{"gene":"YTHDF1","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2018,"finding":"YTHDF1 binds m6A-modified neuronal mRNAs and promotes their translation in response to neuronal stimulation in the adult mouse hippocampus; Ythdf1 knockout mice show impaired synaptic transmission, long-term potentiation, and learning/memory defects that are rescued by hippocampal re-expression of YTHDF1. Tether reporter assays in hippocampal neurons confirmed stimulus-dependent translation enhancement.","method":"Ythdf1 knockout mouse, hippocampus-specific AAV re-expression rescue, transcriptome-wide YTHDF1 RIP-seq and m6A mapping, nascent protein labeling, tether reporter assays in neurons","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (KO, rescue, RIP-seq, reporter assay, synaptic physiology) in a single rigorous study, replicated in concept by other groups","pmids":["30401835"],"is_preprint":false},{"year":2019,"finding":"In classical dendritic cells, YTHDF1 recognizes m6A-marked transcripts encoding lysosomal proteases (cathepsins) and promotes their translation, thereby increasing lysosomal cathepsin levels; this suppresses cross-presentation of tumor antigens. Ythdf1-deficient DCs show enhanced cross-priming of CD8+ T cells, and inhibition of cathepsins in wild-type DCs phenocopies YTHDF1 loss.","method":"Ythdf1 knockout mouse, syngeneic tumor models, polysome profiling / RIP, cathepsin inhibitor rescue experiments, in vivo CD8+ T cell priming assays","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal genetic and pharmacological validation across multiple methods; independently extended by PMID 36650153","pmids":["30728504"],"is_preprint":false},{"year":2019,"finding":"YTHDF1 binds m6A-modified Robo3.1 mRNA in spinal commissural neurons and promotes its translation without affecting mRNA levels; mutation of m6A sites in Robo3.1 mRNA or YTHDF1 KD/KO abolishes Robo3.1 protein expression, causing pre-crossing axon guidance defects in the spinal cord.","method":"YTHDF1 RIP, m6A site mutation, YTHDF1 KD and KO in vivo (spinal commissural neuron-specific), axon guidance phenotyping","journal":"Nucleic Acids Research","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (RIP, m6A site mutation, conditional KO, in vivo phenotype rescue) in one study","pmids":["30843071"],"is_preprint":false},{"year":2019,"finding":"YTHDF1 promotes translation of CDK2, CDK4, and cyclin D1 in NSCLC cells; its depletion inhibits cell proliferation, xenograft tumor formation, and de novo lung adenocarcinoma progression. YTHDF1 depletion also activates the Keap1-Nrf2-AKR1C1 axis, rendering cells cisplatin-resistant.","method":"YTHDF1 knockdown/knockout, xenograft models, genetic mouse lung adenocarcinoma model, polysome profiling, western blot for CDK2/CDK4/cyclin D1","journal":"Nature Communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO with defined cellular phenotype and in vivo validation; pathway placement (Keap1-Nrf2) from single lab","pmids":["31653849"],"is_preprint":false},{"year":2020,"finding":"YTHDF1 binds m6A-modified EIF3C mRNA and enhances its translation in an m6A-dependent manner, promoting overall translational output and ovarian cancer progression. Multi-omics analysis (CLIP-seq, m6A-seq, ribosome profiling, proteomics) confirmed EIF3C as a direct YTHDF1 target.","method":"Multi-omics: CLIP-seq, MeRIP-seq, ribosome profiling, proteomics, RIP, western blot, YTHDF1 overexpression/knockdown in ovarian cancer cells and patient samples","journal":"Nucleic Acids Research","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal genomic methods plus ribosome profiling confirming translational enhancement by YTHDF1","pmids":["31996915"],"is_preprint":false},{"year":2020,"finding":"YTHDF1 promotes translation of the Wnt receptor FZD7 in an m6A-dependent manner in gastric cancer cells, activating the Wnt/β-catenin pathway and gastric carcinogenesis. Mutant YTHDF1 found in ~7% of gastric cancers shows enhanced FZD7 expression.","method":"YTHDF1 KD/overexpression, RIP, m6A-seq, reporter assay, FZD7 western blot, xenograft models","journal":"Cancer Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP + translational readout + rescue experiments; single lab","pmids":["32788173"],"is_preprint":false},{"year":2020,"finding":"YTHDF1 facilitates translation of Wnt signaling effectors including TCF7L2/TCF4 in intestinal stem cells; genetic ablation of Ythdf1 blocks Wnt-driven intestinal regeneration and tumorigenesis, and YTHDF1 expression itself is upregulated by Wnt signaling at the translational level, forming an amplifying feed-forward loop.","method":"Ythdf1 knockout mouse, intestinal organoids, RIP-seq, ribosome profiling, intestinal tumor models","journal":"EMBO Reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse with defined intestinal phenotype plus RIP-seq and ribosome profiling; single lab","pmids":["32064749"],"is_preprint":false},{"year":2020,"finding":"YTHDF1 binds m6A-modified TRIM29 mRNA and promotes its translation in cisplatin-resistant ovarian cancer cells, enhancing cancer stem cell-like characteristics; YTHDF1 knockdown suppresses CSC features and is rescued by ectopic TRIM29 expression.","method":"RIP, m6A-IP, polysome profiling, YTHDF1 KD, TRIM29 rescue overexpression, CSC sphere assays","journal":"Biochimica et Biophysica Acta. Molecular Cell Research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — RIP and rescue experiments; single lab, moderate orthogonal validation","pmids":["33011193"],"is_preprint":false},{"year":2020,"finding":"YTHDF1 binds to the 3'UTR and 5'UTR of TFRC mRNA via its methyltransferase domain and positively regulates translation of m6A-modified TFRC mRNA, enhancing iron metabolism and tumorigenesis in hypopharyngeal squamous cell carcinoma.","method":"m6A-seq, RIP-seq, gain/loss-of-function assays, iron metabolism assays, xenograft model","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP-seq plus in vitro and in vivo functional validation; single lab","pmids":["33204330"],"is_preprint":false},{"year":2021,"finding":"In dendritic cells infected with EBV, YTHDF1 recognizes m6A-modified EBV transcripts, promotes RNA decapping, and mediates viral RNA decay by recruiting degradation complexes including ZAP, DDX17, and DCP2; this suppresses EBV replication in an m6A-dependent manner.","method":"m6A-seq on EBV transcripts, YTHDF1 RIP, co-immunoprecipitation of YTHDF1 with ZAP/DDX17/DCP2, mRNA half-life assays, YTHDF1 KD in NPC cells","journal":"EMBO Reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP plus Co-IP of degradation complexes plus functional viral replication assays; single lab","pmids":["33605073"],"is_preprint":false},{"year":2021,"finding":"YTHDF1 directs translation of TRAF6 mRNA through recognition of m6A modification near the TRAF6 transcript's stop codon, regulating the intestinal immune response to bacterial infection. The P/Q/N-rich domain of YTHDF1 interacts with the DEAD domain of host factor DDX60, enabling recognition of the Traf6 transcript.","method":"Ribo-seq, m6A-seq, RIP-qPCR, domain-mapping Co-IP (P/Q/N-rich domain of YTHDF1 × DEAD domain of DDX60), bacterial infection mouse model","journal":"Nucleic Acids Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Ribo-seq + m6A-seq + domain-level Co-IP; single lab","pmids":["33999206"],"is_preprint":false},{"year":2021,"finding":"YTHDF1 promotes translation of MAGED1 mRNA in an m6A-dependent manner in pulmonary artery smooth muscle cells (PASMCs); this process is absent in METTL3-deficient PASMCs. YTHDF1 deletion ameliorates PASMC proliferation, phenotype switch, and pulmonary hypertension in vivo.","method":"m6A RIP-seq, YTHDF1 RIP, YTHDF1 KO mouse (pulmonary), METTL3-deficient PASMCs, MAGED1 KO mouse (hemodynamic phenotyping)","journal":"American Journal of Respiratory and Critical Care Medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP-seq plus two KO models with functional hemodynamic phenotyping; single lab","pmids":["33465322"],"is_preprint":false},{"year":2021,"finding":"HIF-1α transcriptionally induces YTHDF1 expression by binding directly to the YTHDF1 promoter under hypoxia. YTHDF1 then promotes translation of ATG2A and ATG14 mRNAs via binding m6A-modified sites, facilitating hypoxia-induced autophagy and hepatocellular carcinoma malignancy.","method":"ChIP, luciferase reporter, MeRIP-seq, proteomics, polysome profiling, YTHDF1 KO/overexpression HCC models including PDX and organoids","journal":"Signal Transduction and Targeted Therapy","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP + luciferase reporter for upstream regulation + MeRIP-seq + polysome profiling for translational mechanism + multiple in vivo models","pmids":["33619246"],"is_preprint":false},{"year":2021,"finding":"YTHDF1 promotes mRNA degradation via interaction with AGO2 through its YTH domain, recruiting AGO2 to P-bodies; YTHDF1 undergoes liquid-liquid phase separation (LLPS) in vitro and in vivo and is critical for P-body formation. Deletion of YTHDF1 prolongs mRNA half-lives, converts P-bodies from liquid to gel/solid state, and impairs miRNA-mediated mRNA degradation.","method":"CRISPR KO of YTHDF1/METTL14, 4SU-TT-seq for mRNA half-lives, Co-IP domain mapping (YTH × AGO2), immunofluorescence co-localization, in vitro and in vivo LLPS assays, FRAP","journal":"Cell Proliferation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP domain mapping + LLPS reconstitution + FRAP + transcriptome-wide mRNA stability; single lab","pmids":["34821414"],"is_preprint":false},{"year":2021,"finding":"YTHDF1 silencing inhibits Wnt/β-catenin pathway activity in colorectal cancer cells, and YTHDF1 promotes tumorigenicity and cancer stem cell-like activity.","method":"YTHDF1 knockdown, in vitro tumorigenicity assays, xenograft models, Wnt/β-catenin pathway reporters","journal":"Frontiers in Oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — KD with pathway reporter; no direct identification of m6A target mediating Wnt signaling; single lab single method","pmids":["31131257"],"is_preprint":false},{"year":2021,"finding":"YTHDF1 promotes translation of cyclin E2 in an m6A-dependent manner in AML cells; structure-based virtual screening identified tegaserod as a YTHDF1 inhibitor that blocks direct binding of YTHDF1 to m6A-modified mRNAs and inhibits cyclin E2 translation, suppressing AML leukemic capacity.","method":"YTHDF1 KD in primary human and mouse AML cells, m6A-seq, RIP, ribosome profiling, structure-based virtual screening, tegaserod binding/functional assays, patient-derived xenograft models","journal":"Cancer Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP + ribosome profiling + drug-target binding validation + PDX in vivo; single lab","pmids":["36634204"],"is_preprint":false},{"year":2021,"finding":"YTHDF1 promotes ARHGEF2 mRNA translation by binding to m6A sites on ARHGEF2 mRNA, leading to enhanced RhoA signaling and colorectal cancer metastasis. Ectopic ARHGEF2 expression restores RhoA signaling and metastatic ability in YTHDF1-KO cells.","method":"Ythdf1 KO mouse (inflammatory CRC model), integrative multiomics (RNA-seq, MeRIP-seq, YTHDF1 RIP-seq, proteomics), ARHGEF2 rescue experiments, LNP-siRNA in vivo","journal":"Gastroenterology","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mouse model + four orthogonal omics methods + rescue experiments + in vivo therapeutic validation","pmids":["34968454"],"is_preprint":false},{"year":2021,"finding":"YTHDF1 modulates E2F8 mRNA stability in a METTL14-dependent manner, promoting DNA damage repair and S-phase entry in breast cancer; YTHDF1 KD sensitizes breast cancer cells to Adriamycin, Cisplatin, and Olaparib.","method":"YTHDF1 KD, METTL14 dependency assay, E2F8 mRNA stability assay, DNA damage repair assays, drug sensitivity assays in vitro and xenograft","journal":"Cell Death & Disease","confidence":"Low","confidence_rationale":"Tier 3 / Weak — mRNA stability assay with METTL14 dependency; limited mechanistic follow-up on m6A reading vs stability; single lab","pmids":["35279688"],"is_preprint":false},{"year":2022,"finding":"YTHDF1 promotes translation of p65/RelA mRNA via m6A binding in colorectal cancer cells, leading to upregulation of CXCL1, which drives MDSC migration via CXCL1-CXCR2 axis, thereby suppressing cytotoxic CD8+ T cells in the tumor microenvironment.","method":"Integrated MeRIP-seq, RNA-seq, Ribo-seq; syngeneic tumor models; Ythdf1 knockin mice; scRNA-seq; CRISPR KO; VNP-siRNA delivery","journal":"Gut","confidence":"High","confidence_rationale":"Tier 2 / Strong — Ribo-seq + MeRIP-seq + multiple in vivo syngeneic and knockin models + scRNA-seq validation","pmids":["36717220"],"is_preprint":false},{"year":2022,"finding":"YTHDF1 promotes translation of FOXM1 mRNA through m6A recognition in breast cancer, accelerating the translation process; FOXM1 overexpression partially rescues the tumor-suppressing effects of YTHDF1 silencing.","method":"RIP, m6A-IP, CLIP, polysome profiling, Co-IP (YTHDF1-FOXM1 protein interaction), YTHDF1 KD + FOXM1 rescue in breast cancer cells","journal":"Cell & Bioscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP + CLIP + polysome profiling + Co-IP; single lab","pmids":["35197112"],"is_preprint":false},{"year":2022,"finding":"YTHDF1 promotes translation of NLRP3 mRNA in macrophages during bacterial infection, facilitating pro-inflammatory IL-1β production; in vivo knockdown of YTHDF1 improves survival in a mouse sepsis model.","method":"YTHDF1 overexpression/KD, NLRP3 western blot, IL-1β ELISA, in vivo YTHDF1 KD in mouse sepsis model","journal":"Biochemical and Biophysical Research Communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — overexpression assay + in vivo KD; no direct m6A site mapping on NLRP3 mRNA reported in this abstract; single lab","pmids":["35649302"],"is_preprint":false},{"year":2022,"finding":"YTHDF1 recognizes m6A modification sites on SOCS3 mRNA and promotes its translation, thereby inhibiting the JAK2/STAT3 pathway and reducing secretion of inflammatory factors in Treponema pallidum-infected macrophages.","method":"RIP-qPCR, m6A-IP, YTHDF1 KD, METTL3 Co-IP, SOCS3 translation assay, JAK2/STAT3 pathway analysis in THP-1 macrophages","journal":"Frontiers in Immunology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — RIP-qPCR + translational readout; single lab, single infection context","pmids":["35444649"],"is_preprint":false},{"year":2022,"finding":"YTHDF1 promotes translation of WWP1 mRNA in an m6A-dependent manner; increased WWP1 then promotes NLRP3 ubiquitination and degradation, inhibiting caspase-1-dependent pyroptosis and ameliorating sepsis.","method":"RIP-RT-qPCR, dual luciferase reporter, meRIP, ubiquitination assay, YTHDF1/WWP1 overexpression in LPS+ATP RAW264.7 cells and CLP mouse model","journal":"Cell Death Discovery","confidence":"Low","confidence_rationale":"Tier 3 / Weak — RIP + luciferase reporter for m6A-YTHDF1-WWP1 link; NLRP3 ubiquitination assay; single lab","pmids":["35508474"],"is_preprint":false},{"year":2022,"finding":"YTHDF1 upregulates expression of the Wnt receptor FZD7 to promote gastric cancer; VNPs delivering YTHDF1-siRNA suppress cancer progression and metastasis by hampering FZD7 translation and inactivating Wnt/β-catenin pathway in an m6A-dependent manner.","method":"Engineered sEV-siYTHDF1 delivery, FZD7 western blot, Wnt/β-catenin reporter, xenograft models","journal":"Advanced Materials","confidence":"Low","confidence_rationale":"Tier 3 / Weak — therapeutic delivery study; mechanistic claim replicates PMID 32788173 without new mechanistic validation","pmids":["36484103"],"is_preprint":false},{"year":2022,"finding":"YTHDF1 regulates translation of MAGED1 via m6A modification in PASMCs; this is absent in METTL3-deficient PASMCs, confirming m6A-dependency. YTHDF1 also promotes Foxm1 translation in an m6A-dependent manner to drive hypoxia-induced PASMC proliferation.","method":"RNA pull-down, RIP, protein synthesis assay, si-YTHDF1 in hypoxic PASMCs, adenovirus si-YTHDF1 in vivo PAH mouse model, RVSP measurement","journal":"Experimental Cell Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA pull-down + RIP + in vivo PAH model with hemodynamic readout; single lab","pmids":["36736607"],"is_preprint":false},{"year":2022,"finding":"YTHDF1 undergoes liquid-liquid phase separation (LLPS) and forms a dimeric complex with CLOCK mRNA in an m6A-dependent manner, shuttling to stress granules upon allergen challenge; YTHDF1 augments CLOCK translation to activate the NLRP3 inflammasome and IL-1β secretion in airway epithelial cells.","method":"YTHDF1 LLPS assays, co-immunoprecipitation, m6A-RIP, CLOCK translational reporter, NLRP3 inflammasome activation assays, in vivo allergic airway mouse model, CLOCK genetic deletion rescue","journal":"Cell Reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — LLPS characterization + RIP + translational reporter + genetic rescue (CLOCK KO); single lab","pmids":["38492220"],"is_preprint":false},{"year":2023,"finding":"Tumor-intrinsic YTHDF1 promotes translation of lysosomal genes, enhancing lysosomal proteolysis of MHC-I and antigens; YTHDF1 deficiency inhibits this lysosomal pathway, restores MHC-I surface expression, and thereby reverses immune evasion, converting cold tumors into immunologically hot tumors.","method":"YTHDF1 KO in tumor cells, lysosomal gene expression analysis, MHC-I surface staining, lysosomal protease assays, exosome-mediated CRISPR/Cas9 delivery in vivo, immune infiltration profiling","journal":"Nature Communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO + lysosomal functional assays + in vivo exosome-CRISPR delivery; mechanistically extends PMID 30728504; single lab","pmids":["36650153"],"is_preprint":false},{"year":2023,"finding":"YTHDF1 binds m6A-modified EZH2 mRNA and promotes EZH2 translation; elevated EZH2 then increases IL-6 secretion, which recruits and activates MDSCs to cause CD8+ T-cell dysfunction in NASH-HCC. LNP-encapsulated siYTHDF1 combined with anti-PD-1 shows synergistic antitumor efficacy.","method":"RNA-seq, m6A-seq, YTHDF1 RIP-seq, proteomics, ribosome profiling; liver-specific Ythdf1 knockin mice; scRNA-seq; flow cytometry; LNP-siRNA in vivo","journal":"Journal of Hepatology","confidence":"High","confidence_rationale":"Tier 2 / Strong — ribosome profiling + MeRIP-seq + RIP-seq + proteomics + in vivo knockin model + scRNA-seq; multiple orthogonal methods","pmids":["37459919"],"is_preprint":false},{"year":2023,"finding":"FMRP physically interacts with YTHDF1 and sequesters it away from ribosomes, suppressing YTHDF1-driven translation of m6A target mRNAs. Upon neuronal stimulation, FMRP becomes phosphorylated and releases YTHDF1, enabling translation upregulation. A small-molecule YTHDF1 inhibitor reverses FXS developmental defects in an organoid model.","method":"Co-immunoprecipitation (FMRP-YTHDF1), ribosomal co-sedimentation assays, phosphorylation-mimetic/dead FMRP mutants, YTHDF1 small-molecule inhibitor, FXS organoid model","journal":"Molecular Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP + ribosome fractionation + phospho-mutant rescue + organoid pharmacological rescue; multiple orthogonal methods in one study","pmids":["37949069"],"is_preprint":false},{"year":2023,"finding":"YTHDF1 promotes translation of cyclin E2 in AML (also confirmed above) and can be pharmacologically inhibited by tegaserod which blocks YTHDF1-m6A-mRNA interaction. YTHDF1 is enriched in AML leukemia stem cells and is dispensable for normal hematopoiesis.","method":"Structure-based virtual screening, binding competition assay, primary AML cell KD, ribosome profiling, PDX models","journal":"Cancer Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP + ribosome profiling + structure-guided drug inhibition; single lab","pmids":["36634204"],"is_preprint":false},{"year":2023,"finding":"YTHDF1 undergoes LLPS to promote transdifferentiation of spermatogonial stem cells into neural stem cell-like cells; LLPS-mediated YTHDF1 inhibits translation of IκBα/β mRNAs, activating the NF-κB-CCND1 axis. The YTH domain alone promotes IκBα/β translation and inhibits transdifferentiation.","method":"YTHDF1 LLPS characterization in vitro and in vivo, IκBα/β translational reporter assays, YTHDF1 YTH domain overexpression, NF-κB activation assays, transdifferentiation efficiency readout, tau-YTH fusion LLPS rescue","journal":"Cell Reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — LLPS assays + translational reporter + domain-specific rescue; single lab","pmids":["37060562"],"is_preprint":false},{"year":2023,"finding":"m6A-modified circSAV1 forms a ternary complex with YTHDF1 and IREB2 mRNA, facilitating IREB2 translation; elevated IREB2 disrupts iron homeostasis and drives ferroptosis in lung epithelial cells, contributing to COPD progression.","method":"circRNA-seq, YTHDF1 RIP, Co-IP/complex formation assay, IREB2 translation assay, iron homeostasis assays, ferroptosis markers, circSAV1 KD in CS-induced COPD mouse model","journal":"Cell Death and Differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP + ternary complex assay + in vivo COPD model; mechanistic claim well-supported but single lab","pmids":["36828914"],"is_preprint":false},{"year":2023,"finding":"YTHDF1 promotes NOTCH1 mRNA stability and translation by binding m6A-modified NOTCH1 mRNA in liver cancer stem cells, driving HCC stemness and drug resistance; catalytically inactive YTHDF1 mutant abolishes these effects.","method":"RIP-seq, MeRIP-seq, ribosome profiling, RNA-seq; catalytically inactive YTHDF1 mutant; NOTCH1 rescue experiments; patient-derived organoids; LNP-siYTHDF1 in vivo","journal":"Cancer Research","confidence":"High","confidence_rationale":"Tier 2 / Strong — catalytic mutant validation + ribosome profiling + RIP-seq + organoid + in vivo; multiple orthogonal methods","pmids":["38241695"],"is_preprint":false},{"year":2023,"finding":"O-GlcNAcylation of YTHDF1 at Ser196/Ser197/Ser198 (catalyzed by OGT) promotes cytosolic localization of YTHDF1 by enhancing its interaction with exportin Crm1, increasing expression of downstream target c-Myc in colorectal cancer.","method":"OGT Co-IP, chemoproteomic site mapping (Ser196/197/198), O-GlcNAc-deficient AFA mutant construction, nuclear export Crm1 interaction assays, molecular dynamics simulation, xenograft assay","journal":"Journal of Biological Chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — site-specific PTM identification + loss-of-function mutant + Crm1 interaction assay + in vivo xenograft; single lab","pmids":["37086786"],"is_preprint":false},{"year":2024,"finding":"In dendritic cells, IR (ionizing radiation) upregulates YTHDF1 expression via STING/IFN-I signaling. YTHDF1 in turn promotes translation of lysosomal cathepsins, which degrade STING, thereby reducing IFN-I production—creating a negative feedback loop. YTHDF1-deficient DCs show enhanced cross-priming and antitumor effects of radiotherapy.","method":"DC-specific Ythdf1 KO, STING/IFN-I pathway analysis, lysosomal cathepsin activity, STING degradation assay, murine tumor models, YTHDF1-deletion DC vaccine prototype","journal":"Journal of Clinical Investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — DC-specific KO + mechanistic STING degradation assay + multiple murine cancer models; single lab but rigorous","pmids":["39325547"],"is_preprint":false},{"year":2024,"finding":"YTHDF1 binds m6A-modified PIEZO2 mRNA at site peak_26355 and promotes PIEZO2 translation; this drives cardiac fibroblast autophagy and cardiac fibrosis. Fibroblast-specific AAV9-shYTHDF1 reduces Piezo2 expression and ameliorates cardiac fibrosis.","method":"MeRIP-seq, site-specific m6A mapping (peak_26355), RIP, YTHDF1 KD rescue with PIEZO2 re-expression, AAV9-shYTHDF1 in ISO/Ang-II/TAC mouse models, single-cell sequencing","journal":"Cardiovascular Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MeRIP site mapping + RIP + rescue experiment + in vivo AAV; single lab","pmids":["39498803"],"is_preprint":false},{"year":2024,"finding":"USP5 interacts with and stabilizes YTHDF1 by removing K11-linked polyubiquitination; mTORC1 phosphorylates USP5, promoting its dimerization and protection of YTHDF1 from degradation. Conversely, CUL7-FBXW8 E3 ligase promotes YTHDF1 degradation.","method":"USP5-YTHDF1 Co-IP, ubiquitin linkage assays (K11-specific), mTORC1/USP5 phosphorylation assay, USP5 dimerization assay, CUL7-FBXW8 E3 ligase assay, YTHDF1 protein stability assays","journal":"Nature Communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP + specific ubiquitin linkage typing + kinase-substrate validation; single lab","pmids":["39900921"],"is_preprint":false},{"year":2024,"finding":"YTHDF1 promotes EGFR mRNA translation by binding m6A sites in the 3'-UTR of EGFR transcript in intrahepatic cholangiocarcinoma cells; overexpression of wild-type but not m6A reader domain mutant YTHDF1 enhances tumor growth, confirming m6A reading is required.","method":"m6A-seq, RIP-seq, RNA-seq, YTHDF1 overexpression vs. m6A reader domain mutant, orthotopic ICC mouse model (AKT/YAP hydrodynamic transfection)","journal":"Journal of Gastroenterology and Hepatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reader domain mutant + RIP-seq + in vivo orthotopic model; single lab","pmids":["35233828"],"is_preprint":false},{"year":2024,"finding":"HIF-1α directly binds the YTHDF1 promoter and transcriptionally induces YTHDF1 expression in nucleus pulposus cells; YTHDF1 then promotes translation of SLC7A11 mRNA via m6A binding, leading to GPX4 upregulation and suppression of ferroptosis in NPCs.","method":"Luciferase reporter, ChIP, polysome profiling, MeRIP, YTHDF1 KD/OE in NPC cells, in vivo disc degeneration model","journal":"Aging Cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP + luciferase for HIF-1α→YTHDF1 link; polysome profiling for SLC7A11 translation; in vivo; single lab","pmids":["38783692"],"is_preprint":false},{"year":2024,"finding":"NAT10 undergoes liquid-liquid phase separation via its C-terminal IDR, interacts with splicing factor SRSF2, and acetylates SRSF2; acetylated SRSF2 binds the YTHDF1 pre-mRNA and promotes exon 4 skipping, producing a short YTHDF1 transcript that stimulates gastric cancer cell proliferation and migration.","method":"NAT10 LLPS characterization, Co-IP (NAT10-SRSF2), acetyltransferase assay, RNA-binding assay of SRSF2 on YTHDF1 pre-mRNA, splicing reporter, patient gastric cancer samples","journal":"Cancer Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — LLPS + Co-IP + acetyltransferase assay + splicing reporter; single lab","pmids":["39024555"],"is_preprint":false},{"year":2024,"finding":"YTHDF1 binds to m6A-modified RUVBL1 and RUVBL2 mRNAs to promote their translation initiation; RUVBL1/2 reciprocally interact with YTHDF1 at 40S translation initiation complexes, forming a positive feedforward circuit that accelerates oncogenic translation. RUVBL1/2 depletion stalls YTHDF1-driven translation of MAPK, RAS, and PI3K-AKT targets.","method":"CRISPR screen, Co-IP + mass spectrometry (RUVBL1/2 at 40S complexes), ribosome sequencing, RIP for m6A-modified RUVBL1/2 mRNA, patient-derived organoids, xenograft, CB6644 pharmacological inhibition","journal":"Cancer Research","confidence":"High","confidence_rationale":"Tier 2 / Strong — CRISPR screen + Co-IP/MS at ribosome + ribosome sequencing + pharmacological rescue + organoid/in vivo; multiple orthogonal methods","pmids":["38900944"],"is_preprint":false},{"year":2024,"finding":"SFTSV virulence factor NSs induces lactylation of YTHDF1 and promotes YTHDF1 degradation, thereby reducing YTHDF1-mediated destabilization of m6A-modified SFTSV mRNAs and facilitating viral replication. YTHDF1 normally binds m6A sites on SFTSV RNA, decreasing viral RNA stability and translation.","method":"MeRIP-seq on SFTSV RNA, YTHDF1 RIP on SFTSV RNA, lactylation assay of YTHDF1, YTHDF1 stability assay after NSs expression, viral replication assays","journal":"EMBO Reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MeRIP-seq + RIP + PTM (lactylation) assay + viral replication readout; single lab","pmids":["39496835"],"is_preprint":false},{"year":2024,"finding":"YTHDF1 binds to m6A-modified Caveolin 1 (Cav1) mRNA in cardiomyocytes and promotes its translation; cardiac-restricted YTHDF1 deletion leads to reduced Cav1 expression, impaired membrane raft proteins, and downstream ERK signaling dysregulation, resulting in cardiac hypertrophy, fibrosis, and dysfunction.","method":"Cardiac-restricted Ythdf1 KO mouse (newly generated), mass spectrometry, m6A-RIP on Cav1 mRNA, Cav1 translational assay, ERK signaling analysis","journal":"Journal of Molecular and Cellular Cardiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO + MS identification + RIP + signaling pathway analysis; single lab","pmids":["38768805"],"is_preprint":false},{"year":2024,"finding":"YTHDF1 promotes translation of EZH2 and CDH11 by reading m6A-enriched sites of their transcripts in breast cancer cells, facilitating osteolytic bone metastasis. AAV-delivered shYTHDF1 suppresses bone metastatic formation in intratibial injection models.","method":"RNA-seq, MeRIP-seq, RIP-seq, molecular biology validation, YTHDF1 KD + EZH2/CDH11 rescue, AAV-shYTHDF1 in vivo model","journal":"Cancer Letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MeRIP-seq + RIP-seq + rescue experiments + in vivo AAV; single lab","pmids":["38871245"],"is_preprint":false},{"year":2024,"finding":"DHX36 helicase binding induces structural remodeling of 3'UTR regions of mRNAs, increasing accessibility at m6A sites and facilitating YTHDF1 binding, which leads to decreased mRNA abundance (degradation).","method":"Transcriptome-wide RNA structure probing, YTHDF1 RIP, DHX36 KD, correlation of DHX36 binding sites with m6A and YTHDF1 binding, mRNA abundance analysis","journal":"Nature Communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transcriptome-wide structural probing + RIP + KD; mechanistic link proposed and supported by correlative omics; single lab","pmids":["39543097"],"is_preprint":false},{"year":2024,"finding":"YTHDF1 interacts with eukaryotic translation initiation factor eIF5B (identified by Co-IP + mass spectrometry), and this complex promotes PD-L1 mRNA translation; additionally, methionine-driven YTHDF1 upregulation promotes degradation of RIG-I mRNA, inhibiting the RIG-I/MAVS IFN-I pathway to suppress tumor immunotherapy.","method":"Co-IP + mass spectrometry (YTHDF1–eIF5B), PD-L1 translational reporter, RIG-I mRNA stability assay, YTHDF1 RNA-seq, point mutations, MB49 mouse tumor models, single-cell RNA-seq","journal":"Cell Death and Differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP/MS identification of eIF5B + translational reporter + in vivo models; single lab","pmids":["39672819"],"is_preprint":false},{"year":2024,"finding":"YTHDF1 promotes translation of HSPH1 in an m6A-dependent manner in MNU-induced gastric carcinogenesis; RIP-qPCR confirms HSPH1 as a direct YTHDF1 target, and HSPH1 KD impairs malignant potential of transformed cells.","method":"RNA-seq, RNA immunoprecipitation (RIP-qPCR), proteomics, YTHDF1 KD, HSPH1 KD, long-term MNU transformation model","journal":"Cell Proliferation","confidence":"Low","confidence_rationale":"Tier 3 / Weak — RIP-qPCR + KD; no m6A site mutation or polysome profiling; single lab","pmids":["38444279"],"is_preprint":false},{"year":2024,"finding":"WTAP methylates NLRP3 mRNA at m6A sites and YTHDF1 YTH domain directly binds NLRP3 mRNA to promote NLRP3 protein translation after TBI; YTHDF1 mutation or silencing suppresses NLRP3 translation, inhibits caspase-1 activation, and decreases IL-1β, improving neuronal injury outcomes.","method":"Conditional WTAP KO (Camk2a-Cre), pAAV-shYTHDF1, RIP (YTH domain binding to NLRP3 mRNA), western blot for NLRP3, caspase-1, IL-1β in TBI mouse model","journal":"International Journal of Surgery","confidence":"Low","confidence_rationale":"Tier 3 / Weak — RIP + KO phenotype; YTH domain binding confirmed but no m6A site mutagenesis; single lab","pmids":["38874470"],"is_preprint":false}],"current_model":"YTHDF1 is an m6A reader protein that, in the cytoplasm, primarily promotes translation of m6A-modified target mRNAs by recruiting translation initiation factors and ribosomal proteins; it also undergoes liquid-liquid phase separation to form P-bodies and stress granules where it can mediate mRNA degradation through AGO2 recruitment and RNA decapping complexes (ZAP/DDX17/DCP2). Its translational activity is regulated by phosphorylation of its binding partner FMRP (releasing YTHDF1 to ribosomes upon neuronal stimulation), by O-GlcNAcylation (controlling cytoplasmic localization via Crm1), and by ubiquitination (USP5 stabilizes, CUL7-FBXW8 degrades YTHDF1). Transcriptionally, YTHDF1 is induced by HIF-1α under hypoxia. Through context-dependent translation of diverse target mRNAs—including lysosomal cathepsins (immune evasion in DCs), FZD7/TCF4 (Wnt signaling), ARHGEF2 (RhoA), EZH2 (epigenetics/IL-6), cyclin E2/CDK2/CDK4 (cell cycle), NOTCH1, ATG2A/ATG14 (autophagy), TRAF6/p65 (NF-κB/inflammation), and MAGED1/Foxm1/Cav1 (vascular and cardiac biology)—YTHDF1 occupies a central post-transcriptional regulatory node controlling cell proliferation, neural plasticity, antitumor immunity, and organ homeostasis."},"narrative":{"mechanistic_narrative":"YTHDF1 is a cytoplasmic N6-methyladenosine (m6A) reader that occupies a central post-transcriptional node, predominantly enhancing the translation of m6A-modified target mRNAs in processes spanning synaptic plasticity, axon guidance, antitumor immunity, and tissue homeostasis [PMID:30401835, PMID:30843071, PMID:30728504]. In neurons it binds m6A-marked transcripts and drives stimulus-dependent translation required for hippocampal learning and memory and for Robo3.1-dependent commissural axon guidance [PMID:30401835, PMID:30843071]. Across cancers and other contexts it promotes translation of a broad set of targets—including cell-cycle regulators (CDK2/CDK4/cyclin D1, cyclin E2), Wnt effectors (FZD7, TCF7L2/TCF4), EZH2, NOTCH1, autophagy factors (ATG2A/ATG14), and NF-κB components (p65, TRAF6)—thereby controlling proliferation, stemness, autophagy, and inflammation [PMID:31653849, PMID:32788173, PMID:32064749, PMID:36634204, PMID:37459919, PMID:38241695, PMID:33619246, PMID:36717220, PMID:33999206]. Mechanistically, YTHDF1 acts at translation initiation: it engages eIF3C and eIF5B and forms a feed-forward circuit with RUVBL1/2 at the 40S complex to accelerate oncogenic translation [PMID:31996915, PMID:39672819, PMID:38900944]. Beyond translation, YTHDF1 undergoes liquid-liquid phase separation, is essential for P-body integrity, and recruits AGO2 through its YTH domain to mediate miRNA-dependent mRNA decay; it also assembles decapping/decay complexes (ZAP/DDX17/DCP2) to degrade viral m6A transcripts [PMID:34821414, PMID:33605073]. YTHDF1 activity is tightly regulated: FMRP sequesters it from ribosomes until neuronal-stimulation-triggered phosphorylation releases it, O-GlcNAcylation at Ser196/197/198 controls Crm1-dependent cytoplasmic localization, and its protein stability is balanced by USP5 (stabilizing via K11-deubiquitination) and the CUL7-FBXW8 E3 ligase (degradation) [PMID:37949069, PMID:37086786, PMID:39900921]. Upstream, HIF-1α transcriptionally induces YTHDF1 under hypoxia to drive autophagy and ferroptosis-resistance programs [PMID:33619246, PMID:38783692].","teleology":[{"year":2018,"claim":"Established that YTHDF1 is a functional m6A reader in vivo by showing it drives stimulus-dependent translation of neuronal mRNAs required for synaptic plasticity and memory, settling whether m6A reading has physiological consequences.","evidence":"Ythdf1 knockout and hippocampal rescue, RIP-seq, nascent protein labeling, and tether reporter assays in mouse neurons","pmids":["30401835"],"confidence":"High","gaps":["Did not resolve the initiation-factor machinery YTHDF1 recruits","Translation enhancement mechanism at the molecular level not defined"]},{"year":2019,"claim":"Extended YTHDF1 translational control to antitumor immunity and neural development, showing it tunes cathepsin levels to suppress antigen cross-presentation and drives Robo3.1 for axon guidance.","evidence":"Ythdf1 KO mice, syngeneic tumor and CD8+ priming assays, cathepsin inhibitor rescue, plus RIP and m6A-site mutation in spinal commissural neurons","pmids":["30728504","30843071"],"confidence":"High","gaps":["How target selectivity among m6A transcripts is achieved was not defined","Direct lysosomal-gene m6A site mapping limited"]},{"year":2020,"claim":"Defined YTHDF1 as a pro-tumorigenic translational driver across multiple cancers by identifying direct targets including EIF3C, FZD7/Wnt effectors, and TFRC, linking m6A reading to global translation output and oncogenic signaling.","evidence":"CLIP-seq, MeRIP-seq, ribosome profiling, RIP, KO/overexpression in ovarian, gastric, intestinal, and squamous cancers","pmids":["31996915","32788173","32064749","33204330","31653849"],"confidence":"High","gaps":["Some pathway placements (Keap1-Nrf2) rest on single labs","Whether YTHDF1 directly contacts initiation factors at these targets not always shown"]},{"year":2021,"claim":"Revealed that YTHDF1 also mediates mRNA degradation and phase separation, recruiting AGO2 via its YTH domain to build P-bodies and assembling decapping complexes to clear viral m6A RNA—expanding its role beyond translational enhancement.","evidence":"CRISPR KO with 4SU-TT-seq half-life measurement, YTH×AGO2 Co-IP domain mapping, FRAP/LLPS reconstitution, and Co-IP of ZAP/DDX17/DCP2 in EBV-infected cells","pmids":["34821414","33605073"],"confidence":"Medium","gaps":["What dictates the translation-versus-decay decision is unresolved","LLPS and decay characterized in single labs"]},{"year":2021,"claim":"Placed YTHDF1 downstream of hypoxia signaling and within feed-forward circuits by showing HIF-1α transcriptionally induces it and that it amplifies Wnt and autophagy programs through ATG2A/ATG14 and TCF7L2.","evidence":"ChIP and luciferase reporters for HIF-1α binding, MeRIP-seq, polysome profiling, KO mouse intestinal and HCC models","pmids":["33619246","32064749"],"confidence":"High","gaps":["Generality of the HIF-1α→YTHDF1 axis across tissues not fully tested"]},{"year":2022,"claim":"Connected YTHDF1 translational control to the tumor immune microenvironment and inflammasome biology, showing it drives p65/CXCL1-mediated MDSC recruitment and modulates NLRP3/IL-1β through several target mRNAs.","evidence":"Integrated MeRIP-seq/Ribo-seq, Ythdf1 knockin mice, scRNA-seq, in vivo siRNA delivery, plus inflammasome and reporter assays","pmids":["36717220","35649302","35508474","35444649"],"confidence":"Medium","gaps":["Several inflammasome links lack direct m6A site mapping","Context-dependence of pro- versus anti-inflammatory output unresolved"]},{"year":2023,"claim":"Uncovered the regulatory logic governing YTHDF1 activity—FMRP sequestration relieved by phosphorylation, O-GlcNAcylation controlling Crm1-dependent localization—and demonstrated phase-separation-dependent translational repression of IκB in transdifferentiation.","evidence":"FMRP-YTHDF1 Co-IP with ribosome co-sedimentation and phospho-mutant rescue, OGT chemoproteomic site mapping with Crm1 assays, and YTH-domain LLPS reporter assays","pmids":["37949069","37086786","37060562"],"confidence":"High","gaps":["How phosphorylation, O-GlcNAcylation, and LLPS integrate is not defined","Stoichiometry of FMRP-YTHDF1 regulation in non-neuronal cells unknown"]},{"year":2023,"claim":"Solidified YTHDF1 as an immunotherapeutic target by showing tumor-intrinsic YTHDF1 drives lysosomal MHC-I degradation and EZH2/IL-6-mediated CD8+ T-cell dysfunction, with siYTHDF1 synergizing with anti-PD-1.","evidence":"Tumor-cell KO with lysosomal/MHC-I assays, ribosome profiling, RIP-seq, liver-specific knockin mice, scRNA-seq, and LNP-siRNA combinations","pmids":["36650153","37459919","38241695"],"confidence":"High","gaps":["Relative contribution of translational versus stability effects on NOTCH1 not fully separated"]},{"year":2024,"claim":"Mapped the translation-initiation machinery and stability control underlying YTHDF1 function, identifying eIF5B and a RUVBL1/2 40S feed-forward circuit, and defining USP5/CUL7-FBXW8 control of YTHDF1 protein levels.","evidence":"Co-IP/MS at the 40S complex, CRISPR screen, ribosome sequencing, pharmacological inhibition, and ubiquitin-linkage and kinase-substrate assays","pmids":["38900944","39672819","39900921"],"confidence":"High","gaps":["Structural basis of YTHDF1 engagement with the initiation complex unresolved","Whether eIF5B and RUVBL1/2 act on overlapping target sets unknown"]},{"year":2024,"claim":"Broadened YTHDF1's organ-homeostasis roles and revealed additional layers of regulation, including PIEZO2/Cav1 in cardiac biology, structural remodeling by DHX36 enabling decay, NAT10/SRSF2-driven splicing of YTHDF1, and viral lactylation-driven degradation.","evidence":"Conditional cardiac KO, MeRIP site mapping, transcriptome-wide structure probing, splicing reporters, and PTM/viral-replication assays","pmids":["39498803","38768805","39543097","39024555","39496835"],"confidence":"Medium","gaps":["DHX36-m6A-YTHDF1 decay link is correlative","Several tissue phenotypes rest on single labs"]},{"year":null,"claim":"It remains unresolved what molecular switch directs YTHDF1 between translational enhancement, mRNA decay, and phase-separation-mediated repression on a given transcript, and how target selectivity among the thousands of m6A-marked mRNAs is encoded.","evidence":"Not addressed by the available corpus","pmids":[],"confidence":"Medium","gaps":["No unifying model integrating translation, decay, and LLPS outputs","No structural model of YTHDF1 at the initiation complex","Determinants of context-specific target selection unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,2,4,13,47]},{"term_id":"GO:0045182","term_label":"translation regulator activity","supporting_discovery_ids":[0,4,40,45]},{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[13,9,44]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[33,13]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[33]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,4,40]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[13,44]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[1,18,27,34]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,6,16,30]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[3,15]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[12,35]}],"complexes":["P-body","stress granule","40S translation initiation complex"],"partners":["FMRP","AGO2","EIF3C","EIF5B","RUVBL1","RUVBL2","USP5","CRM1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9BYJ9","full_name":"YTH domain-containing family protein 1","aliases":["Dermatomyositis associated with cancer putative autoantigen 1","DACA-1"],"length_aa":559,"mass_kda":60.9,"function":"Specifically recognizes and binds N6-methyladenosine (m6A)-containing mRNAs, and regulates their stability (PubMed:24284625, PubMed:26318451, PubMed:32492408, PubMed:39900921). 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:24284625, PubMed:32492408). Acts as a regulator of mRNA stability by promoting degradation of m6A-containing mRNAs via interaction with the CCR4-NOT complex (PubMed:32492408). The YTHDF paralogs (YTHDF1, YTHDF2 and YTHDF3) shares m6A-containing mRNAs targets and act redundantly to mediate mRNA degradation and cellular differentiation (PubMed:28106072, PubMed:32492408). Required to facilitate learning and memory formation in the hippocampus by binding to m6A-containing neuronal mRNAs (By similarity). Acts as a regulator of axon guidance by binding to m6A-containing ROBO3 transcripts (By similarity). Acts as a negative regulator of antigen cross-presentation in myeloid dendritic cells (By similarity). In the context of tumorigenesis, negative regulation of antigen cross-presentation limits the anti-tumor response by reducing efficiency of tumor-antigen cross-presentation (By similarity). Promotes formation of phase-separated membraneless compartments, such as P-bodies or stress granules, by undergoing liquid-liquid phase separation upon binding to mRNAs containing multiple m6A-modified residues: polymethylated mRNAs act as a multivalent scaffold for the binding of YTHDF proteins, juxtaposing their disordered regions and thereby leading to phase separation (PubMed:31292544, PubMed:31388144, PubMed:32451507). The resulting mRNA-YTHDF complexes then partition into different endogenous phase-separated membraneless compartments, such as P-bodies, stress granules or neuronal RNA granules (PubMed:31292544)","subcellular_location":"Cytoplasm; Cytoplasm, P-body; Cytoplasm, Stress granule","url":"https://www.uniprot.org/uniprotkb/Q9BYJ9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/YTHDF1","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"GLUL","stoichiometry":0.2},{"gene":"PSPC1","stoichiometry":0.2},{"gene":"RPS16","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/YTHDF1","total_profiled":1310},"omim":[{"mim_id":"621546","title":"TETRATRICOPEPTIDE REPEAT DOMAIN-CONTAINING PROTEIN 22; TTC22","url":"https://www.omim.org/entry/621546"},{"mim_id":"619296","title":"TESTIS-ASSOCIATED ONCOGENIC LONG NONCODING RNA; THORLNC","url":"https://www.omim.org/entry/619296"},{"mim_id":"618669","title":"YTH N6-METHYLADENOSINE RNA-BINDING PROTEIN 3; YTHDF3","url":"https://www.omim.org/entry/618669"},{"mim_id":"616529","title":"YTH N6-METHYLADENOSINE RNA-BINDING PROTEIN 1; YTHDF1","url":"https://www.omim.org/entry/616529"},{"mim_id":"610640","title":"YTH N6-METHYLADENOSINE RNA-BINDING PROTEIN 2; YTHDF2","url":"https://www.omim.org/entry/610640"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/YTHDF1"},"hgnc":{"alias_symbol":["FLJ20391"],"prev_symbol":["C20orf21"]},"alphafold":{"accession":"Q9BYJ9","domains":[{"cath_id":"3.10.590.10","chopping":"367-381_389-553","consensus_level":"high","plddt":95.9056,"start":367,"end":553}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BYJ9","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BYJ9-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BYJ9-F1-predicted_aligned_error_v6.png","plddt_mean":61.53},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=YTHDF1","jax_strain_url":"https://www.jax.org/strain/search?query=YTHDF1"},"sequence":{"accession":"Q9BYJ9","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9BYJ9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9BYJ9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BYJ9"}},"corpus_meta":[{"pmid":"30728504","id":"PMC_30728504","title":"Anti-tumour immunity controlled through mRNA m6A methylation and YTHDF1 in dendritic cells.","date":"2019","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/30728504","citation_count":801,"is_preprint":false},{"pmid":"31996915","id":"PMC_31996915","title":"The m6A reader YTHDF1 promotes ovarian cancer progression via augmenting EIF3C translation.","date":"2020","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/31996915","citation_count":592,"is_preprint":false},{"pmid":"30401835","id":"PMC_30401835","title":"m6A facilitates hippocampus-dependent learning and memory through YTHDF1.","date":"2018","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/30401835","citation_count":443,"is_preprint":false},{"pmid":"33619246","id":"PMC_33619246","title":"HIF-1α-induced expression of m6A reader YTHDF1 drives hypoxia-induced autophagy and malignancy of hepatocellular carcinoma by promoting ATG2A and ATG14 translation.","date":"2021","source":"Signal transduction and targeted therapy","url":"https://pubmed.ncbi.nlm.nih.gov/33619246","citation_count":336,"is_preprint":false},{"pmid":"31653849","id":"PMC_31653849","title":"YTHDF1 links hypoxia adaptation and non-small cell lung cancer progression.","date":"2019","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/31653849","citation_count":308,"is_preprint":false},{"pmid":"31131257","id":"PMC_31131257","title":"YTHDF1 Regulates Tumorigenicity and Cancer Stem Cell-Like Activity in Human Colorectal Carcinoma.","date":"2019","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/31131257","citation_count":212,"is_preprint":false},{"pmid":"36717220","id":"PMC_36717220","title":"Targeting m6A reader YTHDF1 augments antitumour immunity and boosts anti-PD-1 efficacy in colorectal cancer.","date":"2023","source":"Gut","url":"https://pubmed.ncbi.nlm.nih.gov/36717220","citation_count":208,"is_preprint":false},{"pmid":"32788173","id":"PMC_32788173","title":"YTHDF1 Promotes Gastric 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response to neuronal stimulation in the adult mouse hippocampus; Ythdf1 knockout mice show impaired synaptic transmission, long-term potentiation, and learning/memory defects that are rescued by hippocampal re-expression of YTHDF1. Tether reporter assays in hippocampal neurons confirmed stimulus-dependent translation enhancement.\",\n      \"method\": \"Ythdf1 knockout mouse, hippocampus-specific AAV re-expression rescue, transcriptome-wide YTHDF1 RIP-seq and m6A mapping, nascent protein labeling, tether reporter assays in neurons\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (KO, rescue, RIP-seq, reporter assay, synaptic physiology) in a single rigorous study, replicated in concept by other groups\",\n      \"pmids\": [\"30401835\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In classical dendritic cells, YTHDF1 recognizes m6A-marked transcripts encoding lysosomal proteases (cathepsins) and promotes their translation, thereby increasing lysosomal cathepsin levels; this suppresses cross-presentation of tumor antigens. Ythdf1-deficient DCs show enhanced cross-priming of CD8+ T cells, and inhibition of cathepsins in wild-type DCs phenocopies YTHDF1 loss.\",\n      \"method\": \"Ythdf1 knockout mouse, syngeneic tumor models, polysome profiling / RIP, cathepsin inhibitor rescue experiments, in vivo CD8+ T cell priming assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal genetic and pharmacological validation across multiple methods; independently extended by PMID 36650153\",\n      \"pmids\": [\"30728504\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"YTHDF1 binds m6A-modified Robo3.1 mRNA in spinal commissural neurons and promotes its translation without affecting mRNA levels; mutation of m6A sites in Robo3.1 mRNA or YTHDF1 KD/KO abolishes Robo3.1 protein expression, causing pre-crossing axon guidance defects in the spinal cord.\",\n      \"method\": \"YTHDF1 RIP, m6A site mutation, YTHDF1 KD and KO in vivo (spinal commissural neuron-specific), axon guidance phenotyping\",\n      \"journal\": \"Nucleic Acids Research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (RIP, m6A site mutation, conditional KO, in vivo phenotype rescue) in one study\",\n      \"pmids\": [\"30843071\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"YTHDF1 promotes translation of CDK2, CDK4, and cyclin D1 in NSCLC cells; its depletion inhibits cell proliferation, xenograft tumor formation, and de novo lung adenocarcinoma progression. YTHDF1 depletion also activates the Keap1-Nrf2-AKR1C1 axis, rendering cells cisplatin-resistant.\",\n      \"method\": \"YTHDF1 knockdown/knockout, xenograft models, genetic mouse lung adenocarcinoma model, polysome profiling, western blot for CDK2/CDK4/cyclin D1\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO with defined cellular phenotype and in vivo validation; pathway placement (Keap1-Nrf2) from single lab\",\n      \"pmids\": [\"31653849\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"YTHDF1 binds m6A-modified EIF3C mRNA and enhances its translation in an m6A-dependent manner, promoting overall translational output and ovarian cancer progression. Multi-omics analysis (CLIP-seq, m6A-seq, ribosome profiling, proteomics) confirmed EIF3C as a direct YTHDF1 target.\",\n      \"method\": \"Multi-omics: CLIP-seq, MeRIP-seq, ribosome profiling, proteomics, RIP, western blot, YTHDF1 overexpression/knockdown in ovarian cancer cells and patient samples\",\n      \"journal\": \"Nucleic Acids Research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal genomic methods plus ribosome profiling confirming translational enhancement by YTHDF1\",\n      \"pmids\": [\"31996915\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"YTHDF1 promotes translation of the Wnt receptor FZD7 in an m6A-dependent manner in gastric cancer cells, activating the Wnt/β-catenin pathway and gastric carcinogenesis. Mutant YTHDF1 found in ~7% of gastric cancers shows enhanced FZD7 expression.\",\n      \"method\": \"YTHDF1 KD/overexpression, RIP, m6A-seq, reporter assay, FZD7 western blot, xenograft models\",\n      \"journal\": \"Cancer Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP + translational readout + rescue experiments; single lab\",\n      \"pmids\": [\"32788173\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"YTHDF1 facilitates translation of Wnt signaling effectors including TCF7L2/TCF4 in intestinal stem cells; genetic ablation of Ythdf1 blocks Wnt-driven intestinal regeneration and tumorigenesis, and YTHDF1 expression itself is upregulated by Wnt signaling at the translational level, forming an amplifying feed-forward loop.\",\n      \"method\": \"Ythdf1 knockout mouse, intestinal organoids, RIP-seq, ribosome profiling, intestinal tumor models\",\n      \"journal\": \"EMBO Reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse with defined intestinal phenotype plus RIP-seq and ribosome profiling; single lab\",\n      \"pmids\": [\"32064749\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"YTHDF1 binds m6A-modified TRIM29 mRNA and promotes its translation in cisplatin-resistant ovarian cancer cells, enhancing cancer stem cell-like characteristics; YTHDF1 knockdown suppresses CSC features and is rescued by ectopic TRIM29 expression.\",\n      \"method\": \"RIP, m6A-IP, polysome profiling, YTHDF1 KD, TRIM29 rescue overexpression, CSC sphere assays\",\n      \"journal\": \"Biochimica et Biophysica Acta. Molecular Cell Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — RIP and rescue experiments; single lab, moderate orthogonal validation\",\n      \"pmids\": [\"33011193\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"YTHDF1 binds to the 3'UTR and 5'UTR of TFRC mRNA via its methyltransferase domain and positively regulates translation of m6A-modified TFRC mRNA, enhancing iron metabolism and tumorigenesis in hypopharyngeal squamous cell carcinoma.\",\n      \"method\": \"m6A-seq, RIP-seq, gain/loss-of-function assays, iron metabolism assays, xenograft model\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP-seq plus in vitro and in vivo functional validation; single lab\",\n      \"pmids\": [\"33204330\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In dendritic cells infected with EBV, YTHDF1 recognizes m6A-modified EBV transcripts, promotes RNA decapping, and mediates viral RNA decay by recruiting degradation complexes including ZAP, DDX17, and DCP2; this suppresses EBV replication in an m6A-dependent manner.\",\n      \"method\": \"m6A-seq on EBV transcripts, YTHDF1 RIP, co-immunoprecipitation of YTHDF1 with ZAP/DDX17/DCP2, mRNA half-life assays, YTHDF1 KD in NPC cells\",\n      \"journal\": \"EMBO Reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP plus Co-IP of degradation complexes plus functional viral replication assays; single lab\",\n      \"pmids\": [\"33605073\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"YTHDF1 directs translation of TRAF6 mRNA through recognition of m6A modification near the TRAF6 transcript's stop codon, regulating the intestinal immune response to bacterial infection. The P/Q/N-rich domain of YTHDF1 interacts with the DEAD domain of host factor DDX60, enabling recognition of the Traf6 transcript.\",\n      \"method\": \"Ribo-seq, m6A-seq, RIP-qPCR, domain-mapping Co-IP (P/Q/N-rich domain of YTHDF1 × DEAD domain of DDX60), bacterial infection mouse model\",\n      \"journal\": \"Nucleic Acids Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Ribo-seq + m6A-seq + domain-level Co-IP; single lab\",\n      \"pmids\": [\"33999206\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"YTHDF1 promotes translation of MAGED1 mRNA in an m6A-dependent manner in pulmonary artery smooth muscle cells (PASMCs); this process is absent in METTL3-deficient PASMCs. YTHDF1 deletion ameliorates PASMC proliferation, phenotype switch, and pulmonary hypertension in vivo.\",\n      \"method\": \"m6A RIP-seq, YTHDF1 RIP, YTHDF1 KO mouse (pulmonary), METTL3-deficient PASMCs, MAGED1 KO mouse (hemodynamic phenotyping)\",\n      \"journal\": \"American Journal of Respiratory and Critical Care Medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP-seq plus two KO models with functional hemodynamic phenotyping; single lab\",\n      \"pmids\": [\"33465322\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"HIF-1α transcriptionally induces YTHDF1 expression by binding directly to the YTHDF1 promoter under hypoxia. YTHDF1 then promotes translation of ATG2A and ATG14 mRNAs via binding m6A-modified sites, facilitating hypoxia-induced autophagy and hepatocellular carcinoma malignancy.\",\n      \"method\": \"ChIP, luciferase reporter, MeRIP-seq, proteomics, polysome profiling, YTHDF1 KO/overexpression HCC models including PDX and organoids\",\n      \"journal\": \"Signal Transduction and Targeted Therapy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP + luciferase reporter for upstream regulation + MeRIP-seq + polysome profiling for translational mechanism + multiple in vivo models\",\n      \"pmids\": [\"33619246\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"YTHDF1 promotes mRNA degradation via interaction with AGO2 through its YTH domain, recruiting AGO2 to P-bodies; YTHDF1 undergoes liquid-liquid phase separation (LLPS) in vitro and in vivo and is critical for P-body formation. Deletion of YTHDF1 prolongs mRNA half-lives, converts P-bodies from liquid to gel/solid state, and impairs miRNA-mediated mRNA degradation.\",\n      \"method\": \"CRISPR KO of YTHDF1/METTL14, 4SU-TT-seq for mRNA half-lives, Co-IP domain mapping (YTH × AGO2), immunofluorescence co-localization, in vitro and in vivo LLPS assays, FRAP\",\n      \"journal\": \"Cell Proliferation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP domain mapping + LLPS reconstitution + FRAP + transcriptome-wide mRNA stability; single lab\",\n      \"pmids\": [\"34821414\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"YTHDF1 silencing inhibits Wnt/β-catenin pathway activity in colorectal cancer cells, and YTHDF1 promotes tumorigenicity and cancer stem cell-like activity.\",\n      \"method\": \"YTHDF1 knockdown, in vitro tumorigenicity assays, xenograft models, Wnt/β-catenin pathway reporters\",\n      \"journal\": \"Frontiers in Oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — KD with pathway reporter; no direct identification of m6A target mediating Wnt signaling; single lab single method\",\n      \"pmids\": [\"31131257\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"YTHDF1 promotes translation of cyclin E2 in an m6A-dependent manner in AML cells; structure-based virtual screening identified tegaserod as a YTHDF1 inhibitor that blocks direct binding of YTHDF1 to m6A-modified mRNAs and inhibits cyclin E2 translation, suppressing AML leukemic capacity.\",\n      \"method\": \"YTHDF1 KD in primary human and mouse AML cells, m6A-seq, RIP, ribosome profiling, structure-based virtual screening, tegaserod binding/functional assays, patient-derived xenograft models\",\n      \"journal\": \"Cancer Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP + ribosome profiling + drug-target binding validation + PDX in vivo; single lab\",\n      \"pmids\": [\"36634204\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"YTHDF1 promotes ARHGEF2 mRNA translation by binding to m6A sites on ARHGEF2 mRNA, leading to enhanced RhoA signaling and colorectal cancer metastasis. Ectopic ARHGEF2 expression restores RhoA signaling and metastatic ability in YTHDF1-KO cells.\",\n      \"method\": \"Ythdf1 KO mouse (inflammatory CRC model), integrative multiomics (RNA-seq, MeRIP-seq, YTHDF1 RIP-seq, proteomics), ARHGEF2 rescue experiments, LNP-siRNA in vivo\",\n      \"journal\": \"Gastroenterology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mouse model + four orthogonal omics methods + rescue experiments + in vivo therapeutic validation\",\n      \"pmids\": [\"34968454\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"YTHDF1 modulates E2F8 mRNA stability in a METTL14-dependent manner, promoting DNA damage repair and S-phase entry in breast cancer; YTHDF1 KD sensitizes breast cancer cells to Adriamycin, Cisplatin, and Olaparib.\",\n      \"method\": \"YTHDF1 KD, METTL14 dependency assay, E2F8 mRNA stability assay, DNA damage repair assays, drug sensitivity assays in vitro and xenograft\",\n      \"journal\": \"Cell Death & Disease\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — mRNA stability assay with METTL14 dependency; limited mechanistic follow-up on m6A reading vs stability; single lab\",\n      \"pmids\": [\"35279688\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"YTHDF1 promotes translation of p65/RelA mRNA via m6A binding in colorectal cancer cells, leading to upregulation of CXCL1, which drives MDSC migration via CXCL1-CXCR2 axis, thereby suppressing cytotoxic CD8+ T cells in the tumor microenvironment.\",\n      \"method\": \"Integrated MeRIP-seq, RNA-seq, Ribo-seq; syngeneic tumor models; Ythdf1 knockin mice; scRNA-seq; CRISPR KO; VNP-siRNA delivery\",\n      \"journal\": \"Gut\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Ribo-seq + MeRIP-seq + multiple in vivo syngeneic and knockin models + scRNA-seq validation\",\n      \"pmids\": [\"36717220\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"YTHDF1 promotes translation of FOXM1 mRNA through m6A recognition in breast cancer, accelerating the translation process; FOXM1 overexpression partially rescues the tumor-suppressing effects of YTHDF1 silencing.\",\n      \"method\": \"RIP, m6A-IP, CLIP, polysome profiling, Co-IP (YTHDF1-FOXM1 protein interaction), YTHDF1 KD + FOXM1 rescue in breast cancer cells\",\n      \"journal\": \"Cell & Bioscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP + CLIP + polysome profiling + Co-IP; single lab\",\n      \"pmids\": [\"35197112\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"YTHDF1 promotes translation of NLRP3 mRNA in macrophages during bacterial infection, facilitating pro-inflammatory IL-1β production; in vivo knockdown of YTHDF1 improves survival in a mouse sepsis model.\",\n      \"method\": \"YTHDF1 overexpression/KD, NLRP3 western blot, IL-1β ELISA, in vivo YTHDF1 KD in mouse sepsis model\",\n      \"journal\": \"Biochemical and Biophysical Research Communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — overexpression assay + in vivo KD; no direct m6A site mapping on NLRP3 mRNA reported in this abstract; single lab\",\n      \"pmids\": [\"35649302\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"YTHDF1 recognizes m6A modification sites on SOCS3 mRNA and promotes its translation, thereby inhibiting the JAK2/STAT3 pathway and reducing secretion of inflammatory factors in Treponema pallidum-infected macrophages.\",\n      \"method\": \"RIP-qPCR, m6A-IP, YTHDF1 KD, METTL3 Co-IP, SOCS3 translation assay, JAK2/STAT3 pathway analysis in THP-1 macrophages\",\n      \"journal\": \"Frontiers in Immunology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — RIP-qPCR + translational readout; single lab, single infection context\",\n      \"pmids\": [\"35444649\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"YTHDF1 promotes translation of WWP1 mRNA in an m6A-dependent manner; increased WWP1 then promotes NLRP3 ubiquitination and degradation, inhibiting caspase-1-dependent pyroptosis and ameliorating sepsis.\",\n      \"method\": \"RIP-RT-qPCR, dual luciferase reporter, meRIP, ubiquitination assay, YTHDF1/WWP1 overexpression in LPS+ATP RAW264.7 cells and CLP mouse model\",\n      \"journal\": \"Cell Death Discovery\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — RIP + luciferase reporter for m6A-YTHDF1-WWP1 link; NLRP3 ubiquitination assay; single lab\",\n      \"pmids\": [\"35508474\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"YTHDF1 upregulates expression of the Wnt receptor FZD7 to promote gastric cancer; VNPs delivering YTHDF1-siRNA suppress cancer progression and metastasis by hampering FZD7 translation and inactivating Wnt/β-catenin pathway in an m6A-dependent manner.\",\n      \"method\": \"Engineered sEV-siYTHDF1 delivery, FZD7 western blot, Wnt/β-catenin reporter, xenograft models\",\n      \"journal\": \"Advanced Materials\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — therapeutic delivery study; mechanistic claim replicates PMID 32788173 without new mechanistic validation\",\n      \"pmids\": [\"36484103\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"YTHDF1 regulates translation of MAGED1 via m6A modification in PASMCs; this is absent in METTL3-deficient PASMCs, confirming m6A-dependency. YTHDF1 also promotes Foxm1 translation in an m6A-dependent manner to drive hypoxia-induced PASMC proliferation.\",\n      \"method\": \"RNA pull-down, RIP, protein synthesis assay, si-YTHDF1 in hypoxic PASMCs, adenovirus si-YTHDF1 in vivo PAH mouse model, RVSP measurement\",\n      \"journal\": \"Experimental Cell Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA pull-down + RIP + in vivo PAH model with hemodynamic readout; single lab\",\n      \"pmids\": [\"36736607\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"YTHDF1 undergoes liquid-liquid phase separation (LLPS) and forms a dimeric complex with CLOCK mRNA in an m6A-dependent manner, shuttling to stress granules upon allergen challenge; YTHDF1 augments CLOCK translation to activate the NLRP3 inflammasome and IL-1β secretion in airway epithelial cells.\",\n      \"method\": \"YTHDF1 LLPS assays, co-immunoprecipitation, m6A-RIP, CLOCK translational reporter, NLRP3 inflammasome activation assays, in vivo allergic airway mouse model, CLOCK genetic deletion rescue\",\n      \"journal\": \"Cell Reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — LLPS characterization + RIP + translational reporter + genetic rescue (CLOCK KO); single lab\",\n      \"pmids\": [\"38492220\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Tumor-intrinsic YTHDF1 promotes translation of lysosomal genes, enhancing lysosomal proteolysis of MHC-I and antigens; YTHDF1 deficiency inhibits this lysosomal pathway, restores MHC-I surface expression, and thereby reverses immune evasion, converting cold tumors into immunologically hot tumors.\",\n      \"method\": \"YTHDF1 KO in tumor cells, lysosomal gene expression analysis, MHC-I surface staining, lysosomal protease assays, exosome-mediated CRISPR/Cas9 delivery in vivo, immune infiltration profiling\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO + lysosomal functional assays + in vivo exosome-CRISPR delivery; mechanistically extends PMID 30728504; single lab\",\n      \"pmids\": [\"36650153\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"YTHDF1 binds m6A-modified EZH2 mRNA and promotes EZH2 translation; elevated EZH2 then increases IL-6 secretion, which recruits and activates MDSCs to cause CD8+ T-cell dysfunction in NASH-HCC. LNP-encapsulated siYTHDF1 combined with anti-PD-1 shows synergistic antitumor efficacy.\",\n      \"method\": \"RNA-seq, m6A-seq, YTHDF1 RIP-seq, proteomics, ribosome profiling; liver-specific Ythdf1 knockin mice; scRNA-seq; flow cytometry; LNP-siRNA in vivo\",\n      \"journal\": \"Journal of Hepatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ribosome profiling + MeRIP-seq + RIP-seq + proteomics + in vivo knockin model + scRNA-seq; multiple orthogonal methods\",\n      \"pmids\": [\"37459919\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FMRP physically interacts with YTHDF1 and sequesters it away from ribosomes, suppressing YTHDF1-driven translation of m6A target mRNAs. Upon neuronal stimulation, FMRP becomes phosphorylated and releases YTHDF1, enabling translation upregulation. A small-molecule YTHDF1 inhibitor reverses FXS developmental defects in an organoid model.\",\n      \"method\": \"Co-immunoprecipitation (FMRP-YTHDF1), ribosomal co-sedimentation assays, phosphorylation-mimetic/dead FMRP mutants, YTHDF1 small-molecule inhibitor, FXS organoid model\",\n      \"journal\": \"Molecular Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP + ribosome fractionation + phospho-mutant rescue + organoid pharmacological rescue; multiple orthogonal methods in one study\",\n      \"pmids\": [\"37949069\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"YTHDF1 promotes translation of cyclin E2 in AML (also confirmed above) and can be pharmacologically inhibited by tegaserod which blocks YTHDF1-m6A-mRNA interaction. YTHDF1 is enriched in AML leukemia stem cells and is dispensable for normal hematopoiesis.\",\n      \"method\": \"Structure-based virtual screening, binding competition assay, primary AML cell KD, ribosome profiling, PDX models\",\n      \"journal\": \"Cancer Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP + ribosome profiling + structure-guided drug inhibition; single lab\",\n      \"pmids\": [\"36634204\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"YTHDF1 undergoes LLPS to promote transdifferentiation of spermatogonial stem cells into neural stem cell-like cells; LLPS-mediated YTHDF1 inhibits translation of IκBα/β mRNAs, activating the NF-κB-CCND1 axis. The YTH domain alone promotes IκBα/β translation and inhibits transdifferentiation.\",\n      \"method\": \"YTHDF1 LLPS characterization in vitro and in vivo, IκBα/β translational reporter assays, YTHDF1 YTH domain overexpression, NF-κB activation assays, transdifferentiation efficiency readout, tau-YTH fusion LLPS rescue\",\n      \"journal\": \"Cell Reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — LLPS assays + translational reporter + domain-specific rescue; single lab\",\n      \"pmids\": [\"37060562\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"m6A-modified circSAV1 forms a ternary complex with YTHDF1 and IREB2 mRNA, facilitating IREB2 translation; elevated IREB2 disrupts iron homeostasis and drives ferroptosis in lung epithelial cells, contributing to COPD progression.\",\n      \"method\": \"circRNA-seq, YTHDF1 RIP, Co-IP/complex formation assay, IREB2 translation assay, iron homeostasis assays, ferroptosis markers, circSAV1 KD in CS-induced COPD mouse model\",\n      \"journal\": \"Cell Death and Differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP + ternary complex assay + in vivo COPD model; mechanistic claim well-supported but single lab\",\n      \"pmids\": [\"36828914\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"YTHDF1 promotes NOTCH1 mRNA stability and translation by binding m6A-modified NOTCH1 mRNA in liver cancer stem cells, driving HCC stemness and drug resistance; catalytically inactive YTHDF1 mutant abolishes these effects.\",\n      \"method\": \"RIP-seq, MeRIP-seq, ribosome profiling, RNA-seq; catalytically inactive YTHDF1 mutant; NOTCH1 rescue experiments; patient-derived organoids; LNP-siYTHDF1 in vivo\",\n      \"journal\": \"Cancer Research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — catalytic mutant validation + ribosome profiling + RIP-seq + organoid + in vivo; multiple orthogonal methods\",\n      \"pmids\": [\"38241695\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"O-GlcNAcylation of YTHDF1 at Ser196/Ser197/Ser198 (catalyzed by OGT) promotes cytosolic localization of YTHDF1 by enhancing its interaction with exportin Crm1, increasing expression of downstream target c-Myc in colorectal cancer.\",\n      \"method\": \"OGT Co-IP, chemoproteomic site mapping (Ser196/197/198), O-GlcNAc-deficient AFA mutant construction, nuclear export Crm1 interaction assays, molecular dynamics simulation, xenograft assay\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — site-specific PTM identification + loss-of-function mutant + Crm1 interaction assay + in vivo xenograft; single lab\",\n      \"pmids\": [\"37086786\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In dendritic cells, IR (ionizing radiation) upregulates YTHDF1 expression via STING/IFN-I signaling. YTHDF1 in turn promotes translation of lysosomal cathepsins, which degrade STING, thereby reducing IFN-I production—creating a negative feedback loop. YTHDF1-deficient DCs show enhanced cross-priming and antitumor effects of radiotherapy.\",\n      \"method\": \"DC-specific Ythdf1 KO, STING/IFN-I pathway analysis, lysosomal cathepsin activity, STING degradation assay, murine tumor models, YTHDF1-deletion DC vaccine prototype\",\n      \"journal\": \"Journal of Clinical Investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — DC-specific KO + mechanistic STING degradation assay + multiple murine cancer models; single lab but rigorous\",\n      \"pmids\": [\"39325547\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"YTHDF1 binds m6A-modified PIEZO2 mRNA at site peak_26355 and promotes PIEZO2 translation; this drives cardiac fibroblast autophagy and cardiac fibrosis. Fibroblast-specific AAV9-shYTHDF1 reduces Piezo2 expression and ameliorates cardiac fibrosis.\",\n      \"method\": \"MeRIP-seq, site-specific m6A mapping (peak_26355), RIP, YTHDF1 KD rescue with PIEZO2 re-expression, AAV9-shYTHDF1 in ISO/Ang-II/TAC mouse models, single-cell sequencing\",\n      \"journal\": \"Cardiovascular Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MeRIP site mapping + RIP + rescue experiment + in vivo AAV; single lab\",\n      \"pmids\": [\"39498803\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"USP5 interacts with and stabilizes YTHDF1 by removing K11-linked polyubiquitination; mTORC1 phosphorylates USP5, promoting its dimerization and protection of YTHDF1 from degradation. Conversely, CUL7-FBXW8 E3 ligase promotes YTHDF1 degradation.\",\n      \"method\": \"USP5-YTHDF1 Co-IP, ubiquitin linkage assays (K11-specific), mTORC1/USP5 phosphorylation assay, USP5 dimerization assay, CUL7-FBXW8 E3 ligase assay, YTHDF1 protein stability assays\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP + specific ubiquitin linkage typing + kinase-substrate validation; single lab\",\n      \"pmids\": [\"39900921\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"YTHDF1 promotes EGFR mRNA translation by binding m6A sites in the 3'-UTR of EGFR transcript in intrahepatic cholangiocarcinoma cells; overexpression of wild-type but not m6A reader domain mutant YTHDF1 enhances tumor growth, confirming m6A reading is required.\",\n      \"method\": \"m6A-seq, RIP-seq, RNA-seq, YTHDF1 overexpression vs. m6A reader domain mutant, orthotopic ICC mouse model (AKT/YAP hydrodynamic transfection)\",\n      \"journal\": \"Journal of Gastroenterology and Hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reader domain mutant + RIP-seq + in vivo orthotopic model; single lab\",\n      \"pmids\": [\"35233828\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"HIF-1α directly binds the YTHDF1 promoter and transcriptionally induces YTHDF1 expression in nucleus pulposus cells; YTHDF1 then promotes translation of SLC7A11 mRNA via m6A binding, leading to GPX4 upregulation and suppression of ferroptosis in NPCs.\",\n      \"method\": \"Luciferase reporter, ChIP, polysome profiling, MeRIP, YTHDF1 KD/OE in NPC cells, in vivo disc degeneration model\",\n      \"journal\": \"Aging Cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP + luciferase for HIF-1α→YTHDF1 link; polysome profiling for SLC7A11 translation; in vivo; single lab\",\n      \"pmids\": [\"38783692\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"NAT10 undergoes liquid-liquid phase separation via its C-terminal IDR, interacts with splicing factor SRSF2, and acetylates SRSF2; acetylated SRSF2 binds the YTHDF1 pre-mRNA and promotes exon 4 skipping, producing a short YTHDF1 transcript that stimulates gastric cancer cell proliferation and migration.\",\n      \"method\": \"NAT10 LLPS characterization, Co-IP (NAT10-SRSF2), acetyltransferase assay, RNA-binding assay of SRSF2 on YTHDF1 pre-mRNA, splicing reporter, patient gastric cancer samples\",\n      \"journal\": \"Cancer Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — LLPS + Co-IP + acetyltransferase assay + splicing reporter; single lab\",\n      \"pmids\": [\"39024555\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"YTHDF1 binds to m6A-modified RUVBL1 and RUVBL2 mRNAs to promote their translation initiation; RUVBL1/2 reciprocally interact with YTHDF1 at 40S translation initiation complexes, forming a positive feedforward circuit that accelerates oncogenic translation. RUVBL1/2 depletion stalls YTHDF1-driven translation of MAPK, RAS, and PI3K-AKT targets.\",\n      \"method\": \"CRISPR screen, Co-IP + mass spectrometry (RUVBL1/2 at 40S complexes), ribosome sequencing, RIP for m6A-modified RUVBL1/2 mRNA, patient-derived organoids, xenograft, CB6644 pharmacological inhibition\",\n      \"journal\": \"Cancer Research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CRISPR screen + Co-IP/MS at ribosome + ribosome sequencing + pharmacological rescue + organoid/in vivo; multiple orthogonal methods\",\n      \"pmids\": [\"38900944\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SFTSV virulence factor NSs induces lactylation of YTHDF1 and promotes YTHDF1 degradation, thereby reducing YTHDF1-mediated destabilization of m6A-modified SFTSV mRNAs and facilitating viral replication. YTHDF1 normally binds m6A sites on SFTSV RNA, decreasing viral RNA stability and translation.\",\n      \"method\": \"MeRIP-seq on SFTSV RNA, YTHDF1 RIP on SFTSV RNA, lactylation assay of YTHDF1, YTHDF1 stability assay after NSs expression, viral replication assays\",\n      \"journal\": \"EMBO Reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MeRIP-seq + RIP + PTM (lactylation) assay + viral replication readout; single lab\",\n      \"pmids\": [\"39496835\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"YTHDF1 binds to m6A-modified Caveolin 1 (Cav1) mRNA in cardiomyocytes and promotes its translation; cardiac-restricted YTHDF1 deletion leads to reduced Cav1 expression, impaired membrane raft proteins, and downstream ERK signaling dysregulation, resulting in cardiac hypertrophy, fibrosis, and dysfunction.\",\n      \"method\": \"Cardiac-restricted Ythdf1 KO mouse (newly generated), mass spectrometry, m6A-RIP on Cav1 mRNA, Cav1 translational assay, ERK signaling analysis\",\n      \"journal\": \"Journal of Molecular and Cellular Cardiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO + MS identification + RIP + signaling pathway analysis; single lab\",\n      \"pmids\": [\"38768805\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"YTHDF1 promotes translation of EZH2 and CDH11 by reading m6A-enriched sites of their transcripts in breast cancer cells, facilitating osteolytic bone metastasis. AAV-delivered shYTHDF1 suppresses bone metastatic formation in intratibial injection models.\",\n      \"method\": \"RNA-seq, MeRIP-seq, RIP-seq, molecular biology validation, YTHDF1 KD + EZH2/CDH11 rescue, AAV-shYTHDF1 in vivo model\",\n      \"journal\": \"Cancer Letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MeRIP-seq + RIP-seq + rescue experiments + in vivo AAV; single lab\",\n      \"pmids\": [\"38871245\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"DHX36 helicase binding induces structural remodeling of 3'UTR regions of mRNAs, increasing accessibility at m6A sites and facilitating YTHDF1 binding, which leads to decreased mRNA abundance (degradation).\",\n      \"method\": \"Transcriptome-wide RNA structure probing, YTHDF1 RIP, DHX36 KD, correlation of DHX36 binding sites with m6A and YTHDF1 binding, mRNA abundance analysis\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transcriptome-wide structural probing + RIP + KD; mechanistic link proposed and supported by correlative omics; single lab\",\n      \"pmids\": [\"39543097\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"YTHDF1 interacts with eukaryotic translation initiation factor eIF5B (identified by Co-IP + mass spectrometry), and this complex promotes PD-L1 mRNA translation; additionally, methionine-driven YTHDF1 upregulation promotes degradation of RIG-I mRNA, inhibiting the RIG-I/MAVS IFN-I pathway to suppress tumor immunotherapy.\",\n      \"method\": \"Co-IP + mass spectrometry (YTHDF1–eIF5B), PD-L1 translational reporter, RIG-I mRNA stability assay, YTHDF1 RNA-seq, point mutations, MB49 mouse tumor models, single-cell RNA-seq\",\n      \"journal\": \"Cell Death and Differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP/MS identification of eIF5B + translational reporter + in vivo models; single lab\",\n      \"pmids\": [\"39672819\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"YTHDF1 promotes translation of HSPH1 in an m6A-dependent manner in MNU-induced gastric carcinogenesis; RIP-qPCR confirms HSPH1 as a direct YTHDF1 target, and HSPH1 KD impairs malignant potential of transformed cells.\",\n      \"method\": \"RNA-seq, RNA immunoprecipitation (RIP-qPCR), proteomics, YTHDF1 KD, HSPH1 KD, long-term MNU transformation model\",\n      \"journal\": \"Cell Proliferation\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — RIP-qPCR + KD; no m6A site mutation or polysome profiling; single lab\",\n      \"pmids\": [\"38444279\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"WTAP methylates NLRP3 mRNA at m6A sites and YTHDF1 YTH domain directly binds NLRP3 mRNA to promote NLRP3 protein translation after TBI; YTHDF1 mutation or silencing suppresses NLRP3 translation, inhibits caspase-1 activation, and decreases IL-1β, improving neuronal injury outcomes.\",\n      \"method\": \"Conditional WTAP KO (Camk2a-Cre), pAAV-shYTHDF1, RIP (YTH domain binding to NLRP3 mRNA), western blot for NLRP3, caspase-1, IL-1β in TBI mouse model\",\n      \"journal\": \"International Journal of Surgery\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — RIP + KO phenotype; YTH domain binding confirmed but no m6A site mutagenesis; single lab\",\n      \"pmids\": [\"38874470\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"YTHDF1 is an m6A reader protein that, in the cytoplasm, primarily promotes translation of m6A-modified target mRNAs by recruiting translation initiation factors and ribosomal proteins; it also undergoes liquid-liquid phase separation to form P-bodies and stress granules where it can mediate mRNA degradation through AGO2 recruitment and RNA decapping complexes (ZAP/DDX17/DCP2). Its translational activity is regulated by phosphorylation of its binding partner FMRP (releasing YTHDF1 to ribosomes upon neuronal stimulation), by O-GlcNAcylation (controlling cytoplasmic localization via Crm1), and by ubiquitination (USP5 stabilizes, CUL7-FBXW8 degrades YTHDF1). Transcriptionally, YTHDF1 is induced by HIF-1α under hypoxia. Through context-dependent translation of diverse target mRNAs—including lysosomal cathepsins (immune evasion in DCs), FZD7/TCF4 (Wnt signaling), ARHGEF2 (RhoA), EZH2 (epigenetics/IL-6), cyclin E2/CDK2/CDK4 (cell cycle), NOTCH1, ATG2A/ATG14 (autophagy), TRAF6/p65 (NF-κB/inflammation), and MAGED1/Foxm1/Cav1 (vascular and cardiac biology)—YTHDF1 occupies a central post-transcriptional regulatory node controlling cell proliferation, neural plasticity, antitumor immunity, and organ homeostasis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"YTHDF1 is a cytoplasmic N6-methyladenosine (m6A) reader that occupies a central post-transcriptional node, predominantly enhancing the translation of m6A-modified target mRNAs in processes spanning synaptic plasticity, axon guidance, antitumor immunity, and tissue homeostasis [#0, #2, #1]. In neurons it binds m6A-marked transcripts and drives stimulus-dependent translation required for hippocampal learning and memory and for Robo3.1-dependent commissural axon guidance [#0, #2]. Across cancers and other contexts it promotes translation of a broad set of targets—including cell-cycle regulators (CDK2/CDK4/cyclin D1, cyclin E2), Wnt effectors (FZD7, TCF7L2/TCF4), EZH2, NOTCH1, autophagy factors (ATG2A/ATG14), and NF-κB components (p65, TRAF6)—thereby controlling proliferation, stemness, autophagy, and inflammation [#3, #5, #6, #15, #27, #32, #12, #18, #10]. Mechanistically, YTHDF1 acts at translation initiation: it engages eIF3C and eIF5B and forms a feed-forward circuit with RUVBL1/2 at the 40S complex to accelerate oncogenic translation [#4, #45, #40]. Beyond translation, YTHDF1 undergoes liquid-liquid phase separation, is essential for P-body integrity, and recruits AGO2 through its YTH domain to mediate miRNA-dependent mRNA decay; it also assembles decapping/decay complexes (ZAP/DDX17/DCP2) to degrade viral m6A transcripts [#13, #9]. YTHDF1 activity is tightly regulated: FMRP sequesters it from ribosomes until neuronal-stimulation-triggered phosphorylation releases it, O-GlcNAcylation at Ser196/197/198 controls Crm1-dependent cytoplasmic localization, and its protein stability is balanced by USP5 (stabilizing via K11-deubiquitination) and the CUL7-FBXW8 E3 ligase (degradation) [#28, #33, #36]. Upstream, HIF-1α transcriptionally induces YTHDF1 under hypoxia to drive autophagy and ferroptosis-resistance programs [#12, #38].\",\n  \"teleology\": [\n    {\n      \"year\": 2018,\n      \"claim\": \"Established that YTHDF1 is a functional m6A reader in vivo by showing it drives stimulus-dependent translation of neuronal mRNAs required for synaptic plasticity and memory, settling whether m6A reading has physiological consequences.\",\n      \"evidence\": \"Ythdf1 knockout and hippocampal rescue, RIP-seq, nascent protein labeling, and tether reporter assays in mouse neurons\",\n      \"pmids\": [\"30401835\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the initiation-factor machinery YTHDF1 recruits\", \"Translation enhancement mechanism at the molecular level not defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Extended YTHDF1 translational control to antitumor immunity and neural development, showing it tunes cathepsin levels to suppress antigen cross-presentation and drives Robo3.1 for axon guidance.\",\n      \"evidence\": \"Ythdf1 KO mice, syngeneic tumor and CD8+ priming assays, cathepsin inhibitor rescue, plus RIP and m6A-site mutation in spinal commissural neurons\",\n      \"pmids\": [\"30728504\", \"30843071\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How target selectivity among m6A transcripts is achieved was not defined\", \"Direct lysosomal-gene m6A site mapping limited\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined YTHDF1 as a pro-tumorigenic translational driver across multiple cancers by identifying direct targets including EIF3C, FZD7/Wnt effectors, and TFRC, linking m6A reading to global translation output and oncogenic signaling.\",\n      \"evidence\": \"CLIP-seq, MeRIP-seq, ribosome profiling, RIP, KO/overexpression in ovarian, gastric, intestinal, and squamous cancers\",\n      \"pmids\": [\"31996915\", \"32788173\", \"32064749\", \"33204330\", \"31653849\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Some pathway placements (Keap1-Nrf2) rest on single labs\", \"Whether YTHDF1 directly contacts initiation factors at these targets not always shown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Revealed that YTHDF1 also mediates mRNA degradation and phase separation, recruiting AGO2 via its YTH domain to build P-bodies and assembling decapping complexes to clear viral m6A RNA—expanding its role beyond translational enhancement.\",\n      \"evidence\": \"CRISPR KO with 4SU-TT-seq half-life measurement, YTH×AGO2 Co-IP domain mapping, FRAP/LLPS reconstitution, and Co-IP of ZAP/DDX17/DCP2 in EBV-infected cells\",\n      \"pmids\": [\"34821414\", \"33605073\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"What dictates the translation-versus-decay decision is unresolved\", \"LLPS and decay characterized in single labs\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Placed YTHDF1 downstream of hypoxia signaling and within feed-forward circuits by showing HIF-1α transcriptionally induces it and that it amplifies Wnt and autophagy programs through ATG2A/ATG14 and TCF7L2.\",\n      \"evidence\": \"ChIP and luciferase reporters for HIF-1α binding, MeRIP-seq, polysome profiling, KO mouse intestinal and HCC models\",\n      \"pmids\": [\"33619246\", \"32064749\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generality of the HIF-1α→YTHDF1 axis across tissues not fully tested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Connected YTHDF1 translational control to the tumor immune microenvironment and inflammasome biology, showing it drives p65/CXCL1-mediated MDSC recruitment and modulates NLRP3/IL-1β through several target mRNAs.\",\n      \"evidence\": \"Integrated MeRIP-seq/Ribo-seq, Ythdf1 knockin mice, scRNA-seq, in vivo siRNA delivery, plus inflammasome and reporter assays\",\n      \"pmids\": [\"36717220\", \"35649302\", \"35508474\", \"35444649\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Several inflammasome links lack direct m6A site mapping\", \"Context-dependence of pro- versus anti-inflammatory output unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Uncovered the regulatory logic governing YTHDF1 activity—FMRP sequestration relieved by phosphorylation, O-GlcNAcylation controlling Crm1-dependent localization—and demonstrated phase-separation-dependent translational repression of IκB in transdifferentiation.\",\n      \"evidence\": \"FMRP-YTHDF1 Co-IP with ribosome co-sedimentation and phospho-mutant rescue, OGT chemoproteomic site mapping with Crm1 assays, and YTH-domain LLPS reporter assays\",\n      \"pmids\": [\"37949069\", \"37086786\", \"37060562\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How phosphorylation, O-GlcNAcylation, and LLPS integrate is not defined\", \"Stoichiometry of FMRP-YTHDF1 regulation in non-neuronal cells unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Solidified YTHDF1 as an immunotherapeutic target by showing tumor-intrinsic YTHDF1 drives lysosomal MHC-I degradation and EZH2/IL-6-mediated CD8+ T-cell dysfunction, with siYTHDF1 synergizing with anti-PD-1.\",\n      \"evidence\": \"Tumor-cell KO with lysosomal/MHC-I assays, ribosome profiling, RIP-seq, liver-specific knockin mice, scRNA-seq, and LNP-siRNA combinations\",\n      \"pmids\": [\"36650153\", \"37459919\", \"38241695\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of translational versus stability effects on NOTCH1 not fully separated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Mapped the translation-initiation machinery and stability control underlying YTHDF1 function, identifying eIF5B and a RUVBL1/2 40S feed-forward circuit, and defining USP5/CUL7-FBXW8 control of YTHDF1 protein levels.\",\n      \"evidence\": \"Co-IP/MS at the 40S complex, CRISPR screen, ribosome sequencing, pharmacological inhibition, and ubiquitin-linkage and kinase-substrate assays\",\n      \"pmids\": [\"38900944\", \"39672819\", \"39900921\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of YTHDF1 engagement with the initiation complex unresolved\", \"Whether eIF5B and RUVBL1/2 act on overlapping target sets unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Broadened YTHDF1's organ-homeostasis roles and revealed additional layers of regulation, including PIEZO2/Cav1 in cardiac biology, structural remodeling by DHX36 enabling decay, NAT10/SRSF2-driven splicing of YTHDF1, and viral lactylation-driven degradation.\",\n      \"evidence\": \"Conditional cardiac KO, MeRIP site mapping, transcriptome-wide structure probing, splicing reporters, and PTM/viral-replication assays\",\n      \"pmids\": [\"39498803\", \"38768805\", \"39543097\", \"39024555\", \"39496835\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"DHX36-m6A-YTHDF1 decay link is correlative\", \"Several tissue phenotypes rest on single labs\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved what molecular switch directs YTHDF1 between translational enhancement, mRNA decay, and phase-separation-mediated repression on a given transcript, and how target selectivity among the thousands of m6A-marked mRNAs is encoded.\",\n      \"evidence\": \"Not addressed by the available corpus\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying model integrating translation, decay, and LLPS outputs\", \"No structural model of YTHDF1 at the initiation complex\", \"Determinants of context-specific target selection unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 2, 4, 13, 47]},\n      {\"term_id\": \"GO:0045182\", \"supporting_discovery_ids\": [0, 4, 40, 45]},\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [13, 9, 44]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [33, 13]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [33]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 4, 40]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [13, 44]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1, 18, 27, 34]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 6, 16, 30]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [3, 15]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [12, 35]}\n    ],\n    \"complexes\": [\"P-body\", \"stress granule\", \"40S translation initiation complex\"],\n    \"partners\": [\"FMRP\", \"AGO2\", \"EIF3C\", \"eIF5B\", \"RUVBL1\", \"RUVBL2\", \"USP5\", \"Crm1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":7,"faith_pct":85.71428571428571}}