{"gene":"NUDT7","run_date":"2026-04-29T11:37:57","timeline":{"discoveries":[{"year":2001,"finding":"Mouse NUDT7α (Nudt7) is a peroxisomal CoA diphosphatase that hydrolyzes CoA, CoA esters, and oxidized CoA, yielding 3',5'-ADP and the corresponding 4'-phosphopantetheine derivative. Kinetic parameters: Km = 240 µM and kcat = 3.8 s⁻¹ with CoA; activity is optimal at pH 8.0 with 5 mM Mg²⁺ or Mn²⁺; fluoride inhibits with IC₅₀ = 20 µM. Transfection of HeLa cells with RFP-Nudt7α confirmed peroxisomal localization.","method":"In vitro enzymatic assay of recombinant thioredoxin-fusion protein expressed in E. coli; product identification; live-cell imaging of RFP-fusion in HeLa cells","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 — reconstituted in vitro enzyme activity with kinetic characterization plus direct peroxisomal localization imaging","pmids":["11415433"],"is_preprint":false},{"year":2018,"finding":"Nudt19 and Nudt7 both hydrolyze the diphosphate bond of free CoA and acyl-CoAs to form 3',5'-ADP and 4'-(acyl)phosphopantetheine, but differ in regulation and inhibitor sensitivity. Chenodeoxycholic acid specifically inhibits Nudt19 by competing with CoA but does not bind Nudt7. Exchange of Nudix and CoA signature motifs between the two isoforms dramatically decreased their kcat, and substitution of conserved residues within these motifs identified amino acids playing different roles in CoA binding and hydrolysis in each isoform.","method":"In vitro enzymatic assay; active-site mutagenesis and domain-swap experiments; competitive inhibitor binding assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — in vitro assay with mutagenesis defining catalytic residues and inhibitor specificity","pmids":["29378847"],"is_preprint":false},{"year":2019,"finding":"Liver-specific overexpression of Nudt7 in mice decreases the concentration of short-chain acyl-CoAs and choloyl-CoA in fasted livers, reduces hepatic bile acid content, and reduces the rate of peroxisomal fatty acid oxidation, as measured by targeted/untargeted metabolomics and fatty acid oxidation assays in intact hepatocytes, demonstrating that Nudt7 activity modulates the peroxisomal CoA pool and peroxisomal lipid metabolism in vivo.","method":"In vivo overexpression in mouse liver; targeted and untargeted metabolomics; fatty acid oxidation assay in isolated hepatocytes","journal":"Journal of lipid research","confidence":"High","confidence_rationale":"Tier 2 — clean in vivo gain-of-function with multiple orthogonal metabolic readouts","pmids":["30846528"],"is_preprint":false},{"year":2018,"finding":"Knockdown of NUDT7 in normal human chondrocytes disrupts lipid homeostasis. Nudt7⁻/⁻ mice accumulate lipids via peroxisomal dysfunction, upregulate IL-1β, and undergo apoptotic chondrocyte death. Genome-wide analysis identifies PGAM1 as a downstream target; PGAM1 overexpression phenocopies NUDT7 loss, and co-introduction of NUDT7 rescues the PGAM1-driven phenotype, placing NUDT7 upstream of PGAM1 in a pathway controlling chondrocyte lipid homeostasis and survival.","method":"siRNA knockdown in human chondrocytes; Nudt7⁻/⁻ mouse model; overexpression of PGAM1; rescue experiment with co-expression of NUDT7; microarray; apoptosis assays; lipid staining","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — KO mouse + human cell KD + epistasis rescue experiment with defined pathway","pmids":["30143643"],"is_preprint":false},{"year":2022,"finding":"Deletion of Nudt7 in male mice fed a Western diet increases total liver CoA levels, driven by male-specific accumulation of medium-chain dicarboxylic acyl-CoAs from β-oxidation of dicarboxylic fatty acids. Under conditions of elevated chenodeoxycholic acid synthesis, Nudt7 deletion promotes tauromuricholic acid production, decreasing the hydrophobicity index of the intestinal bile acid pool and increasing fecal cholesterol excretion.","method":"Nudt7⁻/⁻ mouse model; targeted metabolomics of hepatic CoA and bile acid pools; fecal cholesterol measurement","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — clean KO mouse with defined metabolic phenotypes replicated across dietary conditions","pmids":["36436558"],"is_preprint":false},{"year":2022,"finding":"Heterozygous deletion of Nudt7 in mice causes accumulation of palmitic acid, which increases H3K4me3 on PPARγ promoters, activates PPARγ, and drives de novo lipogenesis in hepatocytes, linking peroxisomal CoA hydrolase activity to an epigenetic-transcriptional mechanism controlling hepatic lipid synthesis.","method":"Nudt7⁺/⁻ mouse model; RNA sequencing; IPA/KEGG pathway analysis; ChIP for H3K4me3; PPARγ reporter/activity assays; de novo lipogenesis measurement","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 — KO mouse with ChIP data linking palmitic acid accumulation to PPARγ activation, single lab","pmids":["36185359"],"is_preprint":false},{"year":2020,"finding":"Loss of Nudt7 in AOM/DSS-treated mice increases lipid accumulation and activates Wnt/β-catenin signaling (elevated β-catenin, Myc, Ccnd1, Nos2). Palmitic acid accumulation in Nudt7⁻/⁻ colons is implicated as the driver; direct application of palmitic acid-conjugated chitosan to mouse colon phenocopies β-catenin upregulation, placing NUDT7-dependent peroxisomal lipid metabolism upstream of Wnt signaling in Kras-driven CRC.","method":"Nudt7⁻/⁻ mouse model + AOM/DSS carcinogen treatment; xenograft of Nudt7-overexpressing cancer cells; microarray; palmitic acid treatment experiment; Western blot for Wnt pathway components","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 — KO mouse plus xenograft with pathway analysis, single lab","pmids":["32131398"],"is_preprint":false},{"year":2023,"finding":"Double knockout of Acot12 and Nudt7 in mice leads to accumulation of acetyl-CoA, upregulation of FOXM1, and induction of chondrocyte senescence and cartilage breakdown, linking peroxisomal CoA metabolism to a FOXM1-driven senescence pathway in osteoarthritis.","method":"Acot12⁻/⁻Nudt7⁻/⁻ double-knockout mouse; microarray; immunohistochemistry; qRT-PCR; apoptosis/proliferation assays; acetyl-CoA measurement","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 — double KO mouse with defined metabolite–transcription factor axis, single lab","pmids":["37908734"],"is_preprint":false},{"year":2010,"finding":"Overexpression of pig NUDT7 in rat L6 myoblasts significantly reduces heme content (14.2 vs. 63.9 pmol/10⁵ cells), consistent with NUDT7-mediated hydrolysis of succinyl-CoA reducing substrate availability for heme biosynthesis.","method":"Transfection of NUDT7 expression vector into rat L6 myoblasts; heme content measurement at multiple time points","journal":"Meat science","confidence":"Low","confidence_rationale":"Tier 3 — single overexpression experiment in cultured cells, no direct succinyl-CoA measurement","pmids":["20619544"],"is_preprint":false},{"year":2022,"finding":"In zebrafish, nudt7 gene products are localized to the peroxisome during early embryogenesis. CRISPR/Cas9 depletion of nudt7 decreases transcription rate at zygotic genome activation (ZGA) and correlates with a genome-wide decrease in H3K27ac levels, suggesting a role for peroxisomal Nudt7 in regulating active chromatin formation during early development.","method":"Computational localization prediction confirmed by reporter; CRISPR/Cas9 knockout in zebrafish; RNA-seq; H3K27ac ChIP-seq","journal":"Journal of biochemistry","confidence":"Low","confidence_rationale":"Tier 3 — correlative ChIP-seq with KO, mechanism linking CoA hydrolase activity to chromatin state not directly demonstrated","pmids":["36270274"],"is_preprint":false},{"year":2026,"finding":"During PRRSV infection, NUDT7 protein interacts with and promotes proteasomal degradation of the ubiquitin-ribosomal fusion protein UBA52. This blocks UBA52-mediated K11/K27/K48 polyubiquitination of SREBF1, stabilizing SREBF1 and driving lipid droplet formation that supports PRRSV replication. NUDT7 also inhibits type I interferon signaling to facilitate viral immune evasion.","method":"Co-immunoprecipitation; overexpression and knockdown in cells; ubiquitination assay; lipid droplet staining; viral replication assay; interferon signaling reporter","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 3 — reciprocal Co-IP plus ubiquitination assay with functional viral replication readout, single lab","pmids":["41608635"],"is_preprint":false}],"current_model":"NUDT7 is a peroxisome-resident Nudix hydrolase that catalyzes the diphosphohydrolysis of CoA and acyl-CoAs to 3',5'-ADP and 4'-(acyl)phosphopantetheine, thereby regulating the size and composition of the peroxisomal (acyl-)CoA pool; through this activity it controls peroxisomal fatty acid oxidation, bile acid synthesis, and lipid homeostasis in the liver, and its loss activates downstream signaling cascades (Wnt/β-catenin, PPARγ, FOXM1) linked to lipid accumulation, chondrocyte death, and cancer-related phenotypes."},"narrative":{"teleology":[{"year":2001,"claim":"Establishing the enzymatic identity of NUDT7 as a peroxisomal CoA diphosphatase resolved the question of which enzyme degrades CoA within peroxisomes and defined its kinetic parameters and cofactor requirements.","evidence":"Recombinant enzyme kinetics, product identification, and RFP-fusion peroxisomal localization in HeLa cells","pmids":["11415433"],"confidence":"High","gaps":["Human NUDT7 kinetic parameters not directly measured in this study","Physiological substrates in vivo not determined","No structural information on active site"]},{"year":2018,"claim":"Comparative enzymology with NUDT19 defined the distinct catalytic determinants and inhibitor sensitivities of the two mammalian CoA diphosphatases, establishing that their Nudix and CoA-binding motifs are functionally non-interchangeable.","evidence":"Domain-swap mutagenesis and competitive inhibitor binding assays with purified recombinant enzymes","pmids":["29378847"],"confidence":"High","gaps":["Crystal structure of NUDT7 with bound substrate not available","Relative contributions of NUDT7 vs NUDT19 to tissue-level CoA regulation unclear"]},{"year":2018,"claim":"Demonstration that NUDT7 loss disrupts lipid homeostasis and causes apoptotic chondrocyte death via PGAM1 upregulation established the first in vivo phenotypic consequence and a defined downstream effector pathway.","evidence":"Nudt7⁻/⁻ mouse model and siRNA knockdown in human chondrocytes with PGAM1 epistasis rescue","pmids":["30143643"],"confidence":"High","gaps":["Mechanism linking CoA depletion to PGAM1 transcription not defined","Whether chondrocyte phenotype is peroxisome-autonomous not tested"]},{"year":2019,"claim":"Liver-specific overexpression demonstrated that NUDT7 directly modulates the hepatic peroxisomal CoA pool in vivo, reducing short-chain acyl-CoAs, bile acid content, and peroxisomal fatty acid oxidation rate.","evidence":"AAV-driven hepatic Nudt7 overexpression in mice with targeted/untargeted metabolomics and hepatocyte fatty acid oxidation assays","pmids":["30846528"],"confidence":"High","gaps":["Loss-of-function metabolomics not yet performed at this stage","Effects on extra-hepatic tissues not assessed"]},{"year":2020,"claim":"Connecting NUDT7 loss to Wnt/β-catenin activation in a carcinogen-driven colorectal cancer model revealed that palmitic acid accumulation from peroxisomal dysfunction feeds into oncogenic signaling.","evidence":"Nudt7⁻/⁻ mice treated with AOM/DSS; palmitic acid-chitosan colonic application phenocopying β-catenin upregulation","pmids":["32131398"],"confidence":"Medium","gaps":["Direct molecular target of palmitic acid in Wnt activation not identified","Human CRC relevance not validated","Single laboratory finding"]},{"year":2022,"claim":"Global Nudt7 knockout under Western diet conditions revealed sex-specific accumulation of medium-chain dicarboxylic acyl-CoAs and demonstrated that NUDT7 controls bile acid pool hydrophobicity and fecal cholesterol excretion, broadening its metabolic roles beyond simple CoA degradation.","evidence":"Nudt7⁻/⁻ mice on Western diet with hepatic CoA, bile acid, and fecal cholesterol metabolomics","pmids":["36436558"],"confidence":"High","gaps":["Mechanism of sex-specific dicarboxylic acyl-CoA accumulation not elucidated","Whether phenotype is peroxisome-autonomous vs. secondary to bile acid changes unclear"]},{"year":2022,"claim":"Heterozygous Nudt7 deletion linked palmitic acid accumulation to epigenetic activation (H3K4me3) of PPARγ promoters and de novo lipogenesis, providing a chromatin-level mechanism for how peroxisomal CoA hydrolase deficiency drives hepatic steatosis.","evidence":"Nudt7⁺/⁻ mouse with RNA-seq, ChIP for H3K4me3, PPARγ reporter assays, and lipogenesis measurement","pmids":["36185359"],"confidence":"Medium","gaps":["How palmitic acid increases H3K4me3 at PPARγ promoters mechanistically unresolved","Single lab; independent replication lacking","Haploinsufficiency model may not reflect complete loss"]},{"year":2023,"claim":"Double knockout of Acot12 and Nudt7 demonstrated that combined disruption of peroxisomal CoA metabolism drives acetyl-CoA accumulation, FOXM1 upregulation, and chondrocyte senescence, extending the cartilage phenotype to a senescence pathway.","evidence":"Acot12⁻/⁻Nudt7⁻/⁻ double-knockout mouse with acetyl-CoA measurement, microarray, and immunohistochemistry","pmids":["37908734"],"confidence":"Medium","gaps":["Individual contribution of Nudt7 vs. Acot12 to acetyl-CoA accumulation not deconvoluted","FOXM1 as direct transcriptional target of acetyl-CoA not mechanistically proven"]},{"year":2026,"claim":"During PRRSV infection, NUDT7 was found to interact with UBA52, promoting its proteasomal degradation and thereby stabilizing SREBF1 to drive lipid droplet formation and viral replication, revealing a non-enzymatic protein-protein interaction function.","evidence":"Co-immunoprecipitation, ubiquitination assays, and viral replication assays in cell culture","pmids":["41608635"],"confidence":"Medium","gaps":["Whether UBA52 interaction depends on NUDT7 hydrolase activity not tested","Relevance to non-viral physiological contexts unknown","Single laboratory, not independently confirmed"]},{"year":null,"claim":"Key unresolved questions include the crystal structure of NUDT7 with substrate, the mechanism by which CoA/acyl-CoA changes are transduced to nuclear epigenetic and transcriptional outputs, and whether NUDT7's protein-protein interaction with UBA52 is physiologically relevant outside viral infection.","evidence":"","pmids":[],"confidence":"Low","gaps":["No high-resolution structure of NUDT7","Signal transduction from peroxisomal CoA pool to chromatin not mechanistically defined","Tissue-specific and sex-specific regulation of NUDT7 expression poorly understood"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0,1,2,4]}],"localization":[{"term_id":"GO:0005777","term_label":"peroxisome","supporting_discovery_ids":[0,9]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,1,2,4,5]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,6]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[6,7]}],"complexes":[],"partners":["NUDT19","PGAM1","UBA52","ACOT12"],"other_free_text":[]},"mechanistic_narrative":"NUDT7 is a peroxisome-resident Nudix hydrolase that regulates intracellular coenzyme A homeostasis and downstream lipid metabolism. It catalyzes the Mg²⁺/Mn²⁺-dependent diphosphohydrolysis of CoA, acyl-CoAs, and oxidized CoA to 3',5'-ADP and 4'-(acyl)phosphopantetheine, with kinetic parameters of Km ~240 µM and kcat ~3.8 s⁻¹ for free CoA [PMID:11415433, PMID:29378847]. In vivo, hepatic NUDT7 activity controls the size and composition of the peroxisomal short-chain and medium-chain acyl-CoA pool, thereby modulating peroxisomal fatty acid β-oxidation, bile acid conjugation, and cholesterol excretion [PMID:30846528, PMID:36436558]. Loss of NUDT7 causes palmitic acid and acetyl-CoA accumulation that activates PPARγ-dependent de novo lipogenesis, Wnt/β-catenin signaling in colorectal tumorigenesis, and FOXM1-driven chondrocyte senescence linked to osteoarthritis [PMID:36185359, PMID:32131398, PMID:30143643, PMID:37908734]."},"prefetch_data":{"uniprot":{"accession":"P0C024","full_name":"Peroxisomal coenzyme A diphosphatase NUDT7","aliases":["Nucleoside diphosphate-linked moiety X motif 7","Nudix motif 7"],"length_aa":238,"mass_kda":26.9,"function":"Fatty acyl-coenzyme A (CoA) diphosphatase that hydrolyzes fatty acyl-CoA to yield acyl-4'-phosphopantetheine and adenosine 3',5'-bisphosphate (By similarity). Cleaves CoA, CoA esters and oxidized CoA with similar efficiencies (By similarity). Preferentially hydrolyzes medium-chain acyl-CoAs and bile acid-CoAs (By similarity). Has no activity toward NDP-sugars, CDP-alcohols, (deoxy)nucleoside 5'-triphosphates, nucleoside 5'-di or monophosphates, diadenosine polyphosphates, NAD, NADH, NADP, NADPH or thymidine-5'-monophospho-p-nitrophenyl ester (By similarity). May be required to eliminate oxidized CoA from peroxisomes, or regulate CoA and acyl-CoA levels in this organelle in response to metabolic demand (By similarity). Does not play a role in U8 snoRNA decapping activity (By similarity). Binds U8 snoRNA (By similarity). Exhibits decapping activity towards dpCoA-capped RNAs in vitro (By similarity)","subcellular_location":"Peroxisome","url":"https://www.uniprot.org/uniprotkb/P0C024/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/NUDT7","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":[],"url":"https://opencell.sf.czbiohub.org/search/NUDT7","total_profiled":1310},"omim":[{"mim_id":"621403","title":"NUDIX HYDROLASE 19; NUDT19","url":"https://www.omim.org/entry/621403"},{"mim_id":"609231","title":"NUDIX HYDROLASE 7; NUDT7","url":"https://www.omim.org/entry/609231"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Golgi apparatus","reliability":"Approved"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"liver","ntpm":65.6}],"url":"https://www.proteinatlas.org/search/NUDT7"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"P0C024","domains":[{"cath_id":"3.90.79.10","chopping":"10-237","consensus_level":"high","plddt":95.9175,"start":10,"end":237}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P0C024","model_url":"https://alphafold.ebi.ac.uk/files/AF-P0C024-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P0C024-F1-predicted_aligned_error_v6.png","plddt_mean":94.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NUDT7","jax_strain_url":"https://www.jax.org/strain/search?query=NUDT7"},"sequence":{"accession":"P0C024","fasta_url":"https://rest.uniprot.org/uniprotkb/P0C024.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P0C024/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P0C024"}},"corpus_meta":[{"pmid":"16531493","id":"PMC_16531493","title":"Salicylic acid-independent ENHANCED DISEASE SUSCEPTIBILITY1 signaling in Arabidopsis immunity and cell death is regulated by the monooxygenase FMO1 and the Nudix hydrolase NUDT7.","date":"2006","source":"The Plant cell","url":"https://pubmed.ncbi.nlm.nih.gov/16531493","citation_count":406,"is_preprint":false},{"pmid":"11415433","id":"PMC_11415433","title":"The mouse Nudt7 gene encodes a peroxisomal nudix hydrolase specific for coenzyme A and its derivatives.","date":"2001","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/11415433","citation_count":79,"is_preprint":false},{"pmid":"30143643","id":"PMC_30143643","title":"Dysregulation of the NUDT7-PGAM1 axis is responsible for chondrocyte death during osteoarthritis pathogenesis.","date":"2018","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/30143643","citation_count":58,"is_preprint":false},{"pmid":"23004358","id":"PMC_23004358","title":"The ammonium/nitrate ratio is an input signal in the temperature-modulated, SNC1-mediated and EDS1-dependent autoimmunity of nudt6-2 nudt7.","date":"2012","source":"The Plant journal : for cell and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/23004358","citation_count":30,"is_preprint":false},{"pmid":"29378847","id":"PMC_29378847","title":"Nudt19 is a renal CoA diphosphohydrolase with biochemical and regulatory properties that are distinct from the hepatic Nudt7 isoform.","date":"2018","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/29378847","citation_count":29,"is_preprint":false},{"pmid":"30846528","id":"PMC_30846528","title":"Overexpression of Nudt7 decreases bile acid levels and peroxisomal fatty acid oxidation in the liver.","date":"2019","source":"Journal of lipid research","url":"https://pubmed.ncbi.nlm.nih.gov/30846528","citation_count":18,"is_preprint":false},{"pmid":"37908734","id":"PMC_37908734","title":"Upregulated FOXM1 stimulates chondrocyte senescence in Acot12-/-Nudt7-/- double knockout mice.","date":"2023","source":"Theranostics","url":"https://pubmed.ncbi.nlm.nih.gov/37908734","citation_count":10,"is_preprint":false},{"pmid":"19749013","id":"PMC_19749013","title":"Fine mapping of quantitative trait loci for meat color on Sus scrofa chromosome 6: analysis of the swine NUDT7 gene.","date":"2009","source":"Journal of animal science","url":"https://pubmed.ncbi.nlm.nih.gov/19749013","citation_count":10,"is_preprint":false},{"pmid":"32131398","id":"PMC_32131398","title":"NUDT7 Loss Promotes Kras CRC Development.","date":"2020","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/32131398","citation_count":10,"is_preprint":false},{"pmid":"20619544","id":"PMC_20619544","title":"Overexpression of NUDT7, a candidate quantitative trait locus for pork color, downregulates heme biosynthesis in L6 myoblasts.","date":"2010","source":"Meat science","url":"https://pubmed.ncbi.nlm.nih.gov/20619544","citation_count":9,"is_preprint":false},{"pmid":"36436558","id":"PMC_36436558","title":"NUDT7 regulates total hepatic CoA levels and the composition of the intestinal bile acid pool in male mice fed a Western diet.","date":"2022","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/36436558","citation_count":9,"is_preprint":false},{"pmid":"36185359","id":"PMC_36185359","title":"Deficiency of peroxisomal NUDT7 stimulates de novo lipogenesis in hepatocytes.","date":"2022","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/36185359","citation_count":3,"is_preprint":false},{"pmid":"36270274","id":"PMC_36270274","title":"nudt7 gene depletion causes transcriptomic change in early development of zebrafish.","date":"2022","source":"Journal of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/36270274","citation_count":1,"is_preprint":false},{"pmid":"41608635","id":"PMC_41608635","title":"NUDT7 Modulates the UBA52-SREBF1 Signaling Axis to Promote PRRSV Replication via Lipid Synthesis.","date":"2026","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/41608635","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.10.22.683861","title":"Uncoupling hypersensitive cell death response and disease resistance activated by effector-triggered immunity","date":"2025-10-23","source":"bioRxiv","url":"https://doi.org/10.1101/2025.10.22.683861","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":8798,"output_tokens":3095,"usd":0.036409},"stage2":{"model":"claude-opus-4-6","input_tokens":6515,"output_tokens":2475,"usd":0.141675},"total_usd":0.178084,"stage1_batch_id":"msgbatch_012ZiiCUBfB62NCTQd4Bk1Jo","stage2_batch_id":"msgbatch_01Xuqq9aUHoQouS7UVGZNStZ","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2001,\n      \"finding\": \"Mouse NUDT7α (Nudt7) is a peroxisomal CoA diphosphatase that hydrolyzes CoA, CoA esters, and oxidized CoA, yielding 3',5'-ADP and the corresponding 4'-phosphopantetheine derivative. Kinetic parameters: Km = 240 µM and kcat = 3.8 s⁻¹ with CoA; activity is optimal at pH 8.0 with 5 mM Mg²⁺ or Mn²⁺; fluoride inhibits with IC₅₀ = 20 µM. Transfection of HeLa cells with RFP-Nudt7α confirmed peroxisomal localization.\",\n      \"method\": \"In vitro enzymatic assay of recombinant thioredoxin-fusion protein expressed in E. coli; product identification; live-cell imaging of RFP-fusion in HeLa cells\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted in vitro enzyme activity with kinetic characterization plus direct peroxisomal localization imaging\",\n      \"pmids\": [\"11415433\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Nudt19 and Nudt7 both hydrolyze the diphosphate bond of free CoA and acyl-CoAs to form 3',5'-ADP and 4'-(acyl)phosphopantetheine, but differ in regulation and inhibitor sensitivity. Chenodeoxycholic acid specifically inhibits Nudt19 by competing with CoA but does not bind Nudt7. Exchange of Nudix and CoA signature motifs between the two isoforms dramatically decreased their kcat, and substitution of conserved residues within these motifs identified amino acids playing different roles in CoA binding and hydrolysis in each isoform.\",\n      \"method\": \"In vitro enzymatic assay; active-site mutagenesis and domain-swap experiments; competitive inhibitor binding assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro assay with mutagenesis defining catalytic residues and inhibitor specificity\",\n      \"pmids\": [\"29378847\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Liver-specific overexpression of Nudt7 in mice decreases the concentration of short-chain acyl-CoAs and choloyl-CoA in fasted livers, reduces hepatic bile acid content, and reduces the rate of peroxisomal fatty acid oxidation, as measured by targeted/untargeted metabolomics and fatty acid oxidation assays in intact hepatocytes, demonstrating that Nudt7 activity modulates the peroxisomal CoA pool and peroxisomal lipid metabolism in vivo.\",\n      \"method\": \"In vivo overexpression in mouse liver; targeted and untargeted metabolomics; fatty acid oxidation assay in isolated hepatocytes\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean in vivo gain-of-function with multiple orthogonal metabolic readouts\",\n      \"pmids\": [\"30846528\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Knockdown of NUDT7 in normal human chondrocytes disrupts lipid homeostasis. Nudt7⁻/⁻ mice accumulate lipids via peroxisomal dysfunction, upregulate IL-1β, and undergo apoptotic chondrocyte death. Genome-wide analysis identifies PGAM1 as a downstream target; PGAM1 overexpression phenocopies NUDT7 loss, and co-introduction of NUDT7 rescues the PGAM1-driven phenotype, placing NUDT7 upstream of PGAM1 in a pathway controlling chondrocyte lipid homeostasis and survival.\",\n      \"method\": \"siRNA knockdown in human chondrocytes; Nudt7⁻/⁻ mouse model; overexpression of PGAM1; rescue experiment with co-expression of NUDT7; microarray; apoptosis assays; lipid staining\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse + human cell KD + epistasis rescue experiment with defined pathway\",\n      \"pmids\": [\"30143643\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Deletion of Nudt7 in male mice fed a Western diet increases total liver CoA levels, driven by male-specific accumulation of medium-chain dicarboxylic acyl-CoAs from β-oxidation of dicarboxylic fatty acids. Under conditions of elevated chenodeoxycholic acid synthesis, Nudt7 deletion promotes tauromuricholic acid production, decreasing the hydrophobicity index of the intestinal bile acid pool and increasing fecal cholesterol excretion.\",\n      \"method\": \"Nudt7⁻/⁻ mouse model; targeted metabolomics of hepatic CoA and bile acid pools; fecal cholesterol measurement\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO mouse with defined metabolic phenotypes replicated across dietary conditions\",\n      \"pmids\": [\"36436558\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Heterozygous deletion of Nudt7 in mice causes accumulation of palmitic acid, which increases H3K4me3 on PPARγ promoters, activates PPARγ, and drives de novo lipogenesis in hepatocytes, linking peroxisomal CoA hydrolase activity to an epigenetic-transcriptional mechanism controlling hepatic lipid synthesis.\",\n      \"method\": \"Nudt7⁺/⁻ mouse model; RNA sequencing; IPA/KEGG pathway analysis; ChIP for H3K4me3; PPARγ reporter/activity assays; de novo lipogenesis measurement\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse with ChIP data linking palmitic acid accumulation to PPARγ activation, single lab\",\n      \"pmids\": [\"36185359\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Loss of Nudt7 in AOM/DSS-treated mice increases lipid accumulation and activates Wnt/β-catenin signaling (elevated β-catenin, Myc, Ccnd1, Nos2). Palmitic acid accumulation in Nudt7⁻/⁻ colons is implicated as the driver; direct application of palmitic acid-conjugated chitosan to mouse colon phenocopies β-catenin upregulation, placing NUDT7-dependent peroxisomal lipid metabolism upstream of Wnt signaling in Kras-driven CRC.\",\n      \"method\": \"Nudt7⁻/⁻ mouse model + AOM/DSS carcinogen treatment; xenograft of Nudt7-overexpressing cancer cells; microarray; palmitic acid treatment experiment; Western blot for Wnt pathway components\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse plus xenograft with pathway analysis, single lab\",\n      \"pmids\": [\"32131398\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Double knockout of Acot12 and Nudt7 in mice leads to accumulation of acetyl-CoA, upregulation of FOXM1, and induction of chondrocyte senescence and cartilage breakdown, linking peroxisomal CoA metabolism to a FOXM1-driven senescence pathway in osteoarthritis.\",\n      \"method\": \"Acot12⁻/⁻Nudt7⁻/⁻ double-knockout mouse; microarray; immunohistochemistry; qRT-PCR; apoptosis/proliferation assays; acetyl-CoA measurement\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — double KO mouse with defined metabolite–transcription factor axis, single lab\",\n      \"pmids\": [\"37908734\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Overexpression of pig NUDT7 in rat L6 myoblasts significantly reduces heme content (14.2 vs. 63.9 pmol/10⁵ cells), consistent with NUDT7-mediated hydrolysis of succinyl-CoA reducing substrate availability for heme biosynthesis.\",\n      \"method\": \"Transfection of NUDT7 expression vector into rat L6 myoblasts; heme content measurement at multiple time points\",\n      \"journal\": \"Meat science\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single overexpression experiment in cultured cells, no direct succinyl-CoA measurement\",\n      \"pmids\": [\"20619544\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In zebrafish, nudt7 gene products are localized to the peroxisome during early embryogenesis. CRISPR/Cas9 depletion of nudt7 decreases transcription rate at zygotic genome activation (ZGA) and correlates with a genome-wide decrease in H3K27ac levels, suggesting a role for peroxisomal Nudt7 in regulating active chromatin formation during early development.\",\n      \"method\": \"Computational localization prediction confirmed by reporter; CRISPR/Cas9 knockout in zebrafish; RNA-seq; H3K27ac ChIP-seq\",\n      \"journal\": \"Journal of biochemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — correlative ChIP-seq with KO, mechanism linking CoA hydrolase activity to chromatin state not directly demonstrated\",\n      \"pmids\": [\"36270274\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"During PRRSV infection, NUDT7 protein interacts with and promotes proteasomal degradation of the ubiquitin-ribosomal fusion protein UBA52. This blocks UBA52-mediated K11/K27/K48 polyubiquitination of SREBF1, stabilizing SREBF1 and driving lipid droplet formation that supports PRRSV replication. NUDT7 also inhibits type I interferon signaling to facilitate viral immune evasion.\",\n      \"method\": \"Co-immunoprecipitation; overexpression and knockdown in cells; ubiquitination assay; lipid droplet staining; viral replication assay; interferon signaling reporter\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — reciprocal Co-IP plus ubiquitination assay with functional viral replication readout, single lab\",\n      \"pmids\": [\"41608635\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NUDT7 is a peroxisome-resident Nudix hydrolase that catalyzes the diphosphohydrolysis of CoA and acyl-CoAs to 3',5'-ADP and 4'-(acyl)phosphopantetheine, thereby regulating the size and composition of the peroxisomal (acyl-)CoA pool; through this activity it controls peroxisomal fatty acid oxidation, bile acid synthesis, and lipid homeostasis in the liver, and its loss activates downstream signaling cascades (Wnt/β-catenin, PPARγ, FOXM1) linked to lipid accumulation, chondrocyte death, and cancer-related phenotypes.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"NUDT7 is a peroxisome-resident Nudix hydrolase that regulates intracellular coenzyme A homeostasis and downstream lipid metabolism. It catalyzes the Mg²⁺/Mn²⁺-dependent diphosphohydrolysis of CoA, acyl-CoAs, and oxidized CoA to 3',5'-ADP and 4'-(acyl)phosphopantetheine, with kinetic parameters of Km ~240 µM and kcat ~3.8 s⁻¹ for free CoA [PMID:11415433, PMID:29378847]. In vivo, hepatic NUDT7 activity controls the size and composition of the peroxisomal short-chain and medium-chain acyl-CoA pool, thereby modulating peroxisomal fatty acid β-oxidation, bile acid conjugation, and cholesterol excretion [PMID:30846528, PMID:36436558]. Loss of NUDT7 causes palmitic acid and acetyl-CoA accumulation that activates PPARγ-dependent de novo lipogenesis, Wnt/β-catenin signaling in colorectal tumorigenesis, and FOXM1-driven chondrocyte senescence linked to osteoarthritis [PMID:36185359, PMID:32131398, PMID:30143643, PMID:37908734].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Establishing the enzymatic identity of NUDT7 as a peroxisomal CoA diphosphatase resolved the question of which enzyme degrades CoA within peroxisomes and defined its kinetic parameters and cofactor requirements.\",\n      \"evidence\": \"Recombinant enzyme kinetics, product identification, and RFP-fusion peroxisomal localization in HeLa cells\",\n      \"pmids\": [\"11415433\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Human NUDT7 kinetic parameters not directly measured in this study\", \"Physiological substrates in vivo not determined\", \"No structural information on active site\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Comparative enzymology with NUDT19 defined the distinct catalytic determinants and inhibitor sensitivities of the two mammalian CoA diphosphatases, establishing that their Nudix and CoA-binding motifs are functionally non-interchangeable.\",\n      \"evidence\": \"Domain-swap mutagenesis and competitive inhibitor binding assays with purified recombinant enzymes\",\n      \"pmids\": [\"29378847\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Crystal structure of NUDT7 with bound substrate not available\", \"Relative contributions of NUDT7 vs NUDT19 to tissue-level CoA regulation unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstration that NUDT7 loss disrupts lipid homeostasis and causes apoptotic chondrocyte death via PGAM1 upregulation established the first in vivo phenotypic consequence and a defined downstream effector pathway.\",\n      \"evidence\": \"Nudt7⁻/⁻ mouse model and siRNA knockdown in human chondrocytes with PGAM1 epistasis rescue\",\n      \"pmids\": [\"30143643\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking CoA depletion to PGAM1 transcription not defined\", \"Whether chondrocyte phenotype is peroxisome-autonomous not tested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Liver-specific overexpression demonstrated that NUDT7 directly modulates the hepatic peroxisomal CoA pool in vivo, reducing short-chain acyl-CoAs, bile acid content, and peroxisomal fatty acid oxidation rate.\",\n      \"evidence\": \"AAV-driven hepatic Nudt7 overexpression in mice with targeted/untargeted metabolomics and hepatocyte fatty acid oxidation assays\",\n      \"pmids\": [\"30846528\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Loss-of-function metabolomics not yet performed at this stage\", \"Effects on extra-hepatic tissues not assessed\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Connecting NUDT7 loss to Wnt/β-catenin activation in a carcinogen-driven colorectal cancer model revealed that palmitic acid accumulation from peroxisomal dysfunction feeds into oncogenic signaling.\",\n      \"evidence\": \"Nudt7⁻/⁻ mice treated with AOM/DSS; palmitic acid-chitosan colonic application phenocopying β-catenin upregulation\",\n      \"pmids\": [\"32131398\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular target of palmitic acid in Wnt activation not identified\", \"Human CRC relevance not validated\", \"Single laboratory finding\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Global Nudt7 knockout under Western diet conditions revealed sex-specific accumulation of medium-chain dicarboxylic acyl-CoAs and demonstrated that NUDT7 controls bile acid pool hydrophobicity and fecal cholesterol excretion, broadening its metabolic roles beyond simple CoA degradation.\",\n      \"evidence\": \"Nudt7⁻/⁻ mice on Western diet with hepatic CoA, bile acid, and fecal cholesterol metabolomics\",\n      \"pmids\": [\"36436558\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of sex-specific dicarboxylic acyl-CoA accumulation not elucidated\", \"Whether phenotype is peroxisome-autonomous vs. secondary to bile acid changes unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Heterozygous Nudt7 deletion linked palmitic acid accumulation to epigenetic activation (H3K4me3) of PPARγ promoters and de novo lipogenesis, providing a chromatin-level mechanism for how peroxisomal CoA hydrolase deficiency drives hepatic steatosis.\",\n      \"evidence\": \"Nudt7⁺/⁻ mouse with RNA-seq, ChIP for H3K4me3, PPARγ reporter assays, and lipogenesis measurement\",\n      \"pmids\": [\"36185359\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How palmitic acid increases H3K4me3 at PPARγ promoters mechanistically unresolved\", \"Single lab; independent replication lacking\", \"Haploinsufficiency model may not reflect complete loss\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Double knockout of Acot12 and Nudt7 demonstrated that combined disruption of peroxisomal CoA metabolism drives acetyl-CoA accumulation, FOXM1 upregulation, and chondrocyte senescence, extending the cartilage phenotype to a senescence pathway.\",\n      \"evidence\": \"Acot12⁻/⁻Nudt7⁻/⁻ double-knockout mouse with acetyl-CoA measurement, microarray, and immunohistochemistry\",\n      \"pmids\": [\"37908734\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Individual contribution of Nudt7 vs. Acot12 to acetyl-CoA accumulation not deconvoluted\", \"FOXM1 as direct transcriptional target of acetyl-CoA not mechanistically proven\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"During PRRSV infection, NUDT7 was found to interact with UBA52, promoting its proteasomal degradation and thereby stabilizing SREBF1 to drive lipid droplet formation and viral replication, revealing a non-enzymatic protein-protein interaction function.\",\n      \"evidence\": \"Co-immunoprecipitation, ubiquitination assays, and viral replication assays in cell culture\",\n      \"pmids\": [\"41608635\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether UBA52 interaction depends on NUDT7 hydrolase activity not tested\", \"Relevance to non-viral physiological contexts unknown\", \"Single laboratory, not independently confirmed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the crystal structure of NUDT7 with substrate, the mechanism by which CoA/acyl-CoA changes are transduced to nuclear epigenetic and transcriptional outputs, and whether NUDT7's protein-protein interaction with UBA52 is physiologically relevant outside viral infection.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No high-resolution structure of NUDT7\", \"Signal transduction from peroxisomal CoA pool to chromatin not mechanistically defined\", \"Tissue-specific and sex-specific regulation of NUDT7 expression poorly understood\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 1, 2, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005777\", \"supporting_discovery_ids\": [0, 9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 1, 2, 4, 5]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 6]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [6, 7]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"NUDT19\",\n      \"PGAM1\",\n      \"UBA52\",\n      \"ACOT12\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}