{"gene":"ZC3H13","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2018,"finding":"ZC3H13 is required for nuclear localization of the WTAP-Virilizer-Hakai complex; knockdown of Zc3h13 in mouse embryonic stem cells causes WTAP, Virilizer, and Hakai to translocate from nucleus to cytoplasm, leading to decreased global m6A levels on mRNA and impaired mESC self-renewal.","method":"siRNA knockdown, subcellular fractionation, immunofluorescence, m6A dot blot/quantification in mESCs","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal localization and functional assays in mESCs, replicated finding of nuclear anchoring role confirmed by multiple independent labs in same year","pmids":["29547716"],"is_preprint":false},{"year":2018,"finding":"Zc3h13/Flacc promotes m6A deposition by bridging the WTAP homolog Fl(2)d to the mRNA-binding factor Nito/Rbm15, physically connecting the mRNA-binding subunit to the catalytic m6A writer complex in both Drosophila and mice.","method":"Co-immunoprecipitation, mass spectrometry interactome, genetic epistasis in Drosophila sex determination, m6A quantification upon Flacc loss","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP in two organisms, epistasis genetics, independent replication of bridging role across multiple 2018 papers","pmids":["29535189"],"is_preprint":false},{"year":2018,"finding":"Drosophila Xio (ortholog of ZC3H13) colocalizes and physically interacts with all five known m6A writer complex subunits (METTL3, METTL14, Fl(2)d/WTAP, Vir/KIAA1429, Nito/Rbm15) in the nucleus; loss of xio phenocopies loss of other m6A factors (sex transformation, Sxl splicing defect, reduced m6A) and encodes a member of the m6A methyltransferase complex.","method":"Co-immunoprecipitation, immunofluorescence colocalization, genetic loss-of-function (Sxl splicing assay, sex determination phenotypes), m6A quantification","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, multiple orthogonal functional readouts, consistent with findings in two other independent 2018 papers","pmids":["29555755"],"is_preprint":false},{"year":2018,"finding":"ZC3H13 loss in colorectal cancer cells activates Ras-ERK signaling and increases expression of Snail, Cyclin D1, and Cyclin E1 while decreasing Occludin and ZO-1, placing ZC3H13 as an upstream suppressor of the Ras-ERK pathway.","method":"siRNA knockdown and overexpression, Western blot for pathway components, proliferation and invasion assays","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — single lab, single set of methods, no direct biochemical reconstitution of pathway interaction","pmids":["30311220"],"is_preprint":false},{"year":2022,"finding":"ZC3H13-mediated m6A modification of PHF10 mRNA promotes its translation in a YTHDF1-dependent manner; ZC3H13 knockdown downregulates PHF10 m6A methylation and reduces PHF10 protein, impairing homologous recombination repair of DNA double-strand breaks.","method":"MeRIP-qPCR, siRNA knockdown, m6A quantification, γH2AX/RAD51/53BP1 foci assay, YTHDF1-rescue experiments","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MeRIP plus functional rescue, single lab, two orthogonal methods","pmids":["35033590"],"is_preprint":false},{"year":2021,"finding":"ZC3H13-induced m6A modification abolishes PKM2 mRNA stability, thereby reducing PKM2 expression and reprogramming glycolysis in hepatocellular carcinoma cells; rescue of PKM2 reverses the suppressive effect of ZC3H13 on HCC cell glycolysis and malignancy.","method":"MeRIP-qPCR, RNA immunoprecipitation, mRNA stability assay (actinomycin D), luciferase reporter, rescue experiments","journal":"Journal of oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MeRIP plus mRNA stability assay plus rescue, single lab","pmids":["35003256"],"is_preprint":false},{"year":2023,"finding":"ZC3H13 promotes m6A modification of IQGAP1 mRNA, leading to YTHDF2-mediated destabilization and degradation of IQGAP1 mRNA; YTHDF2 knockdown reverses the effect of ZC3H13 overexpression on IQGAP1 mRNA stability, suppressing papillary thyroid carcinoma growth.","method":"MeRIP-qPCR, RIP, actinomycin D mRNA stability assay, YTHDF2 knockdown rescue, xenograft model","journal":"Journal of the Formosan Medical Association","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MeRIP, RIP, stability assay with reader knockdown rescue, single lab","pmids":["36739231"],"is_preprint":false},{"year":2025,"finding":"ZC3H13 promotes m6A modification of NABP1 mRNA, stabilizing it in an IGF2BP1-dependent manner; ZC3H13 knockdown reduces NABP1, alleviating G2/M cell cycle arrest and apoptosis in cisplatin-induced acute kidney injury.","method":"MeRIP, ZC3H13 knockdown/overexpression, IGF2BP1-dependent mRNA stability assay, AAV9-mediated silencing in vivo","journal":"Cellular and molecular life sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MeRIP plus reader-protein-dependent stability assay plus in vivo model, single lab","pmids":["39985591"],"is_preprint":false},{"year":2025,"finding":"ZC3H13 promotes m6A methylation of PRDX6 mRNA, facilitating its degradation in a YTHDF2-dependent manner, reducing PRDX6 expression; reduced PRDX6 activates p53 and suppresses SLC7A11, thereby promoting ferroptosis in alveolar macrophages and contributing to sepsis-associated acute lung injury.","method":"MeRIP, YTHDF2-dependent mRNA stability assay, ZC3H13 knockdown/PRDX6 overexpression rescue, lentiviral knockdown in vivo (CLP model)","journal":"Functional & integrative genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MeRIP, reader rescue, epistasis via double knockdown, in vivo validation, single lab","pmids":["40646387"],"is_preprint":false},{"year":2025,"finding":"ZC3H13 mediates m6A modification of KCNQ1OT1 lncRNA, reducing its stability in a YTHDF2-dependent manner; loss of KCNQ1OT1 prevents MLL4 recruitment to the TRABD promoter (reducing H3K4me1/2/3 enrichment), thereby decreasing TRABD expression and promoting ferroptosis, which sensitizes doxorubicin-resistant TNBC cells.","method":"RIP, RNA pull-down, MeRIP, YTHDF2-RIP, ChIP for H3K4me1/2/3 and MLL4, xenograft model","journal":"Cell biology and toxicology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (MeRIP, RIP, pull-down, ChIP), single lab","pmids":["40000487"],"is_preprint":false},{"year":2024,"finding":"ZC3H13 enhances m6A modification and mRNA stability of ITGA6 in bronchial epithelial cells, promoting ITGA6 expression; ZC3H13/ITGA6 axis drives inflammation, apoptosis, and EMT in COPD models.","method":"MeRIP-PCR, actinomycin D mRNA stability assay, ZC3H13 knockdown in cellular and mouse COPD models","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MeRIP plus stability assay plus in vivo model, single lab","pmids":["38670474"],"is_preprint":false},{"year":2024,"finding":"ZC3H13 promotes m6A modification of Bax mRNA, reducing its stability through the m6A reader YTHDC1, thereby inhibiting Bax expression and lung epithelial cell apoptosis; YTHDC1 was identified as the specific reader mediating this destabilization.","method":"MeRIP-qPCR, RNA binding assay (ZC3H13 binds Bax mRNA), actinomycin D stability assay, YTHDC1 identification, ZC3H13 overexpression in BLM-induced mouse and cellular models","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MeRIP, stability assay, reader identification, in vivo rescue, single lab","pmids":["39307407"],"is_preprint":false},{"year":2023,"finding":"ZC3H13 promotes m6A modification of HIPK2 mRNA, increasing its stability (reduced degradation rate); this elevates HIPK2 expression and promotes keloid fibroblast proliferation and migration.","method":"MeRIP-qPCR, mRNA stability assay (actinomycin D), ZC3H13 knockdown/overexpression in human keloid fibroblasts","journal":"Biochemical genetics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — MeRIP and stability assay but single lab, no reader identification","pmids":["37752292"],"is_preprint":false},{"year":2023,"finding":"ZC3H13 promotes m6A modification of DUOX1 mRNA, repressing DUOX1 expression and thereby reducing DUOX1-mediated ferroptosis in laryngeal squamous cell carcinoma cells; CHIP confirmed interaction between DUOX1 and ZC3H13.","method":"MeRIP, chromatin immunoprecipitation (ChIP), siRNA knockdown/overexpression, ROS and Fe2+ measurement","journal":"Tissue & cell","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single MeRIP assay, limited mechanistic follow-up","pmids":["37536262"],"is_preprint":false},{"year":2026,"finding":"ZC3H13 loss changes m6A writer complex activity and target specificity, decreasing m6A methylation and increasing stability of transcripts that promote migration and invasion; co-loss of ZC3H13 with RB1 and BRCA2 occurs in metastatic prostate cancer; FDA-approved m6A demethylase inhibitors reduce metastatic capabilities of ZC3H13-deficient cells.","method":"In vitro and in vivo functional assays for migration/invasion, m6A sequencing, pharmacological inhibition with FDA-approved demethylase inhibitors, patient genomic data co-deletion analysis","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — m6A sequencing plus in vivo model plus pharmacological rescue, single lab","pmids":["41105668"],"is_preprint":false},{"year":2025,"finding":"ZC3H13 mediates m6A modification of UNC5CL mRNA, stabilizing UNC5CL transcripts via YTHDC1; elevated UNC5CL suppresses the NF-κB–CSF2 signaling axis, thereby inhibiting CSF2-driven recruitment of myeloid-derived suppressor cells and remodeling the immunosuppressive tumor microenvironment in renal cell carcinoma.","method":"m6A sequencing combined with RNA-seq, loss/gain-of-function studies, flow cytometry of tumor-infiltrating immune cells, allograft tumor model","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — integrated m6A-seq and RNA-seq, in vivo allograft, flow cytometry immune profiling, single lab","pmids":["42163390"],"is_preprint":false},{"year":2025,"finding":"ZC3H13 mediates m6A modification and stability of SLC3A2 mRNA in an IGF2BP2-dependent manner; ZC3H13 silencing suppresses BMSC proliferation and osteogenic differentiation while enhancing ferroptosis through SLC3A2 reduction; FOXO3 acts as a transcriptional activator of ZC3H13, placing ZC3H13 downstream of FOXO3 in a FOXO3/ZC3H13/SLC3A2 cascade.","method":"RIP, MeRIP, mRNA stability assay, ChIP and luciferase (FOXO3→ZC3H13 promoter), osteogenic differentiation assays (ALP, Alizarin Red), ROS/Fe2+/MDA measurement","journal":"Journal of bioenergetics and biomembranes","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP, MeRIP, RIP, and multiple functional readouts, single lab","pmids":["42217127"],"is_preprint":false},{"year":2025,"finding":"ZC3H13 silencing in LPS-stimulated macrophages stabilizes Spic mRNA in an m6A-dependent manner; stabilized Spic inhibits NF-κB pathway activation and promotes macrophage polarization from pro-inflammatory M1 to anti-inflammatory phenotype, alleviating LPS-induced liver injury.","method":"Zc3h13 siRNA knockdown in macrophages and C57BL/6 in vivo model, m6A quantification, Spic co-silencing rescue, NF-κB pathway assay","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis rescue (co-silencing of Spic reverses Zc3h13 KD effect), in vivo model, single lab","pmids":["41847860"],"is_preprint":false},{"year":2025,"finding":"ZC3H13 mediates YTHDF1-dependent m6A modification of SNTB1 mRNA, leading to post-transcriptional activation (increased SNTB1 expression), which promotes EMT and metastatic progression in gastric cancer.","method":"MeRIP-seq, RNA-seq, Co-immunoprecipitation, YTHDF1-rescue experiments, in vivo and in vitro functional assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MeRIP-seq plus Co-IP plus YTHDF1 rescue, single lab","pmids":["40774945"],"is_preprint":false},{"year":2029,"finding":"ZC3H13 mutation causes abnormal nuclear-to-cytoplasmic metastasis of METTL14 and METTL3 in esophageal squamous cell carcinoma, consistent with its nuclear anchoring role for the m6A writer complex; ZC3H13 promotes m6A modification of CXCL8 mRNA, enhancing its stability and leading to M2 macrophage polarization via the CXCL8–CXCR2 axis.","method":"ZC3H13 silencing in CDX model, m6A colorimetric assay, METTL3/METTL14 localization assay, CXCL8/CCL5 qRT-PCR and ELISA, CXCR2 inhibitor rescue","journal":"Frontiers in immunology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, limited mechanistic methods for m6A-CXCL8 link (no MeRIP reported in abstract)","pmids":["40959082"],"is_preprint":false},{"year":2024,"finding":"ZC3H13 promotes m6A modification of PJA2 mRNA, stabilizing it; elevated PJA2 ubiquitinates and degrades KSR1, thereby inducing autophagy and suppressing bladder cancer progression.","method":"MeRIP for PJA2 m6A, mRNA stability assay, PJA2/KSR1 knockdown/overexpression rescue, in vitro and in vivo functional assays","journal":"Human cell","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, no reader identification for m6A-PJA2 stability mechanism","pmids":["39614918"],"is_preprint":false},{"year":2025,"finding":"ZC3H13-mediated m6A modification of NSUN4 mRNA represses NSUN4 expression; conversely, ZC3H13 knockdown increases NSUN4 m6A but reduces NSUN4 levels, and NSUN4 knockdown promotes chondrocyte mitochondrial dysfunction and pyroptosis, revealing that ZC3H13 modulates chondrocyte fate via m6A regulation of NSUN4.","method":"ZC3H13 siRNA knockdown, m6A level quantification of NSUN4, RNA sequencing, NSUN4 knockdown functional assays","journal":"Cartilage","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, RNA-seq plus m6A quantification, limited mechanistic detail in abstract","pmids":["40433805"],"is_preprint":false}],"current_model":"ZC3H13 is a zinc-finger CCCH-domain protein that functions as a core scaffolding component of the nuclear m6A methyltransferase (writer) complex: it anchors WTAP, Virilizer/METTL14, and Hakai in the nucleus (and bridges the mRNA-binding factor RBM15/Nito to WTAP/Fl(2)d), thereby enabling METTL3-dependent m6A deposition on mRNA; loss of ZC3H13 causes cytoplasmic mislocalization of the complex, global reduction in mRNA m6A, and downstream effects on mRNA stability, translation, and splicing that regulate stem cell self-renewal, sex determination, and in numerous cancer/disease contexts control the stability or translation of specific target mRNAs (e.g., PKM2, PHF10, IQGAP1, NABP1, PRDX6, SLC3A2, SNTB1, and others) through m6A readers such as YTHDF1, YTHDF2, YTHDC1, and IGF2BP proteins."},"narrative":{"mechanistic_narrative":"ZC3H13 is a CCCH zinc-finger protein that serves as a core scaffolding subunit of the nuclear N6-methyladenosine (m6A) methyltransferase \"writer\" complex, where it anchors the assembly in the nucleus and thereby licenses METTL3-dependent m6A deposition on mRNA [PMID:29547716, PMID:29555755]. It performs this role architecturally: ZC3H13 (and its Drosophila ortholog Xio/Flacc) physically interacts with all known writer subunits and bridges the WTAP homolog Fl(2)d to the mRNA-binding factor Nito/RBM15, physically coupling the RNA-recruiting module to the catalytic core [PMID:29535189, PMID:29555755]. Loss of ZC3H13 causes WTAP, Virilizer, and Hakai to mislocalize from nucleus to cytoplasm, globally reducing mRNA m6A and impairing functions including mouse embryonic stem cell self-renewal and Drosophila sex determination [PMID:29547716, PMID:29555755]. Through this writer activity ZC3H13 controls the fate of specific transcripts in a reader-dependent manner, with outcomes determined by which reader engages the modified mRNA: YTHDF2 and YTHDC1 mediate destabilization of targets such as IQGAP1, PRDX6, and Bax [PMID:36739231, PMID:40646387, PMID:39307407], YTHDF1 promotes translation or post-transcriptional activation of targets including PHF10 and SNTB1 [PMID:35033590, PMID:40774945], and IGF2BP proteins stabilize transcripts such as NABP1 and SLC3A2 [PMID:39985591, PMID:42217127]. These target-level effects govern mRNA stability, translation, DNA damage repair, glycolytic reprogramming, ferroptosis, and immune-cell phenotypes across diverse cancer and tissue-injury contexts [PMID:35033590, PMID:35003256, PMID:40646387, PMID:42163390]. Beyond its scaffolding role in the writer complex and the catalog of individual target transcripts, no further intrinsic enzymatic activity for ZC3H13 itself is characterized in the available corpus.","teleology":[{"year":2018,"claim":"Established that ZC3H13 is not merely associated with the m6A machinery but is structurally required to keep the writer complex in the nucleus, defining its core function as a localization scaffold.","evidence":"siRNA knockdown with subcellular fractionation, immunofluorescence, and m6A quantification in mouse embryonic stem cells","pmids":["29547716"],"confidence":"High","gaps":["Does not resolve the structural basis or domain of ZC3H13 that mediates nuclear anchoring","Does not define how m6A loss mechanistically links to the self-renewal defect"]},{"year":2018,"claim":"Defined the molecular bridging logic of ZC3H13 — connecting the mRNA-binding subunit RBM15/Nito to the WTAP/Fl(2)d core — explaining how the writer is recruited to its RNA substrates.","evidence":"Co-IP, mass spectrometry interactome, and genetic epistasis in Drosophila sex determination with m6A quantification, conserved in mouse","pmids":["29535189"],"confidence":"High","gaps":["Does not map the precise interaction interfaces","Does not establish whether bridging is constitutive or regulated"]},{"year":2018,"claim":"Confirmed ZC3H13/Xio as a bona fide writer-complex member interacting with all five known subunits, with loss-of-function phenocopying other m6A factors.","evidence":"Co-IP, immunofluorescence colocalization, Sxl splicing and sex-determination assays, and m6A quantification in Drosophila","pmids":["29555755"],"confidence":"High","gaps":["Does not establish stoichiometry within the complex","Does not separate scaffolding from any catalytic contribution"]},{"year":2018,"claim":"Began connecting ZC3H13 loss to oncogenic signaling, positioning it as an upstream suppressor of the Ras-ERK pathway in colorectal cancer.","evidence":"siRNA knockdown/overexpression with Western blotting of pathway components and proliferation/invasion assays","pmids":["30311220"],"confidence":"Medium","gaps":["No direct biochemical link between ZC3H13 and Ras-ERK components","Does not identify the m6A target transcripts mediating the effect"]},{"year":2021,"claim":"Demonstrated that ZC3H13-dependent m6A controls metabolic reprogramming by destabilizing PKM2 mRNA, linking the writer scaffold to glycolysis in hepatocellular carcinoma.","evidence":"MeRIP-qPCR, RIP, actinomycin D stability assay, luciferase reporter, and rescue in HCC cells","pmids":["35003256"],"confidence":"Medium","gaps":["Reader protein mediating PKM2 destabilization not identified","Single lab, no in vivo validation reported"]},{"year":2022,"claim":"Showed ZC3H13 m6A can promote (not only repress) target output, driving YTHDF1-dependent translation of PHF10 to sustain homologous recombination repair.","evidence":"MeRIP-qPCR, knockdown, m6A quantification, DNA-damage foci assays, and YTHDF1-rescue experiments","pmids":["35033590"],"confidence":"Medium","gaps":["Does not explain how reader choice (translation vs decay) is determined for ZC3H13 targets","Single lab"]},{"year":2023,"claim":"Distinguished a YTHDF2-mediated decay branch of ZC3H13 function by showing destabilization of IQGAP1 mRNA, with reader knockdown reversing the effect.","evidence":"MeRIP-qPCR, RIP, stability assay, YTHDF2 knockdown rescue, and xenograft in papillary thyroid carcinoma","pmids":["36739231"],"confidence":"Medium","gaps":["Does not address why some ZC3H13 targets use YTHDF2 vs YTHDF1/IGF2BP readers","Single lab"]},{"year":2024,"claim":"Extended the reader repertoire to YTHDC1, showing ZC3H13 m6A destabilizes Bax mRNA via YTHDC1 to limit lung epithelial apoptosis.","evidence":"MeRIP-qPCR, RNA-binding assay, stability assay, reader identification, and in vivo BLM model","pmids":["39307407"],"confidence":"Medium","gaps":["Does not clarify determinants of YTHDC1 versus cytoplasmic reader engagement","Single lab"]},{"year":2025,"claim":"Established IGF2BP-dependent stabilization as another ZC3H13 output, linking the writer to cell-cycle arrest, osteogenesis, and ferroptosis through targets such as NABP1 and SLC3A2.","evidence":"MeRIP, RIP, stability assays with IGF2BP1/IGF2BP2 dependence, ChIP/luciferase for upstream FOXO3, and in vivo models","pmids":["39985591","42217127"],"confidence":"Medium","gaps":["Reader-selection rules across IGF2BP1 vs IGF2BP2 not defined","Upstream transcriptional control (FOXO3) shown in only one context"]},{"year":2025,"claim":"Broadened ZC3H13 m6A regulation to non-coding RNA and immune remodeling, including destabilization of KCNQ1OT1 lncRNA and stabilization of UNC5CL to reshape tumor immunity.","evidence":"MeRIP, RIP, RNA pull-down, ChIP, YTHDF2-RIP, m6A-seq/RNA-seq, flow cytometry, and allograft/xenograft models","pmids":["40000487","42163390","41847860"],"confidence":"Medium","gaps":["lncRNA targeting mechanism by the writer not biochemically reconstituted","Immune-microenvironment effects are downstream and indirect"]},{"year":2025,"claim":"Showed that ZC3H13 loss alters writer-complex activity and target specificity to favor pro-metastatic transcripts, and that this dependency is pharmacologically targetable.","evidence":"m6A sequencing, migration/invasion assays, patient co-deletion genomics, and FDA-approved demethylase inhibitor treatment in prostate cancer","pmids":["41105668"],"confidence":"Medium","gaps":["Mechanism by which ZC3H13 loss shifts target specificity not resolved","Single lab"]},{"year":null,"claim":"It remains unresolved what governs the divergent reader outcomes (YTHDF1/YTHDC1/YTHDF2/IGF2BP) and target specificity downstream of ZC3H13-dependent m6A, and whether ZC3H13 contributes anything beyond nuclear scaffolding/bridging.","evidence":"No timeline discovery defines the rules linking ZC3H13-deposited m6A to a specific reader or downstream fate","pmids":[],"confidence":"Medium","gaps":["No unifying model for reader selection across ZC3H13 targets","No structural model of ZC3H13 within the writer complex","Intrinsic biochemical activity of ZC3H13 (if any) undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,2]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,2]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[11]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,2]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[0,2]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,1,2]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[2]}],"complexes":["m6A methyltransferase (writer) complex"],"partners":["WTAP","METTL3","METTL14","VIRMA","RBM15","CBLL1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q5T200","full_name":"Zinc finger CCCH domain-containing protein 13","aliases":[],"length_aa":1668,"mass_kda":196.6,"function":"Associated component of the WMM complex, a complex that mediates N6-methyladenosine (m6A) methylation of RNAs, a modification that plays a role in the efficiency of mRNA splicing and RNA processing (PubMed:29507755). Acts as a key regulator of m6A methylation by promoting m6A methylation of mRNAs at the 3'-UTR (By similarity). Controls embryonic stem cells (ESCs) pluripotency via its role in m6A methylation (By similarity). In the WMM complex, anchors component of the MACOM subcomplex in the nucleus (By similarity). Also required for bridging WTAP to the RNA-binding component RBM15 (RBM15 or RBM15B) (By similarity)","subcellular_location":"Nucleus speckle; Nucleus, nucleoplasm","url":"https://www.uniprot.org/uniprotkb/Q5T200/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ZC3H13","classification":"Not Classified","n_dependent_lines":415,"n_total_lines":1208,"dependency_fraction":0.3435430463576159},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"DDOST","stoichiometry":0.2},{"gene":"OST4","stoichiometry":0.2},{"gene":"RNF40","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/ZC3H13","total_profiled":1310},"omim":[{"mim_id":"616453","title":"ZINC FINGER CCCH DOMAIN-CONTAINING PROTEIN 13; ZC3H13","url":"https://www.omim.org/entry/616453"},{"mim_id":"616447","title":"VIR-LIKE M6A METHYLTRANSFERASE-ASSOCIATED PROTEIN; VIRMA","url":"https://www.omim.org/entry/616447"},{"mim_id":"612588","title":"BCL2-ASSOCIATED TRANSCRIPTION FACTOR 1; BCLAF1","url":"https://www.omim.org/entry/612588"},{"mim_id":"606872","title":"CAS-BR-M MURINE ECTOPIC RETROVIRAL TRANSFORMING SEQUENCE LIKE-1; CBLL1","url":"https://www.omim.org/entry/606872"},{"mim_id":"606077","title":"RNA-BINDING MOTIF PROTEIN 15; RBM15","url":"https://www.omim.org/entry/606077"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ZC3H13"},"hgnc":{"alias_symbol":["DKFZp434D1812","Xio"],"prev_symbol":["KIAA0853"]},"alphafold":{"accession":"Q5T200","domains":[{"cath_id":"-","chopping":"1520-1616","consensus_level":"medium","plddt":69.8858,"start":1520,"end":1616}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5T200","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q5T200-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q5T200-F1-predicted_aligned_error_v6.png","plddt_mean":46.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ZC3H13","jax_strain_url":"https://www.jax.org/strain/search?query=ZC3H13"},"sequence":{"accession":"Q5T200","fasta_url":"https://rest.uniprot.org/uniprotkb/Q5T200.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q5T200/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5T200"}},"corpus_meta":[{"pmid":"29547716","id":"PMC_29547716","title":"Zc3h13 Regulates Nuclear RNA m6A Methylation and Mouse Embryonic Stem Cell Self-Renewal.","date":"2018","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/29547716","citation_count":768,"is_preprint":false},{"pmid":"29535189","id":"PMC_29535189","title":"Zc3h13/Flacc is required for adenosine methylation by bridging the mRNA-binding factor Rbm15/Spenito to the m6A machinery component Wtap/Fl(2)d.","date":"2018","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/29535189","citation_count":514,"is_preprint":false},{"pmid":"30311220","id":"PMC_30311220","title":"ZC3H13 suppresses colorectal cancer proliferation and invasion via inactivating Ras-ERK signaling.","date":"2018","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/30311220","citation_count":112,"is_preprint":false},{"pmid":"33363011","id":"PMC_33363011","title":"Analysis of N6-Methyladenosine Methyltransferase Reveals METTL14 and ZC3H13 as Tumor Suppressor Genes in Breast Cancer.","date":"2020","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/33363011","citation_count":100,"is_preprint":false},{"pmid":"35418160","id":"PMC_35418160","title":"N6-methyladenosine modification of CENPK mRNA by ZC3H13 promotes cervical cancer stemness and chemoresistance.","date":"2022","source":"Military Medical Research","url":"https://pubmed.ncbi.nlm.nih.gov/35418160","citation_count":92,"is_preprint":false},{"pmid":"29555755","id":"PMC_29555755","title":"Xio is a component of the Drosophila sex determination pathway and RNA N6-methyladenosine methyltransferase complex.","date":"2018","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/29555755","citation_count":84,"is_preprint":false},{"pmid":"35033590","id":"PMC_35033590","title":"ZC3H13-mediated N6-methyladenosine modification of PHF10 is impaired by fisetin which inhibits the DNA damage response in pancreatic 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zhi","url":"https://pubmed.ncbi.nlm.nih.gov/36739231","citation_count":22,"is_preprint":false},{"pmid":"34497769","id":"PMC_34497769","title":"N6-Methyladenosine Writer Gene ZC3H13 Predicts Immune Phenotype and Therapeutic Opportunities in Kidney Renal Clear Cell Carcinoma.","date":"2021","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/34497769","citation_count":20,"is_preprint":false},{"pmid":"38670474","id":"PMC_38670474","title":"ZC3H13 promotes ITGA6 m6A modification for chronic obstructive pulmonary disease progression.","date":"2024","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/38670474","citation_count":17,"is_preprint":false},{"pmid":"37536262","id":"PMC_37536262","title":"ZC3H13 reduced DUOX1-mediated ferroptosis in laryngeal squamous cell carcinoma cells through m6A-dependent modification.","date":"2023","source":"Tissue & 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cell","url":"https://pubmed.ncbi.nlm.nih.gov/39614918","citation_count":4,"is_preprint":false},{"pmid":"40959082","id":"PMC_40959082","title":"The role of ZC3H13 in promoting M2 macrophage infiltration via m6A methylation in esophageal squamous cell carcinoma tumor progression.","date":"2025","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/40959082","citation_count":3,"is_preprint":false},{"pmid":"39307407","id":"PMC_39307407","title":"m6A methyltransferase ZC3H13 improves pulmonary fibrosis in mice through regulating Bax expression.","date":"2024","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/39307407","citation_count":3,"is_preprint":false},{"pmid":"40130382","id":"PMC_40130382","title":"ZC3H13 Regulates Ferroptosis to Enhance Osteogenic Differentiation in Osteoporotic BMSCs.","date":"2025","source":"Tissue engineering. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/40130382","citation_count":2,"is_preprint":false},{"pmid":"40890321","id":"PMC_40890321","title":"N(6)-methyladenosine modification of ADGRA3 by ZC3H13 suppresses papillary thyroid cancer cell malignancy by inactivating the PI3K/Akt/mTOR signaling pathway.","date":"2025","source":"Discover oncology","url":"https://pubmed.ncbi.nlm.nih.gov/40890321","citation_count":1,"is_preprint":false},{"pmid":"40578066","id":"PMC_40578066","title":"M6A methyltransferase ZC3H13-mediated downregulation of GPX4 mRNA stability inhibits the progression of kidney renal clear cell carcinoma (KIRC).","date":"2025","source":"Cellular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/40578066","citation_count":1,"is_preprint":false},{"pmid":"40774945","id":"PMC_40774945","title":"ZC3H13 mediates N6-methyladenosine modification of SNTB1 to promote epithelial-mesenchymal transition in gastric cancer.","date":"2025","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/40774945","citation_count":0,"is_preprint":false},{"pmid":"41105668","id":"PMC_41105668","title":"ZC3H13 Loss Drives Cancer Metastatic Progression by Disrupting m6A RNA Methylation.","date":"2026","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/41105668","citation_count":0,"is_preprint":false},{"pmid":"40433805","id":"PMC_40433805","title":"ZC3H13 Promotes NSUN4-Mediated Chondrocyte Mitochondrial Dysfunction and Pyroptosis in Temporomandibular Joint Osteoarthritis.","date":"2025","source":"Cartilage","url":"https://pubmed.ncbi.nlm.nih.gov/40433805","citation_count":0,"is_preprint":false},{"pmid":"40780498","id":"PMC_40780498","title":"ZC3H13 facilitates the progression of acute myeloid leukemia through m6A-FOXP1-mediated metabolic reprogramming.","date":"2025","source":"Experimental hematology","url":"https://pubmed.ncbi.nlm.nih.gov/40780498","citation_count":0,"is_preprint":false},{"pmid":"41890272","id":"PMC_41890272","title":"Bioinformatics and machine learning identify ITIH4 and ZC3H13 as novel mRNA biomarkers for major depressive disorder that promote microglial M1 polarization.","date":"2026","source":"Cytotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/41890272","citation_count":0,"is_preprint":false},{"pmid":"41175162","id":"PMC_41175162","title":"ZC3H13-induced KLRB1 upregulation relieves the injury of myocardial infarction through N [6]-methyladenosine methylation.","date":"2025","source":"Journal of receptor and signal transduction research","url":"https://pubmed.ncbi.nlm.nih.gov/41175162","citation_count":0,"is_preprint":false},{"pmid":"41847860","id":"PMC_41847860","title":"Silencing of Zc3h13 attenuates LPS-induced inflammatory response in macrophages via m6A-dependent stabilization of Spic mRNA.","date":"2026","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/41847860","citation_count":0,"is_preprint":false},{"pmid":"42217127","id":"PMC_42217127","title":"The FOXO3/ZC3H13/SLC3A2 cascade modulates the osteogenic differentiation and ferroptosis of BMSCs.","date":"2026","source":"Journal of bioenergetics and biomembranes","url":"https://pubmed.ncbi.nlm.nih.gov/42217127","citation_count":0,"is_preprint":false},{"pmid":"42044732","id":"PMC_42044732","title":"ZC3H13-mediated the m6A modification of PAX9 suppresses the progression of reflux esophagitis via improving esophageal epithelial barrier dysfunction.","date":"2026","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/42044732","citation_count":0,"is_preprint":false},{"pmid":"41377025","id":"PMC_41377025","title":"PLAU regulated by a m6A writer ZC3H13 plays the oncogenic role in oral squamous cell carcinoma.","date":"2025","source":"Cytotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/41377025","citation_count":0,"is_preprint":false},{"pmid":"42163390","id":"PMC_42163390","title":"Epitranscriptomic silencing of the ZC3H13/m6A axis orchestrates immunosuppressive microenvironment remodeling in renal cell carcinoma via CSF2-mediated MDSCs recruitment.","date":"2026","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/42163390","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":26886,"output_tokens":5538,"usd":0.081864,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":13875,"output_tokens":3973,"usd":0.08435,"stage2_stop_reason":"end_turn"},"total_usd":0.166214,"stage1_batch_id":"msgbatch_01UT1AahFPCAyn2uVweS7A9z","stage2_batch_id":"msgbatch_01HuKWtKNT4Pqj1bc8eEP5RV","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2018,\n      \"finding\": \"ZC3H13 is required for nuclear localization of the WTAP-Virilizer-Hakai complex; knockdown of Zc3h13 in mouse embryonic stem cells causes WTAP, Virilizer, and Hakai to translocate from nucleus to cytoplasm, leading to decreased global m6A levels on mRNA and impaired mESC self-renewal.\",\n      \"method\": \"siRNA knockdown, subcellular fractionation, immunofluorescence, m6A dot blot/quantification in mESCs\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal localization and functional assays in mESCs, replicated finding of nuclear anchoring role confirmed by multiple independent labs in same year\",\n      \"pmids\": [\"29547716\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Zc3h13/Flacc promotes m6A deposition by bridging the WTAP homolog Fl(2)d to the mRNA-binding factor Nito/Rbm15, physically connecting the mRNA-binding subunit to the catalytic m6A writer complex in both Drosophila and mice.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry interactome, genetic epistasis in Drosophila sex determination, m6A quantification upon Flacc loss\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP in two organisms, epistasis genetics, independent replication of bridging role across multiple 2018 papers\",\n      \"pmids\": [\"29535189\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Drosophila Xio (ortholog of ZC3H13) colocalizes and physically interacts with all five known m6A writer complex subunits (METTL3, METTL14, Fl(2)d/WTAP, Vir/KIAA1429, Nito/Rbm15) in the nucleus; loss of xio phenocopies loss of other m6A factors (sex transformation, Sxl splicing defect, reduced m6A) and encodes a member of the m6A methyltransferase complex.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence colocalization, genetic loss-of-function (Sxl splicing assay, sex determination phenotypes), m6A quantification\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, multiple orthogonal functional readouts, consistent with findings in two other independent 2018 papers\",\n      \"pmids\": [\"29555755\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ZC3H13 loss in colorectal cancer cells activates Ras-ERK signaling and increases expression of Snail, Cyclin D1, and Cyclin E1 while decreasing Occludin and ZO-1, placing ZC3H13 as an upstream suppressor of the Ras-ERK pathway.\",\n      \"method\": \"siRNA knockdown and overexpression, Western blot for pathway components, proliferation and invasion assays\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single set of methods, no direct biochemical reconstitution of pathway interaction\",\n      \"pmids\": [\"30311220\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ZC3H13-mediated m6A modification of PHF10 mRNA promotes its translation in a YTHDF1-dependent manner; ZC3H13 knockdown downregulates PHF10 m6A methylation and reduces PHF10 protein, impairing homologous recombination repair of DNA double-strand breaks.\",\n      \"method\": \"MeRIP-qPCR, siRNA knockdown, m6A quantification, γH2AX/RAD51/53BP1 foci assay, YTHDF1-rescue experiments\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MeRIP plus functional rescue, single lab, two orthogonal methods\",\n      \"pmids\": [\"35033590\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ZC3H13-induced m6A modification abolishes PKM2 mRNA stability, thereby reducing PKM2 expression and reprogramming glycolysis in hepatocellular carcinoma cells; rescue of PKM2 reverses the suppressive effect of ZC3H13 on HCC cell glycolysis and malignancy.\",\n      \"method\": \"MeRIP-qPCR, RNA immunoprecipitation, mRNA stability assay (actinomycin D), luciferase reporter, rescue experiments\",\n      \"journal\": \"Journal of oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MeRIP plus mRNA stability assay plus rescue, single lab\",\n      \"pmids\": [\"35003256\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ZC3H13 promotes m6A modification of IQGAP1 mRNA, leading to YTHDF2-mediated destabilization and degradation of IQGAP1 mRNA; YTHDF2 knockdown reverses the effect of ZC3H13 overexpression on IQGAP1 mRNA stability, suppressing papillary thyroid carcinoma growth.\",\n      \"method\": \"MeRIP-qPCR, RIP, actinomycin D mRNA stability assay, YTHDF2 knockdown rescue, xenograft model\",\n      \"journal\": \"Journal of the Formosan Medical Association\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MeRIP, RIP, stability assay with reader knockdown rescue, single lab\",\n      \"pmids\": [\"36739231\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ZC3H13 promotes m6A modification of NABP1 mRNA, stabilizing it in an IGF2BP1-dependent manner; ZC3H13 knockdown reduces NABP1, alleviating G2/M cell cycle arrest and apoptosis in cisplatin-induced acute kidney injury.\",\n      \"method\": \"MeRIP, ZC3H13 knockdown/overexpression, IGF2BP1-dependent mRNA stability assay, AAV9-mediated silencing in vivo\",\n      \"journal\": \"Cellular and molecular life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MeRIP plus reader-protein-dependent stability assay plus in vivo model, single lab\",\n      \"pmids\": [\"39985591\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ZC3H13 promotes m6A methylation of PRDX6 mRNA, facilitating its degradation in a YTHDF2-dependent manner, reducing PRDX6 expression; reduced PRDX6 activates p53 and suppresses SLC7A11, thereby promoting ferroptosis in alveolar macrophages and contributing to sepsis-associated acute lung injury.\",\n      \"method\": \"MeRIP, YTHDF2-dependent mRNA stability assay, ZC3H13 knockdown/PRDX6 overexpression rescue, lentiviral knockdown in vivo (CLP model)\",\n      \"journal\": \"Functional & integrative genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MeRIP, reader rescue, epistasis via double knockdown, in vivo validation, single lab\",\n      \"pmids\": [\"40646387\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ZC3H13 mediates m6A modification of KCNQ1OT1 lncRNA, reducing its stability in a YTHDF2-dependent manner; loss of KCNQ1OT1 prevents MLL4 recruitment to the TRABD promoter (reducing H3K4me1/2/3 enrichment), thereby decreasing TRABD expression and promoting ferroptosis, which sensitizes doxorubicin-resistant TNBC cells.\",\n      \"method\": \"RIP, RNA pull-down, MeRIP, YTHDF2-RIP, ChIP for H3K4me1/2/3 and MLL4, xenograft model\",\n      \"journal\": \"Cell biology and toxicology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (MeRIP, RIP, pull-down, ChIP), single lab\",\n      \"pmids\": [\"40000487\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ZC3H13 enhances m6A modification and mRNA stability of ITGA6 in bronchial epithelial cells, promoting ITGA6 expression; ZC3H13/ITGA6 axis drives inflammation, apoptosis, and EMT in COPD models.\",\n      \"method\": \"MeRIP-PCR, actinomycin D mRNA stability assay, ZC3H13 knockdown in cellular and mouse COPD models\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MeRIP plus stability assay plus in vivo model, single lab\",\n      \"pmids\": [\"38670474\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ZC3H13 promotes m6A modification of Bax mRNA, reducing its stability through the m6A reader YTHDC1, thereby inhibiting Bax expression and lung epithelial cell apoptosis; YTHDC1 was identified as the specific reader mediating this destabilization.\",\n      \"method\": \"MeRIP-qPCR, RNA binding assay (ZC3H13 binds Bax mRNA), actinomycin D stability assay, YTHDC1 identification, ZC3H13 overexpression in BLM-induced mouse and cellular models\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MeRIP, stability assay, reader identification, in vivo rescue, single lab\",\n      \"pmids\": [\"39307407\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ZC3H13 promotes m6A modification of HIPK2 mRNA, increasing its stability (reduced degradation rate); this elevates HIPK2 expression and promotes keloid fibroblast proliferation and migration.\",\n      \"method\": \"MeRIP-qPCR, mRNA stability assay (actinomycin D), ZC3H13 knockdown/overexpression in human keloid fibroblasts\",\n      \"journal\": \"Biochemical genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — MeRIP and stability assay but single lab, no reader identification\",\n      \"pmids\": [\"37752292\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ZC3H13 promotes m6A modification of DUOX1 mRNA, repressing DUOX1 expression and thereby reducing DUOX1-mediated ferroptosis in laryngeal squamous cell carcinoma cells; CHIP confirmed interaction between DUOX1 and ZC3H13.\",\n      \"method\": \"MeRIP, chromatin immunoprecipitation (ChIP), siRNA knockdown/overexpression, ROS and Fe2+ measurement\",\n      \"journal\": \"Tissue & cell\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single MeRIP assay, limited mechanistic follow-up\",\n      \"pmids\": [\"37536262\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"ZC3H13 loss changes m6A writer complex activity and target specificity, decreasing m6A methylation and increasing stability of transcripts that promote migration and invasion; co-loss of ZC3H13 with RB1 and BRCA2 occurs in metastatic prostate cancer; FDA-approved m6A demethylase inhibitors reduce metastatic capabilities of ZC3H13-deficient cells.\",\n      \"method\": \"In vitro and in vivo functional assays for migration/invasion, m6A sequencing, pharmacological inhibition with FDA-approved demethylase inhibitors, patient genomic data co-deletion analysis\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — m6A sequencing plus in vivo model plus pharmacological rescue, single lab\",\n      \"pmids\": [\"41105668\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ZC3H13 mediates m6A modification of UNC5CL mRNA, stabilizing UNC5CL transcripts via YTHDC1; elevated UNC5CL suppresses the NF-κB–CSF2 signaling axis, thereby inhibiting CSF2-driven recruitment of myeloid-derived suppressor cells and remodeling the immunosuppressive tumor microenvironment in renal cell carcinoma.\",\n      \"method\": \"m6A sequencing combined with RNA-seq, loss/gain-of-function studies, flow cytometry of tumor-infiltrating immune cells, allograft tumor model\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — integrated m6A-seq and RNA-seq, in vivo allograft, flow cytometry immune profiling, single lab\",\n      \"pmids\": [\"42163390\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ZC3H13 mediates m6A modification and stability of SLC3A2 mRNA in an IGF2BP2-dependent manner; ZC3H13 silencing suppresses BMSC proliferation and osteogenic differentiation while enhancing ferroptosis through SLC3A2 reduction; FOXO3 acts as a transcriptional activator of ZC3H13, placing ZC3H13 downstream of FOXO3 in a FOXO3/ZC3H13/SLC3A2 cascade.\",\n      \"method\": \"RIP, MeRIP, mRNA stability assay, ChIP and luciferase (FOXO3→ZC3H13 promoter), osteogenic differentiation assays (ALP, Alizarin Red), ROS/Fe2+/MDA measurement\",\n      \"journal\": \"Journal of bioenergetics and biomembranes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP, MeRIP, RIP, and multiple functional readouts, single lab\",\n      \"pmids\": [\"42217127\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ZC3H13 silencing in LPS-stimulated macrophages stabilizes Spic mRNA in an m6A-dependent manner; stabilized Spic inhibits NF-κB pathway activation and promotes macrophage polarization from pro-inflammatory M1 to anti-inflammatory phenotype, alleviating LPS-induced liver injury.\",\n      \"method\": \"Zc3h13 siRNA knockdown in macrophages and C57BL/6 in vivo model, m6A quantification, Spic co-silencing rescue, NF-κB pathway assay\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis rescue (co-silencing of Spic reverses Zc3h13 KD effect), in vivo model, single lab\",\n      \"pmids\": [\"41847860\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ZC3H13 mediates YTHDF1-dependent m6A modification of SNTB1 mRNA, leading to post-transcriptional activation (increased SNTB1 expression), which promotes EMT and metastatic progression in gastric cancer.\",\n      \"method\": \"MeRIP-seq, RNA-seq, Co-immunoprecipitation, YTHDF1-rescue experiments, in vivo and in vitro functional assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MeRIP-seq plus Co-IP plus YTHDF1 rescue, single lab\",\n      \"pmids\": [\"40774945\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2029,\n      \"finding\": \"ZC3H13 mutation causes abnormal nuclear-to-cytoplasmic metastasis of METTL14 and METTL3 in esophageal squamous cell carcinoma, consistent with its nuclear anchoring role for the m6A writer complex; ZC3H13 promotes m6A modification of CXCL8 mRNA, enhancing its stability and leading to M2 macrophage polarization via the CXCL8–CXCR2 axis.\",\n      \"method\": \"ZC3H13 silencing in CDX model, m6A colorimetric assay, METTL3/METTL14 localization assay, CXCL8/CCL5 qRT-PCR and ELISA, CXCR2 inhibitor rescue\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, limited mechanistic methods for m6A-CXCL8 link (no MeRIP reported in abstract)\",\n      \"pmids\": [\"40959082\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ZC3H13 promotes m6A modification of PJA2 mRNA, stabilizing it; elevated PJA2 ubiquitinates and degrades KSR1, thereby inducing autophagy and suppressing bladder cancer progression.\",\n      \"method\": \"MeRIP for PJA2 m6A, mRNA stability assay, PJA2/KSR1 knockdown/overexpression rescue, in vitro and in vivo functional assays\",\n      \"journal\": \"Human cell\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, no reader identification for m6A-PJA2 stability mechanism\",\n      \"pmids\": [\"39614918\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ZC3H13-mediated m6A modification of NSUN4 mRNA represses NSUN4 expression; conversely, ZC3H13 knockdown increases NSUN4 m6A but reduces NSUN4 levels, and NSUN4 knockdown promotes chondrocyte mitochondrial dysfunction and pyroptosis, revealing that ZC3H13 modulates chondrocyte fate via m6A regulation of NSUN4.\",\n      \"method\": \"ZC3H13 siRNA knockdown, m6A level quantification of NSUN4, RNA sequencing, NSUN4 knockdown functional assays\",\n      \"journal\": \"Cartilage\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, RNA-seq plus m6A quantification, limited mechanistic detail in abstract\",\n      \"pmids\": [\"40433805\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ZC3H13 is a zinc-finger CCCH-domain protein that functions as a core scaffolding component of the nuclear m6A methyltransferase (writer) complex: it anchors WTAP, Virilizer/METTL14, and Hakai in the nucleus (and bridges the mRNA-binding factor RBM15/Nito to WTAP/Fl(2)d), thereby enabling METTL3-dependent m6A deposition on mRNA; loss of ZC3H13 causes cytoplasmic mislocalization of the complex, global reduction in mRNA m6A, and downstream effects on mRNA stability, translation, and splicing that regulate stem cell self-renewal, sex determination, and in numerous cancer/disease contexts control the stability or translation of specific target mRNAs (e.g., PKM2, PHF10, IQGAP1, NABP1, PRDX6, SLC3A2, SNTB1, and others) through m6A readers such as YTHDF1, YTHDF2, YTHDC1, and IGF2BP proteins.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ZC3H13 is a CCCH zinc-finger protein that serves as a core scaffolding subunit of the nuclear N6-methyladenosine (m6A) methyltransferase \\\"writer\\\" complex, where it anchors the assembly in the nucleus and thereby licenses METTL3-dependent m6A deposition on mRNA [#0, #2]. It performs this role architecturally: ZC3H13 (and its Drosophila ortholog Xio/Flacc) physically interacts with all known writer subunits and bridges the WTAP homolog Fl(2)d to the mRNA-binding factor Nito/RBM15, physically coupling the RNA-recruiting module to the catalytic core [#1, #2]. Loss of ZC3H13 causes WTAP, Virilizer, and Hakai to mislocalize from nucleus to cytoplasm, globally reducing mRNA m6A and impairing functions including mouse embryonic stem cell self-renewal and Drosophila sex determination [#0, #2]. Through this writer activity ZC3H13 controls the fate of specific transcripts in a reader-dependent manner, with outcomes determined by which reader engages the modified mRNA: YTHDF2 and YTHDC1 mediate destabilization of targets such as IQGAP1, PRDX6, and Bax [#6, #8, #11], YTHDF1 promotes translation or post-transcriptional activation of targets including PHF10 and SNTB1 [#4, #18], and IGF2BP proteins stabilize transcripts such as NABP1 and SLC3A2 [#7, #16]. These target-level effects govern mRNA stability, translation, DNA damage repair, glycolytic reprogramming, ferroptosis, and immune-cell phenotypes across diverse cancer and tissue-injury contexts [#4, #5, #8, #15]. Beyond its scaffolding role in the writer complex and the catalog of individual target transcripts, no further intrinsic enzymatic activity for ZC3H13 itself is characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2018,\n      \"claim\": \"Established that ZC3H13 is not merely associated with the m6A machinery but is structurally required to keep the writer complex in the nucleus, defining its core function as a localization scaffold.\",\n      \"evidence\": \"siRNA knockdown with subcellular fractionation, immunofluorescence, and m6A quantification in mouse embryonic stem cells\",\n      \"pmids\": [\"29547716\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Does not resolve the structural basis or domain of ZC3H13 that mediates nuclear anchoring\",\n        \"Does not define how m6A loss mechanistically links to the self-renewal defect\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined the molecular bridging logic of ZC3H13 — connecting the mRNA-binding subunit RBM15/Nito to the WTAP/Fl(2)d core — explaining how the writer is recruited to its RNA substrates.\",\n      \"evidence\": \"Co-IP, mass spectrometry interactome, and genetic epistasis in Drosophila sex determination with m6A quantification, conserved in mouse\",\n      \"pmids\": [\"29535189\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Does not map the precise interaction interfaces\",\n        \"Does not establish whether bridging is constitutive or regulated\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Confirmed ZC3H13/Xio as a bona fide writer-complex member interacting with all five known subunits, with loss-of-function phenocopying other m6A factors.\",\n      \"evidence\": \"Co-IP, immunofluorescence colocalization, Sxl splicing and sex-determination assays, and m6A quantification in Drosophila\",\n      \"pmids\": [\"29555755\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Does not establish stoichiometry within the complex\",\n        \"Does not separate scaffolding from any catalytic contribution\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Began connecting ZC3H13 loss to oncogenic signaling, positioning it as an upstream suppressor of the Ras-ERK pathway in colorectal cancer.\",\n      \"evidence\": \"siRNA knockdown/overexpression with Western blotting of pathway components and proliferation/invasion assays\",\n      \"pmids\": [\"30311220\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No direct biochemical link between ZC3H13 and Ras-ERK components\",\n        \"Does not identify the m6A target transcripts mediating the effect\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrated that ZC3H13-dependent m6A controls metabolic reprogramming by destabilizing PKM2 mRNA, linking the writer scaffold to glycolysis in hepatocellular carcinoma.\",\n      \"evidence\": \"MeRIP-qPCR, RIP, actinomycin D stability assay, luciferase reporter, and rescue in HCC cells\",\n      \"pmids\": [\"35003256\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Reader protein mediating PKM2 destabilization not identified\",\n        \"Single lab, no in vivo validation reported\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed ZC3H13 m6A can promote (not only repress) target output, driving YTHDF1-dependent translation of PHF10 to sustain homologous recombination repair.\",\n      \"evidence\": \"MeRIP-qPCR, knockdown, m6A quantification, DNA-damage foci assays, and YTHDF1-rescue experiments\",\n      \"pmids\": [\"35033590\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Does not explain how reader choice (translation vs decay) is determined for ZC3H13 targets\",\n        \"Single lab\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Distinguished a YTHDF2-mediated decay branch of ZC3H13 function by showing destabilization of IQGAP1 mRNA, with reader knockdown reversing the effect.\",\n      \"evidence\": \"MeRIP-qPCR, RIP, stability assay, YTHDF2 knockdown rescue, and xenograft in papillary thyroid carcinoma\",\n      \"pmids\": [\"36739231\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Does not address why some ZC3H13 targets use YTHDF2 vs YTHDF1/IGF2BP readers\",\n        \"Single lab\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended the reader repertoire to YTHDC1, showing ZC3H13 m6A destabilizes Bax mRNA via YTHDC1 to limit lung epithelial apoptosis.\",\n      \"evidence\": \"MeRIP-qPCR, RNA-binding assay, stability assay, reader identification, and in vivo BLM model\",\n      \"pmids\": [\"39307407\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Does not clarify determinants of YTHDC1 versus cytoplasmic reader engagement\",\n        \"Single lab\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Established IGF2BP-dependent stabilization as another ZC3H13 output, linking the writer to cell-cycle arrest, osteogenesis, and ferroptosis through targets such as NABP1 and SLC3A2.\",\n      \"evidence\": \"MeRIP, RIP, stability assays with IGF2BP1/IGF2BP2 dependence, ChIP/luciferase for upstream FOXO3, and in vivo models\",\n      \"pmids\": [\"39985591\", \"42217127\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Reader-selection rules across IGF2BP1 vs IGF2BP2 not defined\",\n        \"Upstream transcriptional control (FOXO3) shown in only one context\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Broadened ZC3H13 m6A regulation to non-coding RNA and immune remodeling, including destabilization of KCNQ1OT1 lncRNA and stabilization of UNC5CL to reshape tumor immunity.\",\n      \"evidence\": \"MeRIP, RIP, RNA pull-down, ChIP, YTHDF2-RIP, m6A-seq/RNA-seq, flow cytometry, and allograft/xenograft models\",\n      \"pmids\": [\"40000487\", \"42163390\", \"41847860\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"lncRNA targeting mechanism by the writer not biochemically reconstituted\",\n        \"Immune-microenvironment effects are downstream and indirect\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed that ZC3H13 loss alters writer-complex activity and target specificity to favor pro-metastatic transcripts, and that this dependency is pharmacologically targetable.\",\n      \"evidence\": \"m6A sequencing, migration/invasion assays, patient co-deletion genomics, and FDA-approved demethylase inhibitor treatment in prostate cancer\",\n      \"pmids\": [\"41105668\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism by which ZC3H13 loss shifts target specificity not resolved\",\n        \"Single lab\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved what governs the divergent reader outcomes (YTHDF1/YTHDC1/YTHDF2/IGF2BP) and target specificity downstream of ZC3H13-dependent m6A, and whether ZC3H13 contributes anything beyond nuclear scaffolding/bridging.\",\n      \"evidence\": \"No timeline discovery defines the rules linking ZC3H13-deposited m6A to a specific reader or downstream fate\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No unifying model for reader selection across ZC3H13 targets\",\n        \"No structural model of ZC3H13 within the writer complex\",\n        \"Intrinsic biochemical activity of ZC3H13 (if any) undefined\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"complexes\": [\"m6A methyltransferase (writer) complex\"],\n    \"partners\": [\"WTAP\", \"METTL3\", \"METTL14\", \"VIRMA\", \"RBM15\", \"CBLL1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}