRNA stability assay for Cx3cl1, cGAS-STING pathway analysis, tumor-bearing liver models","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO plus mRNA stability plus upstream pathway dissection; single lab","pmids":["39237909"],"is_preprint":false},{"year":2024,"finding":"YTHDF2 controls mRNA stability of the ubiquitin ligase ASB2; in skeletal muscle, ASB2 upregulation upon YTHDF2 loss activates SMAD3-dependent anti-growth gene programs, thereby impairing postnatal muscle growth and hypertrophic response.","method":"Muscle-specific Ythdf2 KO mice, mRNA stability assay for ASB2, SMAD3 pathway analysis, hypertrophic stimuli experiments","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with defined muscle phenotype, mRNA stability, downstream SMAD3 pathway established; multiple orthogonal methods","pmids":["38467649"],"is_preprint":false},{"year":2024,"finding":"OTUB1 (deubiquitinase) increases YTHDF2 protein stability by blocking ubiquitin transfer to YTHDF2 independently of its deubiquitinase activity; stabilized YTHDF2 promotes m6A-dependent PRSS8 mRNA degradation, reducing PRSS8-mediated nuclear β-catenin suppression via E-cadherin in prostate cancer.","method":"In vivo and in vitro ubiquitination assays, co-IP (OTUB1-YTHDF2), YTHDF2 RIP assay for PRSS8 mRNA, mRNA stability assay, cellular/mouse models","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro ubiquitination assay plus co-IP plus RIP plus mRNA stability; multiple orthogonal methods in one study","pmids":["38462165"],"is_preprint":false},{"year":2024,"finding":"Ythdf2 in pulmonary artery smooth muscle cells stabilizes (rather than degrades) Myadm mRNA in an m6A-dependent manner; this paradoxical stabilization promotes PASMC proliferation and pulmonary hypertension via an m6A/Myadm/p21 pathway.","method":"Smooth muscle cell-specific Ythdf2 KO mice, proteomics, m6A sequencing, RIP assay, Myadm siRNA rescue, in vivo PH model","journal":"Hypertension","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO, m6A-seq, RIP, and functional rescue; single lab","pmids":["38832511"],"is_preprint":false},{"year":2024,"finding":"ROS activates YTHDF2 and promotes degradation of m6A-modified FOXO3 mRNA; loss of FOXO3 impairs its ability to recruit CBP and Med1 to activate TIMP1 expression, increasing MMP activity and contributing to intervertebral disc degeneration. Pharmacological YTHDF2 inhibition restores FOXO3/TIMP1/MMP balance.","method":"iTRAQ proteomics, YTHDF2 KD/OE, m6A-modified FOXO3 mRNA stability assay, FOXO3-ChIP (CBP/Med1 recruitment), YTHDF2 inhibitor DC-Y13-27 in vivo","journal":"Cellular and molecular life sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteomics plus mRNA stability plus ChIP; single lab, multiple methods","pmids":["39625652"],"is_preprint":false},{"year":2024,"finding":"lncRNA JPX directly interacts with YTHDF2 and blocks USP10-mediated deubiquitination/protection of YTHDF2, promoting YTHDF2 ubiquitin-dependent degradation; reduced YTHDF2 stabilizes BMP2 mRNA and activates AKT phosphorylation in melanoma.","method":"RNA pull-down, RIP, co-IP, Western blot, RNA-seq, ubiquitination assay","journal":"Molecular cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA pull-down + co-IP + ubiquitination assay; single lab","pmids":["38441563"],"is_preprint":false},{"year":2024,"finding":"Conditional deletion of Ythdf2 from proliferating hippocampal NSCs elevates quiescence acquisition; Ythdf2 targets multiple TGF-β signaling pathway components (ligands, receptors, transcription regulators) for m6A-dependent mRNA decay, and TGF-β signaling suppression rescues elevated quiescence in Ythdf2-deficient NSCs.","method":"Conditional KO in NSCs, multimodal m6A/YTHDF2 binding/mRNA decay profiling, TGF-β inhibitor rescue, in vivo/in vitro assays","journal":"Cell stem cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with multimodal profiling, pharmacological epistasis, in vivo/in vitro corroboration; multiple orthogonal methods","pmids":["39476834"],"is_preprint":false},{"year":2024,"finding":"Ythdf2 directly regulates the mRNA stability of Ace and Bmp4 as an m6A reader in retinal microglia; Ythdf2 loss increases Ace and Bmp4 expression, causing aberrant microglial activation and pathological angiogenesis; pharmacological inhibition of Ace or Bmp4 alleviates the Ythdf2-deficiency-driven microvascular disease.","method":"Microglia-specific Ythdf2 KO mice, scRNA-seq, mRNA stability assay, captopril/noggin pharmacological rescue, in vivo OIR model","journal":"Journal of advanced research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO plus mRNA stability plus pharmacological rescue; single lab","pmids":["41627954"],"is_preprint":false},{"year":2025,"finding":"YTHDF2 forms a complex with eIF3F and DDX1 to enhance translation of m6A-modified mRNAs encoding microtubule-associated proteins in ovarian cancer, thereby promoting cancer progression and paclitaxel resistance independently of its mRNA decay function; a small-molecule inhibitor targeting YTHDF2 reverses this translational enhancement.","method":"Co-IP (YTHDF2-eIF3F-DDX1), mRNA stability vs. translation assay, virtual screening for inhibitor, eCLIP, functional paclitaxel resistance assay","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Moderate — co-IP identifying novel translation complex, direct comparison of stability vs. translation, small-molecule validation; multiple orthogonal methods establishing non-canonical function","pmids":["40480228"],"is_preprint":false},{"year":2025,"finding":"YTHDF2 ablation in naive CD4+ T cells promotes Th9 differentiation by stabilizing Gata3 and Smad3 mRNAs under IL-4 and TGF-β signaling respectively; Ythdf2-deficient Th9 cells produce more IL-9 and IL-21, enhancing CD8+ T cell and NK cell tumor infiltration and cytotoxicity.","method":"Ythdf2 KO in mouse and human naive CD4+ T cells, mRNA stability assay for Gata3/Smad3, in vivo antitumor models, CAR-Th9 experiments","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO in both mouse and human T cells, mRNA stability assay, in vivo CAR-T models; multiple orthogonal methods across species","pmids":["40826275"],"is_preprint":false},{"year":2025,"finding":"Phenylpyrazole compounds (e.g., CK-75) bind a small hydrophobic pocket on the YTH domain of YTHDF2, inhibiting its m6A-binding activity; eCLIP confirmed altered global RNA-binding patterns of YTHDF2 upon CK-75 treatment, and the compounds induce cell cycle arrest and apoptosis in cancer cells.","method":"Small-molecule binding to YTH domain (structural pocket), eCLIP, cell viability/apoptosis assays","journal":"JACS Au","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — YTH domain targeting with eCLIP validation; single study but demonstrates binding mechanism; pocket location inferred from computational docking without full crystal structure reported in abstract","pmids":["40017738"],"is_preprint":false}],"current_model":"YTHDF2 is an m6A (and m5C) reader protein that primarily recognizes N6-methyladenosine modifications on target mRNAs via its conserved YTH domain (Trp432 critical) and recruits the CCR4-NOT and PAN2-PAN3 deadenylase complexes to accelerate mRNA decay; however, it also stabilizes select mRNAs, promotes translation of m6A/m5C-modified transcripts by recruiting eIF3F/DDX1 or PABPC1, facilitates pre-miRNA maturation, and performs m6A-independent functions including aggresome formation via UPF1 interaction and nuclear chromatin regulation via IKZF1/3; its protein stability is regulated by CDK1-dependent phosphorylation, OGT-mediated O-GlcNAcylation (S263), HSP90β-mediated protection from STUB1 ubiquitination, and OTUB1-mediated deubiquitination, while its degradation can be induced by autophagy or ubiquitin-proteasome pathways; through these mechanisms YTHDF2 governs diverse cellular processes including cell cycle progression, hematopoietic stem cell maintenance, neural development, spermatogenesis, muscle growth, cardiac homeostasis, and innate and adaptive immune responses."},"narrative":{"mechanistic_narrative":"YTHDF2 is a cytoplasmic m6A reader that recognizes N6-methyladenosine marks on target mRNAs through its YTH domain and primarily routes those transcripts to deadenylation-dependent decay, thereby tuning the abundance of methylated transcripts across cell-cycle, developmental, and immune programs [PMID:32267835, PMID:32905781, PMID:34216543]. Substrate recognition depends on a conserved hydrophobic pocket (Trp432), which also mediates lower-affinity binding to m5C-modified RNA [PMID:31815440], and decay is executed by recruitment of the CCR4-NOT deadenylase complex [PMID:32905781]. Through m6A-dependent turnover of specific substrates YTHDF2 drives mitotic entry by degrading WEE1 [PMID:32267835], maintains hematopoietic and neural stem-cell pools by clearing inflammation- and TGF-β/JAK-STAT-related transcripts [PMID:29855337, PMID:33156926, PMID:39476834], and governs spermatogenesis, cardiac homeostasis, and postnatal muscle growth by destabilizing matrix, hypertrophic, and anti-growth regulators such as Myzap, eEF2, and ASB2 [PMID:37315764, PMID:37791304, PMID:38467649]. Across immune lineages YTHDF2 reshapes NF-κB and interferon signaling—degrading negative regulators of NF-κB in MDSCs and Tregs and innate-immune transcripts such as RIG-I and CXCL10 to promote immune evasion—while being required for NK-cell maturation and germinal-center B-cell fate [PMID:34160549, PMID:35508130, PMID:37236197, PMID:37345898, PMID:36939388, PMID:37129929]. Beyond decay, YTHDF2 stabilizes select transcripts and promotes translation: it recruits eIF3B, or an eIF3F/DDX1 complex, or PABPC1 to enhance translation of methylated mRNAs, and as a dual m6A/m5C reader it can stabilize m5C-modified messages while degrading m6A targets [PMID:38247171, PMID:39694037, PMID:40480228]. It additionally acts independently of m6A, promoting aggresome formation through a UPF1-containing misfolded-polypeptide/dynein complex [PMID:37803021] and entering the nucleus to support nascent transcription via IKZF1/3 [PMID:39500904]. YTHDF2 protein abundance is itself heavily regulated—stabilized by CDK1-dependent phosphorylation, EGFR/SRC/ERK phosphorylation, OGT-mediated O-GlcNAcylation at Ser263, HSP90β-mediated protection from STUB1, and OTUB1 deubiquitination, and degraded via CUL1/CUL4A/DDB1/SKP2 ubiquitin ligases or autophagy [PMID:32267835, PMID:33420027, PMID:36765030, PMID:37515378, PMID:38462165, PMID:38516932].","teleology":[{"year":2018,"claim":"Established that YTHDF2 directly binds m6A sites in target-mRNA UTRs and drives their degradation, providing the first functional substrate evidence in a cancer context.","evidence":"RIP and mRNA stability assays with loss/gain-of-function on EGFR mRNA in HCC cells","pmids":["30423408"],"confidence":"Medium","gaps":["Single substrate, single lab","Did not define the decay machinery recruited"]},{"year":2019,"claim":"Defined YTHDF2 as a transcriptome-wide destabilizer of m6A-modified mRNAs required for leukemic stem cell propagation but dispensable for normal HSCs, establishing a therapeutic window.","evidence":"Conditional KO mouse and human AML models with mRNA half-life and m6A-seq","pmids":["31031138"],"confidence":"High","gaps":["Mechanism of selective LSC dependence not fully resolved","Decay machinery not mapped here"]},{"year":2019,"claim":"Showed the YTH-domain residue Trp432 that reads m6A also recognizes m5C, broadening YTHDF2 to a dual-mark reader and linking it to rRNA processing.","evidence":"Quantitative pulldown, in vitro binding with Trp432 mutagenesis, CRISPR KO with bisulfite sequencing","pmids":["31815440"],"confidence":"High","gaps":["m5C binding affinity lower than m6A; physiological weight unclear","Mechanism connecting YTHDF2 to pre-rRNA processing undefined"]},{"year":2020,"claim":"Identified the effector machinery: YTHDF2 recruits the CCR4-NOT deadenylase complex to clear methylated transcripts, and is degraded via specific cullin-based E3 ligases, placing it in a CDK1-WEE1 mitotic feedforward loop.","evidence":"Reciprocal co-IP of CCR4-NOT, KO/rescue, CDK1 inhibitor, mRNA stability assays in iPSC reprogramming and HeLa","pmids":["32905781","32267835"],"confidence":"High","gaps":["Structural basis of CCR4-NOT recruitment not defined","Determinants choosing decay vs stabilization unknown"]},{"year":2021,"claim":"Demonstrated YTHDF2 protein abundance is gated by post-translational modification—EGFR/SRC/ERK phosphorylation and OGT O-GlcNAcylation at Ser263 stabilize it—coupling oncogenic signaling to reader activity.","evidence":"Phospho/O-GlcNAc site identification by MS and mutagenesis, ubiquitination and mRNA-stability assays in GBM and HCC","pmids":["33420027","36765030"],"confidence":"High","gaps":["How each PTM alters substrate selection not dissected","Crosstalk among the modifications unresolved"]},{"year":2021,"claim":"Established YTHDF2 as a stem-cell and developmental regulator: it maintains neural and hematopoietic stem cells by degrading inflammation- and JAK-STAT-related transcripts, with embryonic lethality on loss.","evidence":"Conditional/hematopoiesis-specific KO mice, serial transplantation, m6A methylome and mRNA stability assays","pmids":["29855337","33156926"],"confidence":"High","gaps":["Tissue-specific substrate sets only partially enumerated","Distinction between cell-intrinsic and niche effects incomplete"]},{"year":2021,"claim":"Revealed YTHDF2 buffers transcriptome output in MYC-driven and TNBC tumors, where its decay activity counteracts elevated mRNA synthesis and its loss triggers ER-stress apoptosis.","evidence":"Pooled CRISPR screen, eCLIP, m6A-seq, scRibo-STAMP, xenografts","pmids":["34216543"],"confidence":"High","gaps":["Generality of the buffering role across tumor types untested here","Translation vs decay contribution not separated"]},{"year":2021,"claim":"Uncovered non-canonical and translation-promoting roles: heat-shock-induced nuclear translocation via the YTH domain, and PBRM1-dependent enhancement of HIF-1α translation, showing YTHDF2 is not solely a decay factor.","evidence":"Deletion-mutant localization imaging, co-IP, RIP, polysome profiling","pmids":["34671198","34200988"],"confidence":"Medium","gaps":["Nuclear function mechanism incompletely defined","Switch between decay and translation promotion unclear"]},{"year":2022,"claim":"Showed YTHDF2 protein is protected from STUB1-mediated degradation by HSP90β, and can paradoxically stabilize substrate mRNAs (ACER2), extending its regulatory repertoire beyond decay.","evidence":"Reciprocal co-IP with domain mapping, ubiquitination assays, MeRIP and stability assays in HCC and DLBCL","pmids":["37515378","37865189"],"confidence":"High","gaps":["Rules governing stabilization vs decay of a given transcript unknown","Whether HSP90β chaperoning affects substrate selection untested"]},{"year":2023,"claim":"Established YTHDF2 as a central node in tumor immune evasion across myeloid, T-regulatory, NK, and innate-sensing pathways, frequently by degrading NF-κB negative regulators or innate-immune transcripts (RIG-I, CXCL10).","evidence":"Lineage-specific conditional KO mice, m6A-dependent decay assays, in vivo tumor/irradiation models","pmids":["36658237","37236197","37345898","36939388","37129929"],"confidence":"High","gaps":["Why YTHDF2 selects NF-κB-regulatory substrates is unresolved","Context-dependent pro- vs anti-inflammatory outputs not unified"]},{"year":2023,"claim":"Demonstrated m6A-independent activities: YTHDF2 promotes aggresome formation through a UPF1/dynein misfolded-polypeptide complex and enters the nucleus to support transcription via IKZF1/3, plus autoregulating its own mRNA.","evidence":"Co-IP of complex components, dynein-interaction and live-cell aggresome imaging, conditional T-cell KO with chromatin assays","pmids":["37803021","39500904"],"confidence":"High","gaps":["Structural basis of m6A-independent protein interactions undefined","Balance between nuclear and cytoplasmic pools unclear"]},{"year":2023,"claim":"Extended YTHDF2's physiological role to cardiac and pulmonary homeostasis through mRNA-stability control of eEF2, Myzap, and Hmox1, with tissue-specific decay or stabilization outcomes.","evidence":"Cardiomyocyte- and myeloid-specific KO mice, Ribo-seq, proteomics, RIP and stability assays, pharmacological epistasis","pmids":["37315764","37791304","36801705"],"confidence":"Medium","gaps":["Why some substrates are stabilized rather than degraded in these tissues unresolved","Upstream signals controlling cardiac YTHDF2 only partly defined"]},{"year":2024,"claim":"Resolved YTHDF2 as a dual m6A/m5C reader with opposing transcript fates—stabilizing m5C mRNAs via PABPC1 to boost translation while degrading m6A targets—and showed its overexpression alone transforms B cells.","evidence":"In vitro reader assays, PABPC1 co-IP, translation/stability assays, overexpression-driven transformation model, small-molecule inhibitor","pmids":["39694037"],"confidence":"High","gaps":["How a single reader partitions m5C vs m6A substrates mechanistically unknown","In vivo contribution of m5C reading versus m6A decay not separated"]},{"year":2024,"claim":"Mapped additional layers of YTHDF2 protein control—OTUB1 and USP10 deubiquitination, lncRNA JPX-mediated destabilization, and IFN-γ/FMDV-VP1-driven autophagic degradation—linking its turnover to immune and viral contexts.","evidence":"In vitro ubiquitination assays, co-IP, RNA pulldown, autophagy modulation, conditional KO tumor models","pmids":["38462165","38441563","38820140","38516932"],"confidence":"High","gaps":["Hierarchy among competing stabilizing/destabilizing inputs unknown","Whether autophagic and proteasomal routes dominate in specific tissues unclear"]},{"year":2025,"claim":"Defined a discrete translation-enhancing complex (YTHDF2-eIF3F-DDX1) acting independently of decay, and validated YTH-domain-targeting small molecules that disrupt m6A binding, advancing YTHDF2 as a druggable target.","evidence":"Co-IP, stability-vs-translation comparison, eCLIP, structure-guided/phenylpyrazole inhibitor binding to the YTH pocket, apoptosis assays","pmids":["40480228","40017738"],"confidence":"High","gaps":["No reported full crystal structure of inhibitor-bound YTH domain","Determinants directing YTHDF2 to translation vs decay complexes unresolved"]},{"year":null,"claim":"The central unresolved question is what molecular switch dictates whether YTHDF2 destabilizes, stabilizes, or promotes translation of a given m6A/m5C transcript, and how its many PTMs and protein partners are integrated to set that outcome in a tissue-specific manner.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking PTM state, partner choice, and transcript fate","Structural basis of m6A-independent functions undefined","Relative in vivo weight of decay vs translation vs nuclear roles unquantified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,3,5,6,11,45]},{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[5,6,11]},{"term_id":"GO:0045182","term_label":"translation regulator activity","supporting_discovery_ids":[33,45,57]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[6,39,57]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[13,24,39]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[13,41]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[5,6,11,45]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[14,21,30,32,34,37]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[5,20,22]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[10,50,55]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[1,8,11,12]}],"complexes":["CCR4-NOT deadenylase complex","misfolded-polypeptide/aggresome complex (UPF1, CTIF, eEF1A1, DCTN1)","YTHDF2-eIF3F-DDX1 translation complex"],"partners":["UPF1","PABPC1","EIF3B","EIF3F","DDX1","HSP90B1","STUB1","OTUB1"],"other_free_text":[]}},"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; 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with and Destabilizing YTHDF2 in Cutaneous Melanoma.","date":"2024","source":"Molecular cancer research : MCR","url":"https://pubmed.ncbi.nlm.nih.gov/38441563","citation_count":15,"is_preprint":false},{"pmid":"34671198","id":"PMC_34671198","title":"YTHDF2 Suppresses Notch Signaling through Post-transcriptional Regulation on Notch1.","date":"2021","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/34671198","citation_count":14,"is_preprint":false},{"pmid":"35755020","id":"PMC_35755020","title":"Expression and Clinical Significance of the m6A RNA-Binding Proteins YTHDF2 in Peripheral Blood Mononuclear Cells From New-Onset Ankylosing Spondylitis.","date":"2022","source":"Frontiers in medicine","url":"https://pubmed.ncbi.nlm.nih.gov/35755020","citation_count":14,"is_preprint":false},{"pmid":"38636894","id":"PMC_38636894","title":"BCLAF1 drives esophageal squamous cell carcinoma progression through regulation of YTHDF2-dependent SIX1 mRNA degradation.","date":"2024","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/38636894","citation_count":12,"is_preprint":false},{"pmid":"39088322","id":"PMC_39088322","title":"METTL3 regulates cartilage development and homeostasis by affecting Lats1 mRNA stability in an m6A-YTHDF2-dependent manner.","date":"2024","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/39088322","citation_count":12,"is_preprint":false},{"pmid":"39424201","id":"PMC_39424201","title":"Biological functions of the m6A reader YTHDF2 and its role in central nervous system disorders.","date":"2024","source":"Biochemical pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/39424201","citation_count":12,"is_preprint":false},{"pmid":"35924072","id":"PMC_35924072","title":"N6-Methyladenosine Reader YTHDF2 Enhances Non-Small-Cell Lung Cancer Cell Proliferation and Metastasis through Mediating circ_SFMBT2 Degradation.","date":"2022","source":"Contrast media & molecular imaging","url":"https://pubmed.ncbi.nlm.nih.gov/35924072","citation_count":12,"is_preprint":false},{"pmid":"39625652","id":"PMC_39625652","title":"YTHDF2-dependent m6A modification of FOXO3 mRNA mediates TIMP1 expression and contributes to intervertebral disc degeneration following ROS stimulation.","date":"2024","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/39625652","citation_count":12,"is_preprint":false},{"pmid":"40826275","id":"PMC_40826275","title":"Loss of YTHDF2 enhances Th9 programming and CAR-Th9 cell antitumor efficacy.","date":"2025","source":"Nature immunology","url":"https://pubmed.ncbi.nlm.nih.gov/40826275","citation_count":11,"is_preprint":false},{"pmid":"38467649","id":"PMC_38467649","title":"YTHDF2 governs muscle size through a targeted modulation of proteostasis.","date":"2024","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/38467649","citation_count":11,"is_preprint":false},{"pmid":"36681189","id":"PMC_36681189","title":"YTHDF2 Regulates Cell Growth and Cycle by Facilitating KDM1A mRNA Stability.","date":"2023","source":"The American journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/36681189","citation_count":11,"is_preprint":false},{"pmid":"40619016","id":"PMC_40619016","title":"Histone lactylation-driven YTHDF2 promotes non-small cell lung cancer cell glycolysis and stemness by recognizing m6A modification of SFRP2.","date":"2025","source":"Biochemical pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/40619016","citation_count":11,"is_preprint":false},{"pmid":"37803021","id":"PMC_37803021","title":"YTHDF2 facilitates aggresome formation via UPF1 in an m6A-independent manner.","date":"2023","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/37803021","citation_count":11,"is_preprint":false},{"pmid":"35763107","id":"PMC_35763107","title":"Novel insights into roles of N6-methyladenosine reader YTHDF2 in cancer progression.","date":"2022","source":"Journal of cancer research and clinical oncology","url":"https://pubmed.ncbi.nlm.nih.gov/35763107","citation_count":11,"is_preprint":false},{"pmid":"37884231","id":"PMC_37884231","title":"Ythdf2-mediated STK11 mRNA decay supports myogenesis by inhibiting the AMPK/mTOR pathway.","date":"2023","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/37884231","citation_count":11,"is_preprint":false},{"pmid":"36960869","id":"PMC_36960869","title":"METTL3/YTHDF2 m6A axis promotes the malignant progression of bladder cancer by epigenetically suppressing RRAS.","date":"2023","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/36960869","citation_count":11,"is_preprint":false},{"pmid":"38832511","id":"PMC_38832511","title":"Smooth Muscle Ythdf2 Abrogation Ameliorates Pulmonary Vascular Remodeling by Regulating Myadm Transcript Stability.","date":"2024","source":"Hypertension (Dallas, Tex. : 1979)","url":"https://pubmed.ncbi.nlm.nih.gov/38832511","citation_count":11,"is_preprint":false},{"pmid":"38462165","id":"PMC_38462165","title":"YTHDF2 protein stabilization by the deubiquitinase OTUB1 promotes prostate cancer cell proliferation via PRSS8 mRNA degradation.","date":"2024","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/38462165","citation_count":9,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":52419,"output_tokens":14074,"usd":0.184183,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":26361,"output_tokens":5503,"usd":0.13469,"stage2_stop_reason":"end_turn"},"total_usd":0.318873,"stage1_batch_id":"msgbatch_01UT1AahFPCAyn2uVweS7A9z","stage2_batch_id":"msgbatch_01HuKWtKNT4Pqj1bc8eEP5RV","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2018,\n      \"finding\": \"YTHDF2 directly binds the m6A modification site in the 3'-UTR of EGFR mRNA and promotes its degradation, suppressing cell proliferation in hepatocellular carcinoma cells.\",\n      \"method\": \"RIP assay, mRNA stability assay, loss-of-function/gain-of-function in HCC cells\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal binding shown by RIP, mRNA stability assay, functional rescue; single lab, two orthogonal methods\",\n      \"pmids\": [\"30423408\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"YTHDF2 decreases the half-life of diverse m6A-modified transcripts in leukemic stem cells (LSCs), including Tnfrsf2, whose upregulation upon YTHDF2 deficiency primes LSCs for apoptosis; YTHDF2 is required for AML disease initiation and propagation but is not essential for normal HSC function.\",\n      \"method\": \"Mouse/human AML models, conditional KO, mRNA half-life assay, m6A sequencing\",\n      \"journal\": \"Cell stem cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (KO mouse model, human AML, mRNA half-life, m6A-seq), replicated across mouse and human systems\",\n      \"pmids\": [\"31031138\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"YTHDF2 promotes decay of m6A-containing IL11 and SERPINE2 mRNAs; its transcription is suppressed by HIF-2α, creating a feedback loop whereby HIF-2α reduction of YTHDF2 leads to inflammation and vascular abnormalization in hepatocellular carcinoma.\",\n      \"method\": \"m6A-IP sequencing, mRNA stability assay, HIF-2α antagonist treatment, KO mouse model\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — m6A-IP-seq and mRNA stability assay in single lab, KO mouse corroborates\",\n      \"pmids\": [\"31735169\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"YTHDF2 binds 5-methylcytosine (m5C) in RNA via Trp432 (the same conserved hydrophobic pocket residue required for m6A recognition), albeit with lower affinity than m6A; YTHDF2 knockout increases m5C levels at the majority of rRNA sites and impairs pre-rRNA processing.\",\n      \"method\": \"Quantitative proteomics pull-down, in vitro binding assay with Trp432 mutagenesis, CRISPR-Cas9 KO, RNA bisulfite sequencing\",\n      \"journal\": \"Analytical chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro binding assay with active-site mutagenesis (Trp432), CRISPR KO + bisulfite sequencing; multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"31815440\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"YTHDF2 depletion in LPS-stimulated macrophages increases the stability of MAP2K4 and MAP4K4 mRNAs, activating MAPK and NF-κB signaling and promoting proinflammatory cytokine expression.\",\n      \"method\": \"YTHDF2 knockdown in RAW264.7 cells, mRNA stability assay, inhibitor rescue experiments\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mRNA stability assay plus signaling inhibitor rescue; single lab, two orthogonal methods\",\n      \"pmids\": [\"30875984\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"YTHDF2 promotes mitotic entry by facilitating m6A-dependent decay of WEE1 mRNA; CDK1 activity stabilizes YTHDF2 protein, forming a CDK1-YTHDF2-WEE1 feedforward loop. YTHDF2 proteolysis is mediated by CUL1, CUL4A, DDB1, and SKP2 E3 ubiquitin ligase complexes.\",\n      \"method\": \"YTHDF2 depletion in HeLa cells, mRNA stability assay, CDK1 inhibitor treatment, identification of E3 ubiquitin ligase components by co-IP\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (KD, mRNA stability, CDK1 inhibitor, co-IP for E3 ligases), mechanistic loop experimentally established\",\n      \"pmids\": [\"32267835\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"YTHDF2 recruits the CCR4-NOT deadenylase complex to mediate mRNA deadenylation and clearance of m6A-modified somatic gene transcripts (including Tead2 and Tgfb1) during somatic reprogramming to iPSCs; YTHDF3 independently recruits PAN2-PAN3 deadenylase complex for the same purpose.\",\n      \"method\": \"Ythdf2/3 knockout, mRNA clearance assays, co-IP of CCR4-NOT and PAN2-PAN3, rescue experiments\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP identifying deadenylase partners, KO with functional rescue, multiple orthogonal methods\",\n      \"pmids\": [\"32905781\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"YTHDF2 knockdown in mouse spermatogonia causes decreased expression of MMP3, MMP13, ADAMTS1, and ADAMTS9, affecting cell-matrix adhesion and proliferation; m6A-IP-PCR and RIP-PCR confirmed these transcripts are m6A-modified and directly bound by YTHDF2.\",\n      \"method\": \"CRISPR/Cas9 KO, m6A-IP-PCR, RIP-PCR, mRNA stability assay, inhibitor rescue\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP-PCR and m6A-IP confirming direct binding, KO phenotype; single lab\",\n      \"pmids\": [\"31959747\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"EGFR/SRC/ERK signaling phosphorylates YTHDF2 at serine 39 and threonine 381, stabilizing the YTHDF2 protein; YTHDF2 in turn facilitates m6A-dependent mRNA decay of LXRA and HIVEP2 to promote GBM tumorigenesis and inhibits LXRα-dependent cholesterol homeostasis.\",\n      \"method\": \"Phosphorylation site identification by mutagenesis, mRNA decay assay, co-IP, YTHDF2 KD/OE in GBM cells and xenografts\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — active-site mutagenesis (S39/T381) plus mRNA decay assay plus co-IP; multiple orthogonal methods in one study\",\n      \"pmids\": [\"33420027\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Histone lactylation drives YTHDF2 expression; YTHDF2 then recognizes m6A-modified PER1 and TP53 mRNAs and promotes their degradation to accelerate tumorigenesis in ocular melanoma.\",\n      \"method\": \"Histone lactylation profiling, RIP assay, mRNA stability assay, in vitro and in vivo KD/OE\",\n      \"journal\": \"Genome biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP assay and mRNA stability assay confirming binding/decay; single lab, two methods\",\n      \"pmids\": [\"33726814\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Conditional depletion of Ythdf2 in mice causes embryonic lethality with compromised neural development; Ythdf2 loss impairs NSPC self-renewal and differentiation, and delays degradation of m6A-containing neural development-related mRNAs including JAK-STAT cascade inhibitory genes.\",\n      \"method\": \"Conditional KO mice, m6A methylome profiling of KO NSPCs, mRNA stability assay in vivo/in vitro\",\n      \"journal\": \"Genome biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO mice with defined developmental phenotype, m6A methylome, and mRNA stability assay; multiple orthogonal methods\",\n      \"pmids\": [\"29855337\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"YTHDF2 disruption in triple-negative breast cancer stabilizes MAPK pathway mRNAs (identified by eCLIP and m6A sequencing), increasing global translation rates and inducing EMT; in MYC-driven tumors, YTHDF2-dependent mRNA degradation counteracts the global increase in mRNA synthesis, and YTHDF2 loss triggers ER stress-induced apoptosis.\",\n      \"method\": \"Pooled CRISPR-Cas9 screen, eCLIP, m6A-seq, scRibo-STAMP, xenograft tumors\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — eCLIP + m6A-seq + scRibo-STAMP; multiple orthogonal methods, rigorous mechanistic dissection\",\n      \"pmids\": [\"34216543\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"YTHDF2 recognizes m6A modification and promotes mRNA decay of AXIN1 (a negative regulator of Wnt/β-catenin), thereby activating Wnt/β-catenin signaling to promote lung adenocarcinoma cell proliferation and migration; AXIN1 KO rescues the inhibitory effect of YTHDF2 depletion.\",\n      \"method\": \"Integrative RNA-seq, m6A-seq, CLIP-seq, RIP-seq, mRNA stability assay, epistasis rescue experiments\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — four orthogonal sequencing datasets plus mRNA stability plus genetic epistasis; single lab but multiple methods\",\n      \"pmids\": [\"33980824\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"YTHDF2 recognizes m6A-modified Notch1 mRNA in the cytoplasm and promotes its decay, suppressing Notch signaling (HES1, HES5); under heat shock, YTHDF2 translocates to the nucleus via its YTH domain, reducing Notch1 mRNA decay and restoring Notch signaling. YTH domain deletion mutants confirm the domain is critical for both m6A binding and nuclear translocation.\",\n      \"method\": \"YTHDF2 deletion mutant analysis, mRNA stability assay, nuclear translocation imaging, heat shock treatment\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — deletion mutant analysis plus mRNA stability plus localization imaging; single lab\",\n      \"pmids\": [\"34671198\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"YTHDF2 is required for NK cell terminal maturation and effector function in antitumor/antiviral immunity; YTHDF2 forms a STAT5-YTHDF2 positive feedback loop upon IL-15 stimulation and targets Tardbp mRNA (involved in cell survival/proliferation) for degradation in NK cells.\",\n      \"method\": \"Ythdf2 conditional KO in NK cells, transcriptome-wide YTHDF2 binding screening, in vivo tumor/viral infection models\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with defined in vivo phenotype, transcriptome-wide binding screen; single lab\",\n      \"pmids\": [\"34160549\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Ythdf2-deficient hematopoietic stem cells chronically upregulate multiple m6A-modified inflammation-related transcripts, activating proinflammatory pathways; YTHDF2 expression is induced by inflammation and is required to protect HSCs from inflammatory insult.\",\n      \"method\": \"Hematopoiesis-specific Ythdf2 KO mice, serial transplantation, m6A-mRNA abundance profiling\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with serial transplantation and long-term in vivo characterization, replicated across two papers from independent labs\",\n      \"pmids\": [\"33156926\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"YTHDF2 recognizes m6A-modified LncRNA FENDRR and promotes its degradation in endometrial cancer cells, thereby elevating SOX4 protein and promoting cell proliferation.\",\n      \"method\": \"RIP assay, mRNA stability assay, knockdown rescue experiments, xenograft model\",\n      \"journal\": \"Laboratory investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP and mRNA stability assay; single lab, two methods\",\n      \"pmids\": [\"33692441\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"YTHDF2 promotes AXIN1 mRNA stability and expression in cervical cancer (opposite to its canonical decay function), and AXIN1 knockdown reverses the effects of YTHDF2 depletion on migration, invasion, EMT, and cisplatin sensitivity.\",\n      \"method\": \"MeRIP-seq, actinomycin D mRNA stability assay, epistasis KD rescue experiments\",\n      \"journal\": \"Drug development research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MeRIP-seq plus stability assay plus genetic epistasis; single lab\",\n      \"pmids\": [\"35489084\"],\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; this interaction promotes HIF-1α mRNA translation, as PBRM1 or YTHDF2 loss reduces HIF-1α protein but not mRNA levels.\",\n      \"method\": \"Co-IP (PBRM1-YTHDF2 interaction), RIP (HIF-1α mRNA binding), polysome profiling, KD experiments\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus RIP plus polysome profiling; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"34200988\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"YTHDF2 depletion in LPS-stimulated osteoclast precursors stabilizes Tnfrsf11a, Traf6, Map4k4, Map2k3, Map2k4, and Nfatc1 mRNAs, enhancing NF-κB and MAPK signaling and promoting inflammatory osteoclastogenesis.\",\n      \"method\": \"Ythdf2 KD in RAW264.7 and BMMs, mRNA stability assay, TRAP/pit formation assays, NF-κB/MAPK inhibitor rescue\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mRNA stability assay plus signaling inhibitor rescue; single lab\",\n      \"pmids\": [\"34089814\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"O-GlcNAc transferase (OGT)-mediated O-GlcNAcylation of YTHDF2 at serine 263 enhances its protein stability by inhibiting its ubiquitination; O-GlcNAcylated YTHDF2 stabilizes MCM2 and MCM5 mRNAs in an m6A-dependent manner to promote cell cycle progression in HBV-related HCC.\",\n      \"method\": \"Mass spectrometry identification of S263 modification, mutagenesis, ubiquitination assay, RIP, m6A-dependent mRNA stability assay\",\n      \"journal\": \"Signal transduction and targeted therapy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — modification site identified by MS and confirmed by mutagenesis (S263), plus ubiquitination assay and RIP; multiple orthogonal methods in one study\",\n      \"pmids\": [\"36765030\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"YTHDF2 requires B cell activation to be upregulated; YTHDF2 enhances decay of methylated transcripts encoding key plasmablast-regulating genes to suppress the plasmablast genetic program and promote germinal center B cell fate commitment.\",\n      \"method\": \"Ythdf2 conditional KO in B cells, single-cell RNA-seq, m6A-mRNA decay assay\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO plus scRNA-seq; single lab\",\n      \"pmids\": [\"35508130\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"YTHDF2 promotes CDKN1B mRNA degradation in an m6A-dependent manner in intrahepatic cholangiocarcinoma, driving cell cycle progression and cisplatin resistance.\",\n      \"method\": \"RNA-seq, MeRIP-seq, anti-YTHDF2 RIP-seq, RNA stability assay, PDX model\",\n      \"journal\": \"Clinical and translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — three orthogonal sequencing methods plus stability assay; single lab\",\n      \"pmids\": [\"35696608\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"YTHDF2 facilitates m6A-dependent mRNA decay of LXRA and promotes YTHDF2/APC and GSK3β mRNA degradation via Wnt-β-catenin pathway activation in glioblastoma; PRMT6 and CDK9 co-regulate YTHDF2 transcription, with PRMT6 acting upstream.\",\n      \"method\": \"Dual-luciferase reporter assay, ChIP-qPCR, mRNA stability assay, in situ tumor model\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-qPCR, luciferase assay, mRNA stability assay; single lab\",\n      \"pmids\": [\"38637831\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"HSP90β physically interacts with YTHDF2 and STUB1 (an E3 ubiquitin ligase) in the cytoplasm; HSP90β inhibits STUB1-induced ubiquitination and degradation of YTHDF2, stabilizing YTHDF2 protein and promoting HCC proliferation and sorafenib resistance.\",\n      \"method\": \"Co-IP, domain mapping (HSP90β large and small middle domain required for interaction), ubiquitination assay, KD/OE experiments\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP, domain mapping, in vitro ubiquitination assay; multiple orthogonal methods establishing the regulatory mechanism\",\n      \"pmids\": [\"37515378\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"YTHDF2 binds to m6A sites on ACER2 mRNA and stabilizes (rather than degrades) it, enhancing ACER2 expression; increased ACER2 hydrolyzes ceramides and activates ERK and PI3K/AKT pathways in diffuse large B-cell lymphoma.\",\n      \"method\": \"RNA-seq, lipidomics, MeRIP-seq, RIP-qPCR, RNA stability assay, luciferase assay, CRISPR KO\",\n      \"journal\": \"Journal of advanced research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple sequencing methods plus stability assay; single lab; notably shows stabilization rather than decay\",\n      \"pmids\": [\"37865189\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"YTHDF2 accelerates EGR1 mRNA degradation in an m6A-dependent manner in multiple myeloma; EGR1 suppresses proliferation by activating p21cip1/waf1 transcription and inhibiting CDK2-cyclinE1.\",\n      \"method\": \"RIP-PCR, MeRIP-qPCR, mRNA stability assay, EGR1 KD rescue, in vivo xenograft\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP plus MeRIP plus mRNA stability plus genetic epistasis; single lab\",\n      \"pmids\": [\"37012388\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"YTHDF2 degrades STAT5A mRNA at its m6A modification site; reduced STAT5A relieves suppression of MAP2K2 transcription (ChIP-seq), thereby increasing p-ERK and promoting multiple myeloma cell proliferation.\",\n      \"method\": \"m6A-RIP-seq, RIP-PCR, ChIP-seq, mRNA stability assay, YTHDF2 KD/OE\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — m6A-RIP-seq plus ChIP-seq plus mRNA stability; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"35075244\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"YBX2 physically interacts with YTHDF2 via its cold-shock domain within YBX2-containing cytoplasmic granules; YTHDF2 knockdown ameliorates YBX2-induced HSPA6 mRNA destabilization, demonstrating synergistic effects of YBX2 and YTHDF2 on mRNA stability.\",\n      \"method\": \"Co-IP, transcriptomic analysis, mRNA stability assay, YTHDF2 KD rescue\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus mRNA stability rescue; single lab\",\n      \"pmids\": [\"37030331\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"YTHDF2 deficiency in tumor-associated macrophages (TAMs) suppresses tumor growth by reprogramming TAMs toward antitumoral phenotype via targeting IFN-γ-STAT1 signaling; YTHDF2 expression in TAMs is regulated by IL-10-STAT3 signaling.\",\n      \"method\": \"Conditional Ythdf2 KO in macrophages, in vivo tumor models, signaling pathway analysis, siRNA-TLR9 agonist conjugate targeting\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with defined in vivo phenotype, upstream/downstream signaling established, multiple cell and in vivo models\",\n      \"pmids\": [\"36658237\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Ionizing radiation induces YTHDF2 expression via NF-κB signaling; YTHDF2 in turn activates NF-κB by degrading m6A-modified transcripts encoding NF-κB negative regulators, creating an IR-YTHDF2-NF-κB positive feedback circuit that promotes MDSC immunosuppression.\",\n      \"method\": \"Conditional Ythdf2 KO in myeloid cells, mRNA binding/degradation assay, NF-κB signaling analysis, in vivo irradiation tumor models\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO mice, m6A-dependent mRNA decay mechanistically established, NF-κB circuit confirmed by multiple methods\",\n      \"pmids\": [\"37236197\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"YTHDF2 directly binds and degrades BAMBI transcripts in an m6A-dependent and NF-κB-signaling-dependent manner in MDSCs after ionizing radiation, reducing BAMBI-mediated suppression of TGF-β signaling and extrinsic radioresistance.\",\n      \"method\": \"YTHDF2 RIP assay, m6A-dependent mRNA stability assay, NF-κB signaling inhibition, AAV-BAMBI rescue in tumor models\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP plus mRNA stability plus in vivo rescue; single lab\",\n      \"pmids\": [\"38099498\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Loss of YTHDF2 in regulatory T cells (Tregs) leads to increased apoptosis and impaired suppressive function in the tumor microenvironment; elevated TNF signaling in the TME promotes YTHDF2 expression, which then accelerates degradation of m6A-modified NF-κB negative regulator transcripts to activate NF-κB signaling in Tregs.\",\n      \"method\": \"Treg-specific Ythdf2 KO mice, in vivo tumor models, m6A mRNA decay analysis, TNF/NF-κB pathway analysis\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with defined cellular phenotype, signaling pathway dissected, multiple in vivo and in vitro methods\",\n      \"pmids\": [\"37345898\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"YTHDF2 recognizes m6A modification in the 5'-UTR of ETV5 mRNA and recruits eukaryotic translation initiation factor 3 subunit B (eIF3B) to facilitate ETV5 translation (rather than decay), which then induces transcription of PD-L1 and VEGFA to promote HCC immune evasion and angiogenesis.\",\n      \"method\": \"RIP assay, m6A modification mapping (5'-UTR), co-IP for eIF3B recruitment, ETV5 ChIP, KD/OE experiments in vitro and in vivo\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP + co-IP + ChIP; identifies a translation-promoting (not decay) function at 5'-UTR m6A; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"38247171\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"YTHDF2 directly binds RIG-I (DDX58) mRNA at its coding sequence and mediates its degradation in an m6A-dependent manner in bladder cancer, suppressing RIG-I-mediated innate immune signaling and promoting immune evasion.\",\n      \"method\": \"Integrative RNA-seq and m6A-seq, RIP assay, mRNA stability assay, epistasis rescue, orthotopic mouse model\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP + RNA-seq + m6A-seq + mRNA stability + genetic rescue; single lab\",\n      \"pmids\": [\"36939388\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"YTHDF2 promotes pre-miR-126 maturation by recognizing m6A modifications in pre-miR-126 and recruiting AGO2, facilitating processing of pre-miR-126 into mature miR-126 to promote AML progression.\",\n      \"method\": \"RIP assay (YTHDF2-pre-miR-126 binding), AGO2 co-IP, forced expression of miR-126 rescue, KD/OE in AML cells and mouse models\",\n      \"journal\": \"Genes & diseases\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP plus co-IP identifying AGO2 recruitment plus genetic rescue; single lab, two orthogonal methods\",\n      \"pmids\": [\"37588203\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"YTHDF2 binds m6A sites on DAPK3 mRNA 3'-UTR and facilitates its degradation in gallbladder cancer; DAPK3 inhibition rescues tumor-suppressive phenotypes from YTHDF2 deficiency and drives gemcitabine resistance.\",\n      \"method\": \"RIP-seq, MeRIP-seq, RNA-seq integration, mRNA stability assay, epistasis rescue, in vivo xenograft\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — three orthogonal sequencing methods plus stability assay; single lab\",\n      \"pmids\": [\"37700438\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"KRT17 causes YTHDF2 degradation through the ubiquitin-proteasome system; YTHDF2 targets CXCL10 mRNA (identified by RIP sequencing) for m6A-dependent decay, thus suppressing CXCL10-mediated T-lymphocyte recruitment in colorectal cancer.\",\n      \"method\": \"Mass spectrometry, co-IP, ubiquitin-proteasome inhibition, high-throughput RIP sequencing, YTHDF2 KD rescue\",\n      \"journal\": \"Cancer immunology research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS + co-IP + RIP-seq; single lab, multiple methods\",\n      \"pmids\": [\"37129929\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Ythdf2 promotes degradation of Hmox1 mRNA in an m6A-dependent manner in alveolar macrophages; myeloid-specific Ythdf2 KO mice are protected from pulmonary hypertension with elevated Hmox1, and Hmox1 inhibition reverses this protection.\",\n      \"method\": \"Myeloid-specific KO mice, mRNA stability assay, Hmox1 inhibitor epistasis, in vivo PH model\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO mouse model, mRNA stability, pharmacological epistasis; multiple orthogonal methods\",\n      \"pmids\": [\"36801705\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"YTHDF2 promotes aggresome formation in an m6A-independent manner by interacting with UPF1 within a misfolded polypeptide-associated complex (containing UPF1, CTIF, eEF1A1, and DCTN1); YTHDF2 increases dynein motor protein interaction with this complex, facilitating movement of misfolded polypeptides toward aggresomes.\",\n      \"method\": \"YTHDF2 KD in HeLa cells, co-IP of protein complex, dynein interaction assay, aggresome circularity/movement analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — co-IP identifying complex components, motor protein interaction assay, functional live-cell imaging; multiple orthogonal methods establishing m6A-independent mechanism\",\n      \"pmids\": [\"37803021\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"YTHDF2 directly binds RXRα mRNA via RIP-qPCR and promotes its degradation, reducing RXRα expression in myeloid cells; Ythdf2 conditional KO mice show elevated MDSCs with enhanced suppressive function in autoimmune hepatitis.\",\n      \"method\": \"m6A RIP, RIP-qPCR, conditional KO mice, flow cytometry, multi-omic m6A-seq + mRNA-seq\",\n      \"journal\": \"Journal of autoimmunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP-qPCR plus conditional KO plus m6A-seq; single lab\",\n      \"pmids\": [\"36642058\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"YTHDF2 mediates decay of Ythdf2 mRNA itself (autoregulation) in an m6A-dependent manner in CD8 T cells; additionally, YTHDF2 translocates to the nucleus where it facilitates nascent RNA synthesis and interacts with IKZF1/3 to sustain transcription of their target genes, reinforcing T cell polyfunctionality.\",\n      \"method\": \"Conditional KO in T cells, m6A recognition mutant analysis, nuclear localization imaging, co-IP (YTHDF2-IKZF1/3), chromatin assays, in vivo tumor models\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO, co-IP, nuclear function established, m6A recognition mutagenesis; multiple orthogonal methods\",\n      \"pmids\": [\"39500904\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Ythdf2 directly regulates mRNA stability of eukaryotic elongation factor 2 (eEF2) in cardiomyocytes (identified by cell-type specific Ribo-seq); cardiomyocyte-specific Ythdf2 deletion leads to cardiac hypertrophy, reduced function, and increased fibrosis during pressure overload and aging.\",\n      \"method\": \"Cardiomyocyte-specific Ythdf2 KO mice, Ribo-seq, mRNA stability analysis, cardiac phenotyping\",\n      \"journal\": \"Journal of molecular and cellular cardiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with cardiac phenotype, Ribo-seq identifying eEF2 as target; single lab\",\n      \"pmids\": [\"37315764\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"YTHDF2 binds m6A-modified Myzap mRNA and controls its stability; cardiomyocyte-specific YTHDF2 KO leads to cardiac dysfunction and upregulation of MYZAP protein, demonstrating YTHDF2 maintains cardiac homeostasis by suppressing this hypertrophic protein.\",\n      \"method\": \"Cardiomyocyte-specific KO mice, proteomics, RIP assay for YTHDF2-Myzap mRNA binding, mRNA stability assay\",\n      \"journal\": \"JACC. Basic to translational science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO, proteomics, RIP; single lab, multiple methods\",\n      \"pmids\": [\"37791304\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"YTHDF2-mediated m6A-dependent mRNA decay of Pyk2 in macrophages attenuates LPS-induced proinflammatory signaling (MAPKs, AKT) and ROS generation; Mettl3 depletion stabilizes Pyk2 mRNA via Ythdf2, and RIP-PCR confirmed direct YTHDF2-Pyk2 mRNA binding.\",\n      \"method\": \"RNA-seq, m6A mapping, RIP-PCR, Mettl3/Ythdf2 KD, Pyk2 inhibitor rescue\",\n      \"journal\": \"Immunology letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP-PCR plus mRNA stability plus pharmacological rescue; single lab\",\n      \"pmids\": [\"37952687\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"YTHDF2 functions as a dual m6A/m5C reader: it stabilizes m5C-modified mRNAs by recruiting PABPC1, enhancing their translation and ATP synthesis (pro-tumorigenic), while simultaneously destabilizing other m6A-modified mRNAs to promote immune evasion in B cell malignancies; YTHDF2 overexpression alone is sufficient to cause B cell transformation.\",\n      \"method\": \"m5C/m6A reader assay, co-IP (YTHDF2-PABPC1), mRNA stability and translation assay, YTHDF2 OE-driven transformation model, small-molecule inhibitor\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro binding assay, co-IP, translation assay, transformation model; multiple orthogonal methods establishing dual-reader mechanism\",\n      \"pmids\": [\"39694037\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FMDV structural protein VP1 promotes autophagy (AKT-MTOR-dependent) and degrades YTHDF2 through the autophagy pathway, leading to increased GTPBP4 mRNA/protein levels; elevated GTPBP4 inhibits IRF3 binding to the Ifnb promoter, suppressing type I interferon production.\",\n      \"method\": \"Co-IP (VP1-YTHDF2 interaction), autophagy inhibitor/activator treatment, IRF3 ChIP assay, YTHDF2 KD rescue of IFN-β, in vivo GTPBP4-deficient mice\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus ChIP plus autophagy pathway dissection; single lab, multiple methods\",\n      \"pmids\": [\"38516932\"],\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 CX3CL1-mediated macrophage recruitment and enhances mitochondrial respiration of CD8+ T cells by impairing tumor glycolysis.\",\n      \"method\": \"Conditional KO tumor models, CX3CL1 mRNA stabilization assay, autophagy inhibitor experiments, metabolic assays in CD8+ T cells\",\n      \"journal\": \"Science immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with multiple mechanistic readouts; single lab\",\n      \"pmids\": [\"38820140\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Protein lactylation elevates YTHDF2 expression in cardiomyocytes; the intrinsic disorder region (not the m6A-binding domain) of YTHDF2 is required for its regulation of cardiomyocyte size and apoptosis via upregulating G3BP1; exercise-induced downregulation of YTHDF2 is required for physiological cardiac hypertrophy.\",\n      \"method\": \"Lactylation inhibition, YTHDF2 domain deletion mutant analysis, OGD/R model, YTHDF2 KD/OE in cardiomyocytes, in vivo ischemia/reperfusion model\",\n      \"journal\": \"Basic research in cardiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain mutant analysis identifying disorder region as functional, in vivo cardiac model; single lab\",\n      \"pmids\": [\"38563985\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"YTHDF2 stabilizes Cx3cl1 transcripts in an m6A-dependent manner in hepatocytes (identified by liver-specific KO model), regulating CD8+ T cell recruitment and antitumor immunity; OXA upregulates YTHDF2 expression via the cGAS-STING signaling pathway.\",\n      \"method\": \"Liver-specific Ythdf2 KO mice, mRNA stability assay for Cx3cl1, cGAS-STING pathway analysis, tumor-bearing liver models\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO plus mRNA stability plus upstream pathway dissection; single lab\",\n      \"pmids\": [\"39237909\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"YTHDF2 controls mRNA stability of the ubiquitin ligase ASB2; in skeletal muscle, ASB2 upregulation upon YTHDF2 loss activates SMAD3-dependent anti-growth gene programs, thereby impairing postnatal muscle growth and hypertrophic response.\",\n      \"method\": \"Muscle-specific Ythdf2 KO mice, mRNA stability assay for ASB2, SMAD3 pathway analysis, hypertrophic stimuli experiments\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with defined muscle phenotype, mRNA stability, downstream SMAD3 pathway established; multiple orthogonal methods\",\n      \"pmids\": [\"38467649\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"OTUB1 (deubiquitinase) increases YTHDF2 protein stability by blocking ubiquitin transfer to YTHDF2 independently of its deubiquitinase activity; stabilized YTHDF2 promotes m6A-dependent PRSS8 mRNA degradation, reducing PRSS8-mediated nuclear β-catenin suppression via E-cadherin in prostate cancer.\",\n      \"method\": \"In vivo and in vitro ubiquitination assays, co-IP (OTUB1-YTHDF2), YTHDF2 RIP assay for PRSS8 mRNA, mRNA stability assay, cellular/mouse models\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro ubiquitination assay plus co-IP plus RIP plus mRNA stability; multiple orthogonal methods in one study\",\n      \"pmids\": [\"38462165\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Ythdf2 in pulmonary artery smooth muscle cells stabilizes (rather than degrades) Myadm mRNA in an m6A-dependent manner; this paradoxical stabilization promotes PASMC proliferation and pulmonary hypertension via an m6A/Myadm/p21 pathway.\",\n      \"method\": \"Smooth muscle cell-specific Ythdf2 KO mice, proteomics, m6A sequencing, RIP assay, Myadm siRNA rescue, in vivo PH model\",\n      \"journal\": \"Hypertension\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO, m6A-seq, RIP, and functional rescue; single lab\",\n      \"pmids\": [\"38832511\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ROS activates YTHDF2 and promotes degradation of m6A-modified FOXO3 mRNA; loss of FOXO3 impairs its ability to recruit CBP and Med1 to activate TIMP1 expression, increasing MMP activity and contributing to intervertebral disc degeneration. Pharmacological YTHDF2 inhibition restores FOXO3/TIMP1/MMP balance.\",\n      \"method\": \"iTRAQ proteomics, YTHDF2 KD/OE, m6A-modified FOXO3 mRNA stability assay, FOXO3-ChIP (CBP/Med1 recruitment), YTHDF2 inhibitor DC-Y13-27 in vivo\",\n      \"journal\": \"Cellular and molecular life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteomics plus mRNA stability plus ChIP; single lab, multiple methods\",\n      \"pmids\": [\"39625652\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"lncRNA JPX directly interacts with YTHDF2 and blocks USP10-mediated deubiquitination/protection of YTHDF2, promoting YTHDF2 ubiquitin-dependent degradation; reduced YTHDF2 stabilizes BMP2 mRNA and activates AKT phosphorylation in melanoma.\",\n      \"method\": \"RNA pull-down, RIP, co-IP, Western blot, RNA-seq, ubiquitination assay\",\n      \"journal\": \"Molecular cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA pull-down + co-IP + ubiquitination assay; single lab\",\n      \"pmids\": [\"38441563\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Conditional deletion of Ythdf2 from proliferating hippocampal NSCs elevates quiescence acquisition; Ythdf2 targets multiple TGF-β signaling pathway components (ligands, receptors, transcription regulators) for m6A-dependent mRNA decay, and TGF-β signaling suppression rescues elevated quiescence in Ythdf2-deficient NSCs.\",\n      \"method\": \"Conditional KO in NSCs, multimodal m6A/YTHDF2 binding/mRNA decay profiling, TGF-β inhibitor rescue, in vivo/in vitro assays\",\n      \"journal\": \"Cell stem cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with multimodal profiling, pharmacological epistasis, in vivo/in vitro corroboration; multiple orthogonal methods\",\n      \"pmids\": [\"39476834\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Ythdf2 directly regulates the mRNA stability of Ace and Bmp4 as an m6A reader in retinal microglia; Ythdf2 loss increases Ace and Bmp4 expression, causing aberrant microglial activation and pathological angiogenesis; pharmacological inhibition of Ace or Bmp4 alleviates the Ythdf2-deficiency-driven microvascular disease.\",\n      \"method\": \"Microglia-specific Ythdf2 KO mice, scRNA-seq, mRNA stability assay, captopril/noggin pharmacological rescue, in vivo OIR model\",\n      \"journal\": \"Journal of advanced research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO plus mRNA stability plus pharmacological rescue; single lab\",\n      \"pmids\": [\"41627954\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"YTHDF2 forms a complex with eIF3F and DDX1 to enhance translation of m6A-modified mRNAs encoding microtubule-associated proteins in ovarian cancer, thereby promoting cancer progression and paclitaxel resistance independently of its mRNA decay function; a small-molecule inhibitor targeting YTHDF2 reverses this translational enhancement.\",\n      \"method\": \"Co-IP (YTHDF2-eIF3F-DDX1), mRNA stability vs. translation assay, virtual screening for inhibitor, eCLIP, functional paclitaxel resistance assay\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — co-IP identifying novel translation complex, direct comparison of stability vs. translation, small-molecule validation; multiple orthogonal methods establishing non-canonical function\",\n      \"pmids\": [\"40480228\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"YTHDF2 ablation in naive CD4+ T cells promotes Th9 differentiation by stabilizing Gata3 and Smad3 mRNAs under IL-4 and TGF-β signaling respectively; Ythdf2-deficient Th9 cells produce more IL-9 and IL-21, enhancing CD8+ T cell and NK cell tumor infiltration and cytotoxicity.\",\n      \"method\": \"Ythdf2 KO in mouse and human naive CD4+ T cells, mRNA stability assay for Gata3/Smad3, in vivo antitumor models, CAR-Th9 experiments\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO in both mouse and human T cells, mRNA stability assay, in vivo CAR-T models; multiple orthogonal methods across species\",\n      \"pmids\": [\"40826275\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Phenylpyrazole compounds (e.g., CK-75) bind a small hydrophobic pocket on the YTH domain of YTHDF2, inhibiting its m6A-binding activity; eCLIP confirmed altered global RNA-binding patterns of YTHDF2 upon CK-75 treatment, and the compounds induce cell cycle arrest and apoptosis in cancer cells.\",\n      \"method\": \"Small-molecule binding to YTH domain (structural pocket), eCLIP, cell viability/apoptosis assays\",\n      \"journal\": \"JACS Au\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — YTH domain targeting with eCLIP validation; single study but demonstrates binding mechanism; pocket location inferred from computational docking without full crystal structure reported in abstract\",\n      \"pmids\": [\"40017738\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"YTHDF2 is an m6A (and m5C) reader protein that primarily recognizes N6-methyladenosine modifications on target mRNAs via its conserved YTH domain (Trp432 critical) and recruits the CCR4-NOT and PAN2-PAN3 deadenylase complexes to accelerate mRNA decay; however, it also stabilizes select mRNAs, promotes translation of m6A/m5C-modified transcripts by recruiting eIF3F/DDX1 or PABPC1, facilitates pre-miRNA maturation, and performs m6A-independent functions including aggresome formation via UPF1 interaction and nuclear chromatin regulation via IKZF1/3; its protein stability is regulated by CDK1-dependent phosphorylation, OGT-mediated O-GlcNAcylation (S263), HSP90β-mediated protection from STUB1 ubiquitination, and OTUB1-mediated deubiquitination, while its degradation can be induced by autophagy or ubiquitin-proteasome pathways; through these mechanisms YTHDF2 governs diverse cellular processes including cell cycle progression, hematopoietic stem cell maintenance, neural development, spermatogenesis, muscle growth, cardiac homeostasis, and innate and adaptive immune responses.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"YTHDF2 is a cytoplasmic m6A reader that recognizes N6-methyladenosine marks on target mRNAs through its YTH domain and primarily routes those transcripts to deadenylation-dependent decay, thereby tuning the abundance of methylated transcripts across cell-cycle, developmental, and immune programs [#5, #6, #11]. Substrate recognition depends on a conserved hydrophobic pocket (Trp432), which also mediates lower-affinity binding to m5C-modified RNA [#3], and decay is executed by recruitment of the CCR4-NOT deadenylase complex [#6]. Through m6A-dependent turnover of specific substrates YTHDF2 drives mitotic entry by degrading WEE1 [#5], maintains hematopoietic and neural stem-cell pools by clearing inflammation- and TGF-β/JAK-STAT-related transcripts [#10, #15, #55], and governs spermatogenesis, cardiac homeostasis, and postnatal muscle growth by destabilizing matrix, hypertrophic, and anti-growth regulators such as Myzap, eEF2, and ASB2 [#42, #43, #50]. Across immune lineages YTHDF2 reshapes NF-κB and interferon signaling—degrading negative regulators of NF-κB in MDSCs and Tregs and innate-immune transcripts such as RIG-I and CXCL10 to promote immune evasion—while being required for NK-cell maturation and germinal-center B-cell fate [#14, #21, #30, #32, #34, #37]. Beyond decay, YTHDF2 stabilizes select transcripts and promotes translation: it recruits eIF3B, or an eIF3F/DDX1 complex, or PABPC1 to enhance translation of methylated mRNAs, and as a dual m6A/m5C reader it can stabilize m5C-modified messages while degrading m6A targets [#33, #45, #57]. It additionally acts independently of m6A, promoting aggresome formation through a UPF1-containing misfolded-polypeptide/dynein complex [#39] and entering the nucleus to support nascent transcription via IKZF1/3 [#41]. YTHDF2 protein abundance is itself heavily regulated—stabilized by CDK1-dependent phosphorylation, EGFR/SRC/ERK phosphorylation, OGT-mediated O-GlcNAcylation at Ser263, HSP90β-mediated protection from STUB1, and OTUB1 deubiquitination, and degraded via CUL1/CUL4A/DDB1/SKP2 ubiquitin ligases or autophagy [#5, #8, #20, #24, #51, #46].\",\n  \"teleology\": [\n    {\n      \"year\": 2018,\n      \"claim\": \"Established that YTHDF2 directly binds m6A sites in target-mRNA UTRs and drives their degradation, providing the first functional substrate evidence in a cancer context.\",\n      \"evidence\": \"RIP and mRNA stability assays with loss/gain-of-function on EGFR mRNA in HCC cells\",\n      \"pmids\": [\"30423408\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single substrate, single lab\", \"Did not define the decay machinery recruited\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined YTHDF2 as a transcriptome-wide destabilizer of m6A-modified mRNAs required for leukemic stem cell propagation but dispensable for normal HSCs, establishing a therapeutic window.\",\n      \"evidence\": \"Conditional KO mouse and human AML models with mRNA half-life and m6A-seq\",\n      \"pmids\": [\"31031138\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of selective LSC dependence not fully resolved\", \"Decay machinery not mapped here\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showed the YTH-domain residue Trp432 that reads m6A also recognizes m5C, broadening YTHDF2 to a dual-mark reader and linking it to rRNA processing.\",\n      \"evidence\": \"Quantitative pulldown, in vitro binding with Trp432 mutagenesis, CRISPR KO with bisulfite sequencing\",\n      \"pmids\": [\"31815440\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"m5C binding affinity lower than m6A; physiological weight unclear\", \"Mechanism connecting YTHDF2 to pre-rRNA processing undefined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified the effector machinery: YTHDF2 recruits the CCR4-NOT deadenylase complex to clear methylated transcripts, and is degraded via specific cullin-based E3 ligases, placing it in a CDK1-WEE1 mitotic feedforward loop.\",\n      \"evidence\": \"Reciprocal co-IP of CCR4-NOT, KO/rescue, CDK1 inhibitor, mRNA stability assays in iPSC reprogramming and HeLa\",\n      \"pmids\": [\"32905781\", \"32267835\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of CCR4-NOT recruitment not defined\", \"Determinants choosing decay vs stabilization unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrated YTHDF2 protein abundance is gated by post-translational modification—EGFR/SRC/ERK phosphorylation and OGT O-GlcNAcylation at Ser263 stabilize it—coupling oncogenic signaling to reader activity.\",\n      \"evidence\": \"Phospho/O-GlcNAc site identification by MS and mutagenesis, ubiquitination and mRNA-stability assays in GBM and HCC\",\n      \"pmids\": [\"33420027\", \"36765030\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How each PTM alters substrate selection not dissected\", \"Crosstalk among the modifications unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established YTHDF2 as a stem-cell and developmental regulator: it maintains neural and hematopoietic stem cells by degrading inflammation- and JAK-STAT-related transcripts, with embryonic lethality on loss.\",\n      \"evidence\": \"Conditional/hematopoiesis-specific KO mice, serial transplantation, m6A methylome and mRNA stability assays\",\n      \"pmids\": [\"29855337\", \"33156926\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tissue-specific substrate sets only partially enumerated\", \"Distinction between cell-intrinsic and niche effects incomplete\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Revealed YTHDF2 buffers transcriptome output in MYC-driven and TNBC tumors, where its decay activity counteracts elevated mRNA synthesis and its loss triggers ER-stress apoptosis.\",\n      \"evidence\": \"Pooled CRISPR screen, eCLIP, m6A-seq, scRibo-STAMP, xenografts\",\n      \"pmids\": [\"34216543\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generality of the buffering role across tumor types untested here\", \"Translation vs decay contribution not separated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Uncovered non-canonical and translation-promoting roles: heat-shock-induced nuclear translocation via the YTH domain, and PBRM1-dependent enhancement of HIF-1α translation, showing YTHDF2 is not solely a decay factor.\",\n      \"evidence\": \"Deletion-mutant localization imaging, co-IP, RIP, polysome profiling\",\n      \"pmids\": [\"34671198\", \"34200988\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Nuclear function mechanism incompletely defined\", \"Switch between decay and translation promotion unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed YTHDF2 protein is protected from STUB1-mediated degradation by HSP90β, and can paradoxically stabilize substrate mRNAs (ACER2), extending its regulatory repertoire beyond decay.\",\n      \"evidence\": \"Reciprocal co-IP with domain mapping, ubiquitination assays, MeRIP and stability assays in HCC and DLBCL\",\n      \"pmids\": [\"37515378\", \"37865189\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Rules governing stabilization vs decay of a given transcript unknown\", \"Whether HSP90β chaperoning affects substrate selection untested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established YTHDF2 as a central node in tumor immune evasion across myeloid, T-regulatory, NK, and innate-sensing pathways, frequently by degrading NF-κB negative regulators or innate-immune transcripts (RIG-I, CXCL10).\",\n      \"evidence\": \"Lineage-specific conditional KO mice, m6A-dependent decay assays, in vivo tumor/irradiation models\",\n      \"pmids\": [\"36658237\", \"37236197\", \"37345898\", \"36939388\", \"37129929\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Why YTHDF2 selects NF-κB-regulatory substrates is unresolved\", \"Context-dependent pro- vs anti-inflammatory outputs not unified\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrated m6A-independent activities: YTHDF2 promotes aggresome formation through a UPF1/dynein misfolded-polypeptide complex and enters the nucleus to support transcription via IKZF1/3, plus autoregulating its own mRNA.\",\n      \"evidence\": \"Co-IP of complex components, dynein-interaction and live-cell aggresome imaging, conditional T-cell KO with chromatin assays\",\n      \"pmids\": [\"37803021\", \"39500904\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of m6A-independent protein interactions undefined\", \"Balance between nuclear and cytoplasmic pools unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended YTHDF2's physiological role to cardiac and pulmonary homeostasis through mRNA-stability control of eEF2, Myzap, and Hmox1, with tissue-specific decay or stabilization outcomes.\",\n      \"evidence\": \"Cardiomyocyte- and myeloid-specific KO mice, Ribo-seq, proteomics, RIP and stability assays, pharmacological epistasis\",\n      \"pmids\": [\"37315764\", \"37791304\", \"36801705\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Why some substrates are stabilized rather than degraded in these tissues unresolved\", \"Upstream signals controlling cardiac YTHDF2 only partly defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Resolved YTHDF2 as a dual m6A/m5C reader with opposing transcript fates—stabilizing m5C mRNAs via PABPC1 to boost translation while degrading m6A targets—and showed its overexpression alone transforms B cells.\",\n      \"evidence\": \"In vitro reader assays, PABPC1 co-IP, translation/stability assays, overexpression-driven transformation model, small-molecule inhibitor\",\n      \"pmids\": [\"39694037\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How a single reader partitions m5C vs m6A substrates mechanistically unknown\", \"In vivo contribution of m5C reading versus m6A decay not separated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Mapped additional layers of YTHDF2 protein control—OTUB1 and USP10 deubiquitination, lncRNA JPX-mediated destabilization, and IFN-γ/FMDV-VP1-driven autophagic degradation—linking its turnover to immune and viral contexts.\",\n      \"evidence\": \"In vitro ubiquitination assays, co-IP, RNA pulldown, autophagy modulation, conditional KO tumor models\",\n      \"pmids\": [\"38462165\", \"38441563\", \"38820140\", \"38516932\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Hierarchy among competing stabilizing/destabilizing inputs unknown\", \"Whether autophagic and proteasomal routes dominate in specific tissues unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined a discrete translation-enhancing complex (YTHDF2-eIF3F-DDX1) acting independently of decay, and validated YTH-domain-targeting small molecules that disrupt m6A binding, advancing YTHDF2 as a druggable target.\",\n      \"evidence\": \"Co-IP, stability-vs-translation comparison, eCLIP, structure-guided/phenylpyrazole inhibitor binding to the YTH pocket, apoptosis assays\",\n      \"pmids\": [\"40480228\", \"40017738\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No reported full crystal structure of inhibitor-bound YTH domain\", \"Determinants directing YTHDF2 to translation vs decay complexes unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The central unresolved question is what molecular switch dictates whether YTHDF2 destabilizes, stabilizes, or promotes translation of a given m6A/m5C transcript, and how its many PTMs and protein partners are integrated to set that outcome in a tissue-specific manner.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking PTM state, partner choice, and transcript fate\", \"Structural basis of m6A-independent functions undefined\", \"Relative in vivo weight of decay vs translation vs nuclear roles unquantified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 3, 5, 6, 11, 45]},\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [5, 6, 11]},\n      {\"term_id\": \"GO:0045182\", \"supporting_discovery_ids\": [33, 45, 57]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [6, 39, 57]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [13, 24, 39]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [13, 41]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [5, 6, 11, 45]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [14, 21, 30, 32, 34, 37]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [5, 20, 22]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [10, 50, 55]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [1, 8, 11, 12]}\n    ],\n    \"complexes\": [\n      \"CCR4-NOT deadenylase complex\",\n      \"misfolded-polypeptide/aggresome complex (UPF1, CTIF, eEF1A1, DCTN1)\",\n      \"YTHDF2-eIF3F-DDX1 translation complex\"\n    ],\n    \"partners\": [\n      \"UPF1\",\n      \"PABPC1\",\n      \"eIF3B\",\n      \"eIF3F\",\n      \"DDX1\",\n      \"HSP90B1\",\n      \"STUB1\",\n      \"OTUB1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}