{"gene":"CDO1","run_date":"2026-04-28T17:28:52","timeline":{"discoveries":[{"year":2022,"finding":"CDO1 (Cdo1) interacts with PPARγ and facilitates recruitment of Med24 (a core subunit of the mediator complex) to ATGL and HSL gene promoters, thereby transactivating their expression and promoting lipolysis in adipose tissue. Adipose-specific Cdo1 knockout impairs lipolysis, energy expenditure, and cold tolerance, while overexpression ameliorates diet-induced obesity.","method":"Co-IP (Cdo1-PPARγ interaction), ChIP (Med24 recruitment to promoters), adipose-specific KO and transgenic overexpression mouse models with lipolysis/obesity phenotypic readouts","journal":"Nature metabolism","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, ChIP, and tissue-specific KO/OE with defined phenotype in multiple orthogonal experiments","pmids":["36253617"],"is_preprint":false},{"year":2023,"finding":"CDO1 (Cdo1) tethers Camkk2 to AMPK by physically interacting with both kinases, thereby activating AMPK signaling to promote fatty acid oxidation and mitochondrial biogenesis in hepatocytes. Exercise induces hepatic Cdo1 expression via the cAMP/PKA/CREB signaling pathway. Hepatocyte-specific Cdo1 KO impairs exercise-induced protection against NAFLD, while hepatocyte-specific overexpression synergizes with exercise to ameliorate NAFLD.","method":"Co-IP (Cdo1-Camkk2 and Cdo1-AMPK interactions), hepatocyte-specific KO (Cdo1LKO) and transgenic overexpression (Cdo1LTG) mice with NAFLD phenotypic readouts, cAMP/PKA/CREB pathway dissection","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP demonstrating ternary complex, tissue-specific KO and OE with defined metabolic phenotypes, upstream pathway mapped","pmids":["38110408"],"is_preprint":false},{"year":2024,"finding":"TRIM47, an E3 ubiquitin ligase, interacts with CDO1 via its B30.2 domain and facilitates K48-linked ubiquitination of CDO1, leading to decreased CDO1 protein abundance in hepatocellular carcinoma cells, thereby suppressing CDO1-mediated ferroptosis and promoting HCC proliferation, migration, and invasion.","method":"Co-IP (TRIM47-CDO1 interaction, B30.2 domain-dependence), ubiquitination assay (K48-linkage), gain- and loss-of-function experiments with ferroptosis and proliferation readouts","journal":"Free radical biology & medicine","confidence":"High","confidence_rationale":"Tier 2 — Co-IP with domain mapping, K48 ubiquitination assay, functional rescue experiments with defined ferroptosis phenotype","pmids":["38614226"],"is_preprint":false},{"year":2023,"finding":"The transcription factor HBP1 reduces UHRF1 expression at the transcriptional level; reduced UHRF1 then epigenetically upregulates CDO1, increasing cellular sensitivity to ferroptosis in hepatocellular carcinoma and cervical cancer cells.","method":"Transcriptional reporter assays, western blot for protein levels, ferroptosis sensitivity assays, epistasis via HBP1 overexpression → UHRF1 reduction → CDO1 upregulation","journal":"PLoS biology","confidence":"Medium","confidence_rationale":"Tier 2 — pathway epistasis with multiple components validated, but single lab with moderate orthogonal methods","pmids":["37406020"],"is_preprint":false},{"year":2024,"finding":"LncRNA FAM83H-AS1 recruits DNMT1 to the CDO1 promoter, increasing CDO1 promoter methylation and suppressing CDO1 expression in endometrial cancer cells, thereby inhibiting erastin-induced ferroptosis and promoting tumor growth in vivo.","method":"RNA-binding protein immunoprecipitation (FAM83H-AS1/DNMT1 interaction), chromatin immunoprecipitation (DNMT1 at CDO1 promoter), bisulfite-sequencing PCR for methylation, xenograft mouse model","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — RIP and ChIP for lncRNA-DNMT1-chromatin interaction, in vivo xenograft validation, multiple orthogonal methods in single study","pmids":["39159808"],"is_preprint":false},{"year":2024,"finding":"DNMT3L inhibits DNMT3A-mediated methylation of the CDO1 promoter by competitive inhibition, thereby upregulating CDO1 expression and suppressing hepatocellular carcinoma cell proliferation and metastasis.","method":"Methylation-specific PCR (MSP), western blot, dual-luciferase assay, in vitro and in vivo gain/loss-of-function experiments","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 — dual-luciferase and MSP with functional validation, single lab","pmids":["38308276"],"is_preprint":false},{"year":2025,"finding":"Ionizing radiation-induced oxidative stress triggers glutathionylation of CDO1 at cysteine 164 (C164), which impairs CDO1 enzymatic activity by disrupting its interaction with the substrate cysteine. This glutathionylation is essential for maintaining cellular redox homeostasis and cell viability under irradiation.","method":"Site-directed mutagenesis (C164 mutant), enzymatic activity assay, redox/glutathionylation biochemical assays, cell viability under ionizing radiation","journal":"Redox biology","confidence":"High","confidence_rationale":"Tier 1 — active-site mutagenesis with enzymatic activity assay and functional consequence of PTM, mechanistically rigorous","pmids":["40347691"],"is_preprint":false},{"year":2025,"finding":"AKT1 phosphorylates CDO1 at threonine 89 (T89) upon IL-6 treatment, repressing CDO1 enzymatic activity by disrupting iron incorporation, thereby increasing cysteine availability to support oral squamous cell carcinoma (OSCC) cell growth.","method":"Site-directed mutagenesis (T89 mutant), kinase assay (AKT1), enzymatic activity assay, in vitro and in vivo OSCC proliferation assays","journal":"Cell communication and signaling : CCS","confidence":"High","confidence_rationale":"Tier 1 — active-site mutagenesis, kinase identification, enzymatic activity assay with mechanistic explanation (iron incorporation disruption)","pmids":["40269955"],"is_preprint":false},{"year":2018,"finding":"Forced expression of CDO1 in colorectal cancer cell lines increases mitochondrial membrane potential (MMP) and confers chemoresistance and tolerance to hypoxic conditions, suggesting a functionally oncogenic property of CDO1 through MMP modulation.","method":"Stable CDO1 overexpression cell lines, JC-1 MMP assay, chemosensitivity assay, hypoxia tolerance assay","journal":"Annals of surgical oncology","confidence":"Medium","confidence_rationale":"Tier 2 — defined cellular phenotype with MMP functional assay in stable overexpression lines, single lab","pmids":["30311169"],"is_preprint":false},{"year":2020,"finding":"Forced expression of CDO1 in gastric cancer cell lines increases mitochondrial membrane potential (MMP) and augments cell survival under anaerobic conditions, consistent with CDO1 contributing to chemoresistance through MMP modulation.","method":"CDO1 forced expression, JC-1 MMP assay, anaerobic survival assay in gastric cancer cell lines","journal":"The Journal of surgical research","confidence":"Medium","confidence_rationale":"Tier 2 — functional cellular assay with defined mechanistic readout (MMP), consistent with prior colorectal cancer findings","pmids":["32777557"],"is_preprint":false},{"year":2023,"finding":"CRISPR/dCas9-Tet1CD-based targeted demethylation of the CDO1 promoter restores CDO1 expression in breast cancer cells, suppressing cell proliferation, migration, invasion, and promoting apoptosis and ferroptosis, establishing CDO1 promoter methylation as functionally causative for its silencing.","method":"LentiCRISPR/dCas9-Tet1CD targeted demethylation, methylation quantification (MethyLight), cell proliferation/migration/invasion/apoptosis/ferroptosis assays","journal":"Clinical and translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 — epigenetic editing directly links methylation to gene silencing and downstream functional phenotypes, single lab","pmids":["37740473"],"is_preprint":false},{"year":2025,"finding":"LRRC58 forms an active CUL2- or CUL5-based cullin-RING ligase (CRL) that selectively ubiquitylates CDO1 at Lys8, mediating its proteasomal degradation under cysteine starvation. When cysteine is replete, LRRC58 is auto-ubiquitinated and degraded; upon cysteine deprivation, LRRC58 is stabilized and targets CDO1 for degradation. This axis prevents ferroptotic cell death under cysteine scarcity. CDO1 mutations causing neurodevelopmental disease are refractory to LRRC58 recognition.","method":"Quantitative proteomics, active CRL profiling, biochemical reconstitution, cryo-EM structure of CDO1-LRRC58-CRL complex, saturation mutagenesis stability profiling, ubiquitination site mapping (Lys8)","journal":"bioRxiv","confidence":"High","confidence_rationale":"Tier 1 — cryo-EM structure, biochemical reconstitution, mutagenesis, and quantitative proteomics; multiple orthogonal methods in single preprint","pmids":["bio_10.1101_2025.11.14.688510"],"is_preprint":true},{"year":2025,"finding":"LRRC58 defines a CUL2-based E3 ubiquitin ligase complex that conditionally degrades CDO1 in response to cysteine abundance. When cysteine is replete, LRRC58 undergoes auto-ubiquitination and proteasomal degradation; upon cysteine deprivation, LRRC58 is stabilized and mediates CDO1 degradation to prevent ferroptosis. LRRC58 C-terminal residues are required for cysteine-dependent instability.","method":"CRL biochemical reconstitution, saturation mutagenesis, structural model validation, cellular stability assays, ferroptosis assays in CDO1/LRRC58 mutant cells","journal":"bioRxiv","confidence":"High","confidence_rationale":"Tier 1–2 — biochemical reconstitution, saturation mutagenesis, functional ferroptosis rescue; independent preprint corroborating the LRRC58-CDO1 axis","pmids":["bio_10.1101_2025.09.23.678073"],"is_preprint":true},{"year":2017,"finding":"CDO1-null mice are unable to synthesize hypotaurine and taurine via the cysteine/cysteine sulfinate pathway, leading to very low taurine in all tissues. Taurine depletion strongly regulates hepatic expression of CSAD, BHMT, CYP7A1, and CYP3A11; dietary taurine supplementation of Cdo1-null mice restores these to wild-type levels, demonstrating CDO1 is the essential entry point for taurine synthesis.","method":"Cdo1-null mouse model, dietary taurine supplementation rescue, hepatic protein/mRNA quantification","journal":"Advances in experimental medicine and biology","confidence":"High","confidence_rationale":"Tier 2 — genetic KO with defined biochemical phenotype and dietary rescue, establishing pathway position","pmids":["28849476"],"is_preprint":false},{"year":2025,"finding":"CDO1 knockdown in a rat osteoarthritis model significantly delayed OA progression, with improved cartilage structure, increased chondrocyte numbers, and enhanced type II collagen expression, identifying CDO1 as a contributor to OA progression through ferroptosis and related pathways.","method":"siRNA-mediated CDO1 knockdown in vivo rat OA model, histology, immunohistochemistry for type II collagen and chondrocyte markers","journal":"Endocrine, metabolic & immune disorders drug targets","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo KD with defined histological phenotype, single lab","pmids":["41017094"],"is_preprint":false},{"year":2025,"finding":"CDO1 negatively regulates ACSM3 expression in renal tubular epithelial cells; CDO1 knockdown alleviates lipid deposition and cellular injury in lupus nephritis by restoring ACSM3-mediated lipid metabolism, with ACSM3 deficiency reversing these protective effects and mediating mitochondrial morphological abnormalities and dysfunction.","method":"CDO1 knockdown in vitro (HK-2 and TCMK-1 cells) and in vivo (MRL/lpr mice), ACSM3 rescue experiments, mitochondrial morphology and function assays, lipid deposition quantification","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 — genetic KD with pathway epistasis (ACSM3 rescue) and in vivo validation, single lab","pmids":["41827894"],"is_preprint":false},{"year":2014,"finding":"CDO1 promoter DNA methylation is negatively correlated with CDO1 gene expression across multiple cancer cell lines, establishing promoter methylation as the primary epigenetic mechanism silencing CDO1 expression in gastrointestinal cancers.","method":"Quantitative methylation-specific PCR (qMSP) paired with real-time RT-PCR expression analysis across 74 cancer cell lines","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 3 — correlation of methylation with expression across many cell lines, no functional rescue, but replicated across multiple cancer types","pmids":["24948044"],"is_preprint":false}],"current_model":"CDO1 is a non-heme Fe(II) dioxygenase that catalyzes the rate-limiting oxidation of cysteine to cysteine sulfinic acid, the entry point for taurine synthesis; its enzymatic activity is regulated post-translationally by AKT1-mediated phosphorylation at T89 (repressing activity via iron incorporation disruption) and by glutathionylation at C164 under oxidative stress, while its protein abundance is controlled by the LRRC58-CUL2/CUL5 cullin-RING E3 ligase (ubiquitylating CDO1 at K48/Lys8 for proteasomal degradation under cysteine deprivation) and by TRIM47-mediated K48-linked ubiquitination in HCC; beyond cysteine catabolism, CDO1 also functions as a transcriptional co-activator by interacting with PPARγ and recruiting the mediator subunit Med24 to lipolytic gene promoters (ATGL, HSL), and scaffolds Camkk2-AMPK to activate fatty acid oxidation and mitochondrial biogenesis in hepatocytes downstream of exercise-induced cAMP/PKA/CREB signaling, while its promoter is epigenetically silenced by DNMT1 (recruited by lncRNA FAM83H-AS1) and DNMT3A in multiple cancers, with silencing promoting ferroptosis resistance and tumor progression."},"narrative":{"teleology":[{"year":2014,"claim":"Whether CDO1 silencing in cancer is epigenetically driven was addressed by demonstrating that CDO1 promoter DNA methylation inversely correlates with CDO1 expression across diverse cancer cell lines, establishing promoter methylation as the primary silencing mechanism.","evidence":"Quantitative methylation-specific PCR paired with RT-PCR across 74 cancer cell lines","pmids":["24948044"],"confidence":"Medium","gaps":["Correlation-based; no functional demethylation rescue performed in this study","Upstream factors recruiting DNMTs to CDO1 promoter not identified"]},{"year":2017,"claim":"Whether CDO1 is the obligate enzyme for taurine biosynthesis was resolved by showing that Cdo1-null mice lack hypotaurine and taurine in all tissues, and dietary taurine supplementation rescues downstream hepatic gene expression changes.","evidence":"Cdo1-null mouse model with dietary taurine rescue and hepatic gene expression profiling","pmids":["28849476"],"confidence":"High","gaps":["Whether CDO1 has cysteine-independent enzymatic substrates in vivo remains untested","Contribution of cysteamine dioxygenase activity versus cysteine dioxygenase activity not dissected"]},{"year":2022,"claim":"Whether CDO1 has functions beyond cysteine catabolism was answered by discovering that CDO1 interacts with PPARγ and recruits the mediator subunit Med24 to ATGL/HSL promoters, transactivating lipolysis in adipose tissue independently of its enzymatic activity.","evidence":"Co-IP of CDO1–PPARγ, ChIP for Med24 at promoters, adipose-specific KO and overexpression mouse models with lipolysis and obesity phenotypes","pmids":["36253617"],"confidence":"High","gaps":["Whether the co-activator function requires the CDO1 iron-binding site or is structurally separable from enzymatic activity","Direct DNA-binding contribution of CDO1 versus purely scaffolding role not resolved"]},{"year":2023,"claim":"CDO1's non-enzymatic scaffolding role was extended to hepatic AMPK signaling, where CDO1 physically tethers Camkk2 to AMPK to activate fatty acid oxidation and mitochondrial biogenesis, with hepatic expression induced by the cAMP/PKA/CREB axis during exercise.","evidence":"Co-IP of CDO1–Camkk2 and CDO1–AMPK, hepatocyte-specific KO and overexpression mice with NAFLD readouts and upstream pathway dissection","pmids":["38110408"],"confidence":"High","gaps":["Structural basis for CDO1 scaffolding Camkk2–AMPK unknown","Whether enzymatic and scaffolding functions of CDO1 are simultaneously active in the same cell"]},{"year":2023,"claim":"Functional causation of epigenetic silencing was demonstrated: targeted demethylation of the CDO1 promoter by dCas9-Tet1CD restores CDO1 expression and induces ferroptosis, apoptosis, and growth suppression in breast cancer cells, and the HBP1–UHRF1 axis epigenetically regulates CDO1 to control ferroptosis sensitivity.","evidence":"CRISPR/dCas9-Tet1CD epigenetic editing with functional phenotypic assays; HBP1 overexpression–UHRF1 epistasis in HCC/cervical cancer cells","pmids":["37740473","37406020"],"confidence":"Medium","gaps":["Whether CDO1's ferroptosis-promoting function operates through cysteine depletion, taurine production, or an independent mechanism is not fully resolved","Single-lab studies for each"]},{"year":2024,"claim":"How CDO1 protein abundance is regulated by ubiquitination was clarified: TRIM47 ubiquitinates CDO1 via K48-linkage through its B30.2 domain in HCC, suppressing CDO1-mediated ferroptosis and promoting tumor progression; meanwhile, DNMT1 is recruited to the CDO1 promoter by lncRNA FAM83H-AS1 in endometrial cancer and DNMT3A silences CDO1 in HCC.","evidence":"Co-IP with domain mapping, K48 ubiquitination assays, ferroptosis rescue; RIP and ChIP for lncRNA–DNMT1–CDO1 promoter; MSP and dual-luciferase for DNMT3A","pmids":["38614226","39159808","38308276"],"confidence":"High","gaps":["Relative contributions of transcriptional silencing versus post-translational degradation to CDO1 loss in individual tumor contexts not quantified","Whether TRIM47 and LRRC58 compete for CDO1 binding"]},{"year":2025,"claim":"Post-translational regulation of CDO1 enzymatic activity was mechanistically resolved: AKT1 phosphorylates CDO1 at T89 to disrupt iron incorporation and repress activity (promoting OSCC growth), while oxidative stress-induced glutathionylation at C164 impairs substrate binding and is required for redox homeostasis under ionizing radiation.","evidence":"Kinase assay with AKT1, T89 mutagenesis, iron incorporation and enzymatic activity assays; C164 mutagenesis, glutathionylation biochemistry, radiation survival assays","pmids":["40269955","40347691"],"confidence":"High","gaps":["Whether T89 phosphorylation and C164 glutathionylation occur simultaneously or are mutually exclusive","Structural consequences of these PTMs not visualized at atomic resolution"]},{"year":2025,"claim":"A cysteine-sensing degradation circuit for CDO1 was defined: LRRC58 assembles a CUL2/CUL5-based E3 ligase that ubiquitylates CDO1 at Lys8 for proteasomal degradation under cysteine deprivation; LRRC58 itself is auto-ubiquitinated and degraded when cysteine is abundant, creating a substrate-sensing toggle that prevents ferroptosis.","evidence":"Cryo-EM structure of CDO1–LRRC58–CRL complex, biochemical reconstitution, saturation mutagenesis, ferroptosis assays (two independent preprints)","pmids":["bio_10.1101_2025.11.14.688510","bio_10.1101_2025.09.23.678073"],"confidence":"High","gaps":["Preprint status; peer review pending","How LRRC58 senses cysteine concentration at the molecular level (cysteine-binding site on LRRC58 not mapped)","Disease-associated CDO1 mutations refractory to LRRC58: clinical characterization incomplete"]},{"year":null,"claim":"How CDO1's enzymatic and non-enzymatic (scaffolding/co-activator) functions are coordinated in the same cell, whether they are mutually exclusive or operate in distinct subcellular pools, and the structural basis for the co-activator interaction with PPARγ remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structure of CDO1–PPARγ–Med24 complex","Whether enzymatic-dead CDO1 mutants retain full scaffolding/co-activator function not systematically tested","In vivo tissue-specific balance of cysteine catabolism versus signaling functions not quantified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016491","term_label":"oxidoreductase activity","supporting_discovery_ids":[6,7,13]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[6,7]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,1,13]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[2,3,4,10]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[2,11,12]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,4,5]}],"complexes":[],"partners":["PPARG","MED24","CAMKK2","PRKAA1","TRIM47","LRRC58","AKT1"],"other_free_text":[]},"mechanistic_narrative":"CDO1 is a non-heme iron(II)-dependent dioxygenase that catalyzes the oxidation of cysteine to cysteine sulfinic acid, serving as the essential and rate-limiting entry point for taurine biosynthesis [PMID:28849476]. Its enzymatic activity is post-translationally regulated by AKT1-mediated phosphorylation at T89, which disrupts iron incorporation [PMID:40269955], and by glutathionylation at C164 under oxidative stress, which impairs substrate binding [PMID:40347691]; its protein abundance is controlled by TRIM47-mediated K48-linked ubiquitination in hepatocellular carcinoma [PMID:38614226] and by the LRRC58-CUL2 cullin-RING E3 ligase that conditionally degrades CDO1 at Lys8 under cysteine deprivation to prevent ferroptosis [PMID:bio_10.1101_2025.11.14.688510, PMID:bio_10.1101_2025.09.23.678073]. Beyond cysteine catabolism, CDO1 functions as a transcriptional co-activator by interacting with PPARγ and recruiting the mediator subunit Med24 to lipolytic gene promoters in adipose tissue [PMID:36253617], and scaffolds Camkk2–AMPK to activate fatty acid oxidation and mitochondrial biogenesis in hepatocytes downstream of exercise-induced cAMP/PKA/CREB signaling [PMID:38110408]. CDO1 promoter hypermethylation by DNMT1 (recruited by lncRNA FAM83H-AS1) and DNMT3A silences CDO1 expression across multiple cancers, conferring ferroptosis resistance and promoting tumor progression [PMID:39159808, PMID:38308276, PMID:37740473]."},"prefetch_data":{"uniprot":{"accession":"Q16878","full_name":"Cysteine dioxygenase type 1","aliases":["Cysteine dioxygenase type I","CDO","CDO-I"],"length_aa":200,"mass_kda":23.0,"function":"Catalyzes the oxidation of cysteine to cysteine sulfinic acid with addition of molecular dioxygen","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q16878/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CDO1","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/CDO1","total_profiled":1310},"omim":[{"mim_id":"603943","title":"CYSTEINE DIOXYGENASE; CDO","url":"https://www.omim.org/entry/603943"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Uncertain","locations":[{"location":"Nucleoplasm","reliability":"Uncertain"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"choroid plexus","ntpm":318.9},{"tissue":"liver","ntpm":473.7}],"url":"https://www.proteinatlas.org/search/CDO1"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q16878","domains":[{"cath_id":"2.60.120.10","chopping":"11-180","consensus_level":"high","plddt":97.0609,"start":11,"end":180}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q16878","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q16878-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q16878-F1-predicted_aligned_error_v6.png","plddt_mean":93.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CDO1","jax_strain_url":"https://www.jax.org/strain/search?query=CDO1"},"sequence":{"accession":"Q16878","fasta_url":"https://rest.uniprot.org/uniprotkb/Q16878.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q16878/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q16878"}},"corpus_meta":[{"pmid":"18033314","id":"PMC_18033314","title":"Sézary syndrome is a unique cutaneous T-cell lymphoma as identified by an expanded gene signature including diagnostic marker molecules CDO1 and DNM3.","date":"2007","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/18033314","citation_count":83,"is_preprint":false},{"pmid":"24948044","id":"PMC_24948044","title":"The novel colorectal cancer biomarkers CDO1, ZSCAN18 and ZNF331 are frequently methylated across gastrointestinal cancers.","date":"2014","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/24948044","citation_count":72,"is_preprint":false},{"pmid":"24486589","id":"PMC_24486589","title":"Functional identification of cancer-specific methylation of CDO1, HOXA9, and TAC1 for the diagnosis of lung cancer.","date":"2014","source":"Clinical cancer research : an official journal of the American Association for Cancer 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research","url":"https://pubmed.ncbi.nlm.nih.gov/32777557","citation_count":4,"is_preprint":false},{"pmid":"38732110","id":"PMC_38732110","title":"Analysis of CDO1, PITX2, and CDH13 Gene Methylation in Early Endometrial Cancer for Prediction of Medical Treatment Outcomes.","date":"2024","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/38732110","citation_count":3,"is_preprint":false},{"pmid":"31069006","id":"PMC_31069006","title":"Prediction of onset of remnant gastric cancer by promoter DNA methylation of CDO1/HOPX/Reprimo/E-cadherin.","date":"2019","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/31069006","citation_count":3,"is_preprint":false},{"pmid":"41017094","id":"PMC_41017094","title":"Integrated Multiomics Analysis Identifies CDO1 as a Novel Therapeutic Target for Osteoarthritis.","date":"2025","source":"Endocrine, metabolic & immune disorders drug 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\"CDO1 (Cdo1) interacts with PPARγ and facilitates recruitment of Med24 (a core subunit of the mediator complex) to ATGL and HSL gene promoters, thereby transactivating their expression and promoting lipolysis in adipose tissue. Adipose-specific Cdo1 knockout impairs lipolysis, energy expenditure, and cold tolerance, while overexpression ameliorates diet-induced obesity.\",\n      \"method\": \"Co-IP (Cdo1-PPARγ interaction), ChIP (Med24 recruitment to promoters), adipose-specific KO and transgenic overexpression mouse models with lipolysis/obesity phenotypic readouts\",\n      \"journal\": \"Nature metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, ChIP, and tissue-specific KO/OE with defined phenotype in multiple orthogonal experiments\",\n      \"pmids\": [\"36253617\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CDO1 (Cdo1) tethers Camkk2 to AMPK by physically interacting with both kinases, thereby activating AMPK signaling to promote fatty acid oxidation and mitochondrial biogenesis in hepatocytes. Exercise induces hepatic Cdo1 expression via the cAMP/PKA/CREB signaling pathway. Hepatocyte-specific Cdo1 KO impairs exercise-induced protection against NAFLD, while hepatocyte-specific overexpression synergizes with exercise to ameliorate NAFLD.\",\n      \"method\": \"Co-IP (Cdo1-Camkk2 and Cdo1-AMPK interactions), hepatocyte-specific KO (Cdo1LKO) and transgenic overexpression (Cdo1LTG) mice with NAFLD phenotypic readouts, cAMP/PKA/CREB pathway dissection\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP demonstrating ternary complex, tissue-specific KO and OE with defined metabolic phenotypes, upstream pathway mapped\",\n      \"pmids\": [\"38110408\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TRIM47, an E3 ubiquitin ligase, interacts with CDO1 via its B30.2 domain and facilitates K48-linked ubiquitination of CDO1, leading to decreased CDO1 protein abundance in hepatocellular carcinoma cells, thereby suppressing CDO1-mediated ferroptosis and promoting HCC proliferation, migration, and invasion.\",\n      \"method\": \"Co-IP (TRIM47-CDO1 interaction, B30.2 domain-dependence), ubiquitination assay (K48-linkage), gain- and loss-of-function experiments with ferroptosis and proliferation readouts\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP with domain mapping, K48 ubiquitination assay, functional rescue experiments with defined ferroptosis phenotype\",\n      \"pmids\": [\"38614226\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The transcription factor HBP1 reduces UHRF1 expression at the transcriptional level; reduced UHRF1 then epigenetically upregulates CDO1, increasing cellular sensitivity to ferroptosis in hepatocellular carcinoma and cervical cancer cells.\",\n      \"method\": \"Transcriptional reporter assays, western blot for protein levels, ferroptosis sensitivity assays, epistasis via HBP1 overexpression → UHRF1 reduction → CDO1 upregulation\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pathway epistasis with multiple components validated, but single lab with moderate orthogonal methods\",\n      \"pmids\": [\"37406020\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"LncRNA FAM83H-AS1 recruits DNMT1 to the CDO1 promoter, increasing CDO1 promoter methylation and suppressing CDO1 expression in endometrial cancer cells, thereby inhibiting erastin-induced ferroptosis and promoting tumor growth in vivo.\",\n      \"method\": \"RNA-binding protein immunoprecipitation (FAM83H-AS1/DNMT1 interaction), chromatin immunoprecipitation (DNMT1 at CDO1 promoter), bisulfite-sequencing PCR for methylation, xenograft mouse model\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — RIP and ChIP for lncRNA-DNMT1-chromatin interaction, in vivo xenograft validation, multiple orthogonal methods in single study\",\n      \"pmids\": [\"39159808\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"DNMT3L inhibits DNMT3A-mediated methylation of the CDO1 promoter by competitive inhibition, thereby upregulating CDO1 expression and suppressing hepatocellular carcinoma cell proliferation and metastasis.\",\n      \"method\": \"Methylation-specific PCR (MSP), western blot, dual-luciferase assay, in vitro and in vivo gain/loss-of-function experiments\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — dual-luciferase and MSP with functional validation, single lab\",\n      \"pmids\": [\"38308276\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Ionizing radiation-induced oxidative stress triggers glutathionylation of CDO1 at cysteine 164 (C164), which impairs CDO1 enzymatic activity by disrupting its interaction with the substrate cysteine. This glutathionylation is essential for maintaining cellular redox homeostasis and cell viability under irradiation.\",\n      \"method\": \"Site-directed mutagenesis (C164 mutant), enzymatic activity assay, redox/glutathionylation biochemical assays, cell viability under ionizing radiation\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — active-site mutagenesis with enzymatic activity assay and functional consequence of PTM, mechanistically rigorous\",\n      \"pmids\": [\"40347691\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"AKT1 phosphorylates CDO1 at threonine 89 (T89) upon IL-6 treatment, repressing CDO1 enzymatic activity by disrupting iron incorporation, thereby increasing cysteine availability to support oral squamous cell carcinoma (OSCC) cell growth.\",\n      \"method\": \"Site-directed mutagenesis (T89 mutant), kinase assay (AKT1), enzymatic activity assay, in vitro and in vivo OSCC proliferation assays\",\n      \"journal\": \"Cell communication and signaling : CCS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — active-site mutagenesis, kinase identification, enzymatic activity assay with mechanistic explanation (iron incorporation disruption)\",\n      \"pmids\": [\"40269955\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Forced expression of CDO1 in colorectal cancer cell lines increases mitochondrial membrane potential (MMP) and confers chemoresistance and tolerance to hypoxic conditions, suggesting a functionally oncogenic property of CDO1 through MMP modulation.\",\n      \"method\": \"Stable CDO1 overexpression cell lines, JC-1 MMP assay, chemosensitivity assay, hypoxia tolerance assay\",\n      \"journal\": \"Annals of surgical oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — defined cellular phenotype with MMP functional assay in stable overexpression lines, single lab\",\n      \"pmids\": [\"30311169\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Forced expression of CDO1 in gastric cancer cell lines increases mitochondrial membrane potential (MMP) and augments cell survival under anaerobic conditions, consistent with CDO1 contributing to chemoresistance through MMP modulation.\",\n      \"method\": \"CDO1 forced expression, JC-1 MMP assay, anaerobic survival assay in gastric cancer cell lines\",\n      \"journal\": \"The Journal of surgical research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional cellular assay with defined mechanistic readout (MMP), consistent with prior colorectal cancer findings\",\n      \"pmids\": [\"32777557\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CRISPR/dCas9-Tet1CD-based targeted demethylation of the CDO1 promoter restores CDO1 expression in breast cancer cells, suppressing cell proliferation, migration, invasion, and promoting apoptosis and ferroptosis, establishing CDO1 promoter methylation as functionally causative for its silencing.\",\n      \"method\": \"LentiCRISPR/dCas9-Tet1CD targeted demethylation, methylation quantification (MethyLight), cell proliferation/migration/invasion/apoptosis/ferroptosis assays\",\n      \"journal\": \"Clinical and translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — epigenetic editing directly links methylation to gene silencing and downstream functional phenotypes, single lab\",\n      \"pmids\": [\"37740473\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"LRRC58 forms an active CUL2- or CUL5-based cullin-RING ligase (CRL) that selectively ubiquitylates CDO1 at Lys8, mediating its proteasomal degradation under cysteine starvation. When cysteine is replete, LRRC58 is auto-ubiquitinated and degraded; upon cysteine deprivation, LRRC58 is stabilized and targets CDO1 for degradation. This axis prevents ferroptotic cell death under cysteine scarcity. CDO1 mutations causing neurodevelopmental disease are refractory to LRRC58 recognition.\",\n      \"method\": \"Quantitative proteomics, active CRL profiling, biochemical reconstitution, cryo-EM structure of CDO1-LRRC58-CRL complex, saturation mutagenesis stability profiling, ubiquitination site mapping (Lys8)\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — cryo-EM structure, biochemical reconstitution, mutagenesis, and quantitative proteomics; multiple orthogonal methods in single preprint\",\n      \"pmids\": [\"bio_10.1101_2025.11.14.688510\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"LRRC58 defines a CUL2-based E3 ubiquitin ligase complex that conditionally degrades CDO1 in response to cysteine abundance. When cysteine is replete, LRRC58 undergoes auto-ubiquitination and proteasomal degradation; upon cysteine deprivation, LRRC58 is stabilized and mediates CDO1 degradation to prevent ferroptosis. LRRC58 C-terminal residues are required for cysteine-dependent instability.\",\n      \"method\": \"CRL biochemical reconstitution, saturation mutagenesis, structural model validation, cellular stability assays, ferroptosis assays in CDO1/LRRC58 mutant cells\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — biochemical reconstitution, saturation mutagenesis, functional ferroptosis rescue; independent preprint corroborating the LRRC58-CDO1 axis\",\n      \"pmids\": [\"bio_10.1101_2025.09.23.678073\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CDO1-null mice are unable to synthesize hypotaurine and taurine via the cysteine/cysteine sulfinate pathway, leading to very low taurine in all tissues. Taurine depletion strongly regulates hepatic expression of CSAD, BHMT, CYP7A1, and CYP3A11; dietary taurine supplementation of Cdo1-null mice restores these to wild-type levels, demonstrating CDO1 is the essential entry point for taurine synthesis.\",\n      \"method\": \"Cdo1-null mouse model, dietary taurine supplementation rescue, hepatic protein/mRNA quantification\",\n      \"journal\": \"Advances in experimental medicine and biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with defined biochemical phenotype and dietary rescue, establishing pathway position\",\n      \"pmids\": [\"28849476\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CDO1 knockdown in a rat osteoarthritis model significantly delayed OA progression, with improved cartilage structure, increased chondrocyte numbers, and enhanced type II collagen expression, identifying CDO1 as a contributor to OA progression through ferroptosis and related pathways.\",\n      \"method\": \"siRNA-mediated CDO1 knockdown in vivo rat OA model, histology, immunohistochemistry for type II collagen and chondrocyte markers\",\n      \"journal\": \"Endocrine, metabolic & immune disorders drug targets\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo KD with defined histological phenotype, single lab\",\n      \"pmids\": [\"41017094\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CDO1 negatively regulates ACSM3 expression in renal tubular epithelial cells; CDO1 knockdown alleviates lipid deposition and cellular injury in lupus nephritis by restoring ACSM3-mediated lipid metabolism, with ACSM3 deficiency reversing these protective effects and mediating mitochondrial morphological abnormalities and dysfunction.\",\n      \"method\": \"CDO1 knockdown in vitro (HK-2 and TCMK-1 cells) and in vivo (MRL/lpr mice), ACSM3 rescue experiments, mitochondrial morphology and function assays, lipid deposition quantification\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic KD with pathway epistasis (ACSM3 rescue) and in vivo validation, single lab\",\n      \"pmids\": [\"41827894\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CDO1 promoter DNA methylation is negatively correlated with CDO1 gene expression across multiple cancer cell lines, establishing promoter methylation as the primary epigenetic mechanism silencing CDO1 expression in gastrointestinal cancers.\",\n      \"method\": \"Quantitative methylation-specific PCR (qMSP) paired with real-time RT-PCR expression analysis across 74 cancer cell lines\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — correlation of methylation with expression across many cell lines, no functional rescue, but replicated across multiple cancer types\",\n      \"pmids\": [\"24948044\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CDO1 is a non-heme Fe(II) dioxygenase that catalyzes the rate-limiting oxidation of cysteine to cysteine sulfinic acid, the entry point for taurine synthesis; its enzymatic activity is regulated post-translationally by AKT1-mediated phosphorylation at T89 (repressing activity via iron incorporation disruption) and by glutathionylation at C164 under oxidative stress, while its protein abundance is controlled by the LRRC58-CUL2/CUL5 cullin-RING E3 ligase (ubiquitylating CDO1 at K48/Lys8 for proteasomal degradation under cysteine deprivation) and by TRIM47-mediated K48-linked ubiquitination in HCC; beyond cysteine catabolism, CDO1 also functions as a transcriptional co-activator by interacting with PPARγ and recruiting the mediator subunit Med24 to lipolytic gene promoters (ATGL, HSL), and scaffolds Camkk2-AMPK to activate fatty acid oxidation and mitochondrial biogenesis in hepatocytes downstream of exercise-induced cAMP/PKA/CREB signaling, while its promoter is epigenetically silenced by DNMT1 (recruited by lncRNA FAM83H-AS1) and DNMT3A in multiple cancers, with silencing promoting ferroptosis resistance and tumor progression.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"CDO1 is a non-heme iron(II)-dependent dioxygenase that catalyzes the oxidation of cysteine to cysteine sulfinic acid, serving as the essential and rate-limiting entry point for taurine biosynthesis [PMID:28849476]. Its enzymatic activity is post-translationally regulated by AKT1-mediated phosphorylation at T89, which disrupts iron incorporation [PMID:40269955], and by glutathionylation at C164 under oxidative stress, which impairs substrate binding [PMID:40347691]; its protein abundance is controlled by TRIM47-mediated K48-linked ubiquitination in hepatocellular carcinoma [PMID:38614226] and by the LRRC58-CUL2 cullin-RING E3 ligase that conditionally degrades CDO1 at Lys8 under cysteine deprivation to prevent ferroptosis [PMID:bio_10.1101_2025.11.14.688510, PMID:bio_10.1101_2025.09.23.678073]. Beyond cysteine catabolism, CDO1 functions as a transcriptional co-activator by interacting with PPARγ and recruiting the mediator subunit Med24 to lipolytic gene promoters in adipose tissue [PMID:36253617], and scaffolds Camkk2–AMPK to activate fatty acid oxidation and mitochondrial biogenesis in hepatocytes downstream of exercise-induced cAMP/PKA/CREB signaling [PMID:38110408]. CDO1 promoter hypermethylation by DNMT1 (recruited by lncRNA FAM83H-AS1) and DNMT3A silences CDO1 expression across multiple cancers, conferring ferroptosis resistance and promoting tumor progression [PMID:39159808, PMID:38308276, PMID:37740473].\",\n  \"teleology\": [\n    {\n      \"year\": 2014,\n      \"claim\": \"Whether CDO1 silencing in cancer is epigenetically driven was addressed by demonstrating that CDO1 promoter DNA methylation inversely correlates with CDO1 expression across diverse cancer cell lines, establishing promoter methylation as the primary silencing mechanism.\",\n      \"evidence\": \"Quantitative methylation-specific PCR paired with RT-PCR across 74 cancer cell lines\",\n      \"pmids\": [\"24948044\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Correlation-based; no functional demethylation rescue performed in this study\", \"Upstream factors recruiting DNMTs to CDO1 promoter not identified\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Whether CDO1 is the obligate enzyme for taurine biosynthesis was resolved by showing that Cdo1-null mice lack hypotaurine and taurine in all tissues, and dietary taurine supplementation rescues downstream hepatic gene expression changes.\",\n      \"evidence\": \"Cdo1-null mouse model with dietary taurine rescue and hepatic gene expression profiling\",\n      \"pmids\": [\"28849476\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CDO1 has cysteine-independent enzymatic substrates in vivo remains untested\", \"Contribution of cysteamine dioxygenase activity versus cysteine dioxygenase activity not dissected\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Whether CDO1 has functions beyond cysteine catabolism was answered by discovering that CDO1 interacts with PPARγ and recruits the mediator subunit Med24 to ATGL/HSL promoters, transactivating lipolysis in adipose tissue independently of its enzymatic activity.\",\n      \"evidence\": \"Co-IP of CDO1–PPARγ, ChIP for Med24 at promoters, adipose-specific KO and overexpression mouse models with lipolysis and obesity phenotypes\",\n      \"pmids\": [\"36253617\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the co-activator function requires the CDO1 iron-binding site or is structurally separable from enzymatic activity\", \"Direct DNA-binding contribution of CDO1 versus purely scaffolding role not resolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"CDO1's non-enzymatic scaffolding role was extended to hepatic AMPK signaling, where CDO1 physically tethers Camkk2 to AMPK to activate fatty acid oxidation and mitochondrial biogenesis, with hepatic expression induced by the cAMP/PKA/CREB axis during exercise.\",\n      \"evidence\": \"Co-IP of CDO1–Camkk2 and CDO1–AMPK, hepatocyte-specific KO and overexpression mice with NAFLD readouts and upstream pathway dissection\",\n      \"pmids\": [\"38110408\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for CDO1 scaffolding Camkk2–AMPK unknown\", \"Whether enzymatic and scaffolding functions of CDO1 are simultaneously active in the same cell\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Functional causation of epigenetic silencing was demonstrated: targeted demethylation of the CDO1 promoter by dCas9-Tet1CD restores CDO1 expression and induces ferroptosis, apoptosis, and growth suppression in breast cancer cells, and the HBP1–UHRF1 axis epigenetically regulates CDO1 to control ferroptosis sensitivity.\",\n      \"evidence\": \"CRISPR/dCas9-Tet1CD epigenetic editing with functional phenotypic assays; HBP1 overexpression–UHRF1 epistasis in HCC/cervical cancer cells\",\n      \"pmids\": [\"37740473\", \"37406020\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether CDO1's ferroptosis-promoting function operates through cysteine depletion, taurine production, or an independent mechanism is not fully resolved\", \"Single-lab studies for each\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"How CDO1 protein abundance is regulated by ubiquitination was clarified: TRIM47 ubiquitinates CDO1 via K48-linkage through its B30.2 domain in HCC, suppressing CDO1-mediated ferroptosis and promoting tumor progression; meanwhile, DNMT1 is recruited to the CDO1 promoter by lncRNA FAM83H-AS1 in endometrial cancer and DNMT3A silences CDO1 in HCC.\",\n      \"evidence\": \"Co-IP with domain mapping, K48 ubiquitination assays, ferroptosis rescue; RIP and ChIP for lncRNA–DNMT1–CDO1 promoter; MSP and dual-luciferase for DNMT3A\",\n      \"pmids\": [\"38614226\", \"39159808\", \"38308276\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contributions of transcriptional silencing versus post-translational degradation to CDO1 loss in individual tumor contexts not quantified\", \"Whether TRIM47 and LRRC58 compete for CDO1 binding\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Post-translational regulation of CDO1 enzymatic activity was mechanistically resolved: AKT1 phosphorylates CDO1 at T89 to disrupt iron incorporation and repress activity (promoting OSCC growth), while oxidative stress-induced glutathionylation at C164 impairs substrate binding and is required for redox homeostasis under ionizing radiation.\",\n      \"evidence\": \"Kinase assay with AKT1, T89 mutagenesis, iron incorporation and enzymatic activity assays; C164 mutagenesis, glutathionylation biochemistry, radiation survival assays\",\n      \"pmids\": [\"40269955\", \"40347691\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether T89 phosphorylation and C164 glutathionylation occur simultaneously or are mutually exclusive\", \"Structural consequences of these PTMs not visualized at atomic resolution\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"A cysteine-sensing degradation circuit for CDO1 was defined: LRRC58 assembles a CUL2/CUL5-based E3 ligase that ubiquitylates CDO1 at Lys8 for proteasomal degradation under cysteine deprivation; LRRC58 itself is auto-ubiquitinated and degraded when cysteine is abundant, creating a substrate-sensing toggle that prevents ferroptosis.\",\n      \"evidence\": \"Cryo-EM structure of CDO1–LRRC58–CRL complex, biochemical reconstitution, saturation mutagenesis, ferroptosis assays (two independent preprints)\",\n      \"pmids\": [\"bio_10.1101_2025.11.14.688510\", \"bio_10.1101_2025.09.23.678073\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Preprint status; peer review pending\", \"How LRRC58 senses cysteine concentration at the molecular level (cysteine-binding site on LRRC58 not mapped)\", \"Disease-associated CDO1 mutations refractory to LRRC58: clinical characterization incomplete\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CDO1's enzymatic and non-enzymatic (scaffolding/co-activator) functions are coordinated in the same cell, whether they are mutually exclusive or operate in distinct subcellular pools, and the structural basis for the co-activator interaction with PPARγ remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structure of CDO1–PPARγ–Med24 complex\", \"Whether enzymatic-dead CDO1 mutants retain full scaffolding/co-activator function not systematically tested\", \"In vivo tissue-specific balance of cysteine catabolism versus signaling functions not quantified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [6, 7, 13]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [6, 7]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 1, 13]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [2, 3, 4, 10]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [2, 11, 12]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 4, 5]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"PPARG\",\n      \"MED24\",\n      \"CAMKK2\",\n      \"PRKAA1\",\n      \"TRIM47\",\n      \"LRRC58\",\n      \"AKT1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}