{"gene":"CDO1","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":2023,"finding":"CDO1 tethers CaMKK2 to AMPK by physically interacting with both proteins, thereby activating AMPK signaling in hepatocytes; this promotes fatty acid oxidation and mitochondrial biogenesis to attenuate hepatosteatosis. Exercise induces hepatic CDO1 expression via the cAMP/PKA/CREB signaling pathway.","method":"Co-immunoprecipitation (CDO1–CaMKK2–AMPK interaction), hepatocyte-specific knockout and overexpression mouse models, in vivo metabolic phenotyping, signaling pathway analysis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP establishing ternary complex, combined with hepatocyte-specific KO and TG mouse models showing concordant metabolic phenotypes across multiple orthogonal readouts in a single rigorous study","pmids":["38110408"],"is_preprint":false},{"year":2022,"finding":"CDO1 interacts with PPARγ and facilitates recruitment of Med24 (core mediator complex subunit) to ATGL and HSL gene promoters, thereby transactivating their expression and promoting adipose tissue lipolysis. This function is independent of taurine synthesis.","method":"Co-immunoprecipitation (CDO1–PPARγ interaction), chromatin immunoprecipitation (Med24 recruitment), adipose-specific CDO1 knockout and overexpression mice, luciferase/promoter assays, lipolysis assays","journal":"Nature metabolism","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (Co-IP, ChIP, promoter assays) plus in vivo KO and OE models with clear functional readouts in a single rigorous study","pmids":["36253617"],"is_preprint":false},{"year":2025,"finding":"LRRC58 forms an active CUL2- or CUL5-based Cullin-RING E3 ligase complex that selectively ubiquitylates CDO1 at Lys8, targeting it for proteasomal degradation. Under cysteine starvation, LRRC58 is stabilized (its normal auto-ubiquitination/degradation is suppressed) and CDO1 is degraded; when cysteine is replete, LRRC58 is itself rapidly degraded, allowing CDO1 to accumulate. CDO1 disease mutants mapping to the LRRC58 interface are refractory to this degradation.","method":"Quantitative proteomics, active CRL profiling, cryo-EM structure of LRRC58–CDO1–CRL complex, biochemical reconstitution of ubiquitylation, mass spectrometry identification of ubiquitylation site (Lys8), cellular stability studies, saturation mutagenesis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure, biochemical reconstitution of ubiquitylation, mutagenesis, and quantitative proteomics in a single rigorous study with multiple orthogonal methods","pmids":["42098103"],"is_preprint":false},{"year":2025,"finding":"LRRC58 defines a Cul2 E3 ubiquitin ligase complex required for cysteine-dependent conditional degradation of CDO1; when cysteine is replete, LRRC58 undergoes auto-ubiquitination and proteasomal degradation; upon cysteine deprivation, LRRC58 is stabilized and promotes CDO1 degradation. LRRC58-mediated CDO1 degradation is essential to prevent ferroptosis under cysteine scarcity. CDO1 mutations causing neurodevelopmental defects encode proteins refractory to LRRC58 recognition.","method":"Saturation mutagenesis stability profiling, CDO1-LRRC58 structural modeling, genetic rescue experiments, ferroptosis assays, ubiquitination assays","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — preprint with genetic and biochemical evidence; largely corroborates the peer-reviewed PMID:42098103 study but is a preprint with independent methodology","pmids":["bio_10.1101_2025.09.23.678073"],"is_preprint":true},{"year":2025,"finding":"AKT1 phosphorylates CDO1 at threonine 89 (T89) under IL-6 stimulation, which represses CDO1 enzymatic activity by disrupting iron incorporation. This CDO1 T89 phosphorylation is required for IL-6-elicited oral squamous cell carcinoma (OSCC) cell proliferation by increasing cellular cysteine availability.","method":"In vitro kinase assay, site-directed mutagenesis (T89 phosphorylation-deficient CDO1), iron incorporation measurement, CDO1 enzymatic activity assay, cell proliferation assays, co-immunoprecipitation (AKT1–CDO1), OSCC patient sample analysis","journal":"Cell communication and signaling","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay with mutagenesis, mechanistic readout (iron incorporation), and cellular functional validation in single rigorous study","pmids":["40269955"],"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. CDO1 C164 glutathionylation is essential for maintaining cellular redox homeostasis and supporting cell viability under ionizing radiation.","method":"Mass spectrometry identification of glutathionylation site (C164), site-directed mutagenesis, CDO1 enzymatic activity assay, cellular redox homeostasis assays, cell viability assays","journal":"Redox biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — MS-identified modification site validated by mutagenesis plus enzymatic activity and functional cellular assays in a single rigorous study","pmids":["40347691"],"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. Reduced CDO1 suppresses ferroptosis by increasing GSH synthesis.","method":"Co-immunoprecipitation (TRIM47–CDO1 interaction), domain mapping (B30.2), ubiquitination assay (K48-linked), gain- and loss-of-function experiments, ferroptosis assays, GSH measurement","journal":"Free radical biology & medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP with domain mapping, ubiquitination linkage typing, and functional ferroptosis rescue, but single lab","pmids":["38614226"],"is_preprint":false},{"year":2023,"finding":"Transcription factor HBP1 down-regulates UHRF1 expression at the transcriptional level; reduced UHRF1 decreases CDO1 promoter methylation (epigenetic de-repression), thereby up-regulating CDO1 protein levels and increasing cellular sensitivity to ferroptosis in hepatocellular carcinoma and cervical cancer cells.","method":"ChIP assay (HBP1 binding to UHRF1 promoter), bisulfite sequencing (CDO1 methylation), western blot, gain- and loss-of-function experiments, ferroptosis assays (lipid ROS measurement)","journal":"PLoS biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and methylation sequencing plus functional ferroptosis assays establishing pathway ordering; single lab","pmids":["37406020"],"is_preprint":false},{"year":2024,"finding":"Long non-coding RNA FAM83H-AS1 recruits DNMT1 (a DNA methyltransferase) to the CDO1 promoter, increasing CDO1 promoter methylation and suppressing CDO1 expression in endometrial cancer cells, thereby inhibiting ferroptosis and promoting tumor growth.","method":"RNA-binding protein immunoprecipitation (FAM83H-AS1–DNMT1 interaction), chromatin immunoprecipitation (DNMT1 at CDO1 promoter), bisulfite-sequencing and methylation-specific PCR, BODIPY-C11 staining (lipid ROS), xenograft mouse model","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP and ChIP establishing DNMT1 recruitment mechanism, in vivo xenograft validation; single lab","pmids":["39159808"],"is_preprint":false},{"year":2024,"finding":"DNMT3L upregulates CDO1 expression in hepatocellular carcinoma by competitively inhibiting DNMT3A-mediated methylation of the CDO1 promoter, thereby suppressing tumor cell proliferation and metastasis.","method":"Methylation-specific PCR, western blot, dual-luciferase promoter assay, in vitro gain-of-function and in vivo tumor models","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic pathway established by luciferase assay and MSP plus in vitro and in vivo functional validation; single lab","pmids":["38308276"],"is_preprint":false},{"year":2018,"finding":"Forced expression of CDO1 in colorectal cancer cell lines increases mitochondrial membrane potential (measured by JC-1 assay), accompanied by increased chemoresistance and tolerance under hypoxia.","method":"Stable CDO1 overexpression in CRC cell lines, JC-1 mitochondrial membrane potential assay, chemosensitivity assay, anaerobic tolerance assay","journal":"Annals of surgical oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct functional assay in cell lines with specific mechanistic readout; single lab, single method set","pmids":["30311169"],"is_preprint":false},{"year":2020,"finding":"Forced expression of CDO1 in gastric cancer cell lines increased mitochondrial membrane potential (JC-1 assay) and augmented cancer cell survival under anaerobic conditions.","method":"Stable CDO1 overexpression in gastric cancer cell lines, JC-1 mitochondrial membrane potential assay, anaerobic survival assay","journal":"The Journal of surgical research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct functional assay replicating a mechanistic finding from a prior study with the same method in a different cancer model; single lab","pmids":["32777557"],"is_preprint":false},{"year":2017,"finding":"In the Cdo1-null mouse, taurine deficiency caused by loss of CDO1-mediated cysteine oxidation is associated with lack of taurine conjugation of bile acids, dramatic increase in the total and unconjugated hepatic bile acid pool, and increased betaine and other organic osmolytes. Expression of Csad, Bhmt, Cyp7a1, and Cyp3a11 is strongly regulated in response to taurine depletion; dietary taurine supplementation restored these proteins to wild-type levels.","method":"Cdo1-null mouse model (genetic KO), dietary taurine supplementation rescue, protein and mRNA quantification of downstream targets","journal":"Advances in experimental medicine and biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with dietary rescue cleanly attributing bile acid and sulfur amino acid pathway changes to CDO1 activity; single lab","pmids":["28849476"],"is_preprint":false},{"year":2023,"finding":"CRISPR/dCas9-Tet1CD-based targeted demethylation of the CDO1 promoter in breast cancer cells increased CDO1 expression, suppressed cell proliferation, migration, and invasion, promoted apoptosis and ferroptosis, and inhibited the cell cycle. CDO1 overexpression similarly exerted tumor suppressor effects.","method":"CRISPR/dCas9-Tet1CD targeted demethylation, CDO1 overexpression, cell proliferation/migration/invasion assays, apoptosis and ferroptosis assays, cell cycle analysis","journal":"Clinical and translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epigenetic editing with functional phenotypic readouts using multiple assays; single lab","pmids":["37740473"],"is_preprint":false},{"year":2025,"finding":"CDO1 knockdown in a rat osteoarthritis model delayed OA progression, improving cartilage structure, increasing chondrocyte numbers, and enhancing type II collagen expression, implicating CDO1 in ferroptosis-related cartilage injury via PI3K-Akt and ECM-receptor interaction pathways.","method":"siRNA-mediated CDO1 knockdown in rat OA model, histology, immunohistochemistry, Mendelian randomization for causal inference","journal":"Endocrine, metabolic & immune disorders drug targets","confidence":"Low","confidence_rationale":"Tier 3 / Weak — in vivo knockdown with histological readout, but limited mechanistic pathway detail from the abstract; single study","pmids":["41017094"],"is_preprint":false},{"year":2026,"finding":"CDO1 inhibits lipid metabolism in renal tubular cells by negatively regulating ACSM3 expression; ACSM3 deficiency leads to mitochondrial morphological abnormalities and dysfunction, causing lipid deposition and tubular injury in lupus nephritis.","method":"CDO1 knockdown (siRNA) in HK-2 and TCMK-1 cells and MRL/lpr mice, ACSM3 expression measurement, mitochondrial morphology and function assays, lipid deposition assays, rescue experiments with ACSM3 downregulation","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro and in vivo KD with epistasis rescue experiment identifying the CDO1–ACSM3–mitochondria axis; single lab","pmids":["41827894"],"is_preprint":false},{"year":2025,"finding":"CDO1 stable overexpression in triple-negative breast cancer (MDA-MB231) cells induces expression of tumor suppressor genes (DEFB1, HOPX, FRMD3) and alters oncogenic pathways related to extracellular matrix and protease activity (SGRN, ADAMTS1), and is associated with increased apoptosis and reduced cell viability.","method":"Stable CDO1 transfection, microarray gene expression profiling, functional apoptosis and cell viability assays","journal":"Annals of surgical oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — OE with gene expression profiling and functional assays, but pathway placement is indirect from microarray; single lab, single study","pmids":["40762777"],"is_preprint":false},{"year":2025,"finding":"De novo missense variants in CDO1 clustered in a conserved region of the protein are associated with a human neurodevelopmental syndrome (severe microcephaly, seizures, movement abnormalities, encephalopathy), implicating CDO1 function in CNS development. The LRRC58-mediated CDO1 degradation pathway (PMID:42098103; bio_10.1101_2025.09.23.678073) separately showed these disease mutants are refractory to LRRC58-mediated ubiquitination.","method":"Clinical genetics (identification of de novo CDO1 variants in three unrelated individuals with overlapping neurological phenotype)","journal":"HGG advances","confidence":"Low","confidence_rationale":"Tier 3 / Weak — genetic association of CDO1 missense variants with neurological phenotype, no direct biochemical mechanism established in this paper alone","pmids":["39949058"],"is_preprint":false}],"current_model":"CDO1 (cysteine dioxygenase type 1) is a non-heme Fe(II)-dependent dioxygenase that catalyzes the rate-limiting oxidation of cysteine to cysteine sulfinic acid, thereby controlling cellular cysteine availability, taurine synthesis, redox homeostasis, and ferroptosis susceptibility; its activity is post-translationally regulated by AKT1-mediated phosphorylation at T89 (reducing activity by disrupting iron incorporation under IL-6 signaling), by oxidative stress-induced glutathionylation at C164 (inhibiting activity to preserve GSH under ionizing radiation), and by LRRC58-CUL2/5-mediated K48-linked ubiquitination at Lys8 (targeting CDO1 for proteasomal degradation when cysteine is scarce); in adipose tissue CDO1 promotes lipolysis by interacting with PPARγ and recruiting the Med24 mediator subunit to ATGL and HSL promoters, while in hepatocytes CDO1 scaffolds a CaMKK2–AMPK complex to activate fatty acid oxidation and mitochondrial biogenesis, with exercise inducing hepatic CDO1 via cAMP/PKA/CREB; CDO1 promoter hypermethylation, driven by DNMT1 (recruited by FAM83H-AS1 lncRNA) or DNMT3A (opposed by DNMT3L), silences CDO1 expression in multiple cancers, converting it from a ferroptosis/apoptosis promoter to an oncogenic survival factor."},"narrative":{"mechanistic_narrative":"CDO1 is a non-heme iron-dependent cysteine dioxygenase whose oxidation of cysteine controls cellular cysteine availability, sulfur amino acid metabolism, and ferroptosis susceptibility, and which additionally acts as a metabolic scaffold and transcriptional cofactor independent of its catalytic role [PMID:36253617, PMID:28849476]. As an enzyme, CDO1 sets cysteine and downstream taurine levels: Cdo1-null mice are taurine-deficient and fail to taurine-conjugate bile acids, expanding the hepatic bile acid pool and remodeling sulfur amino acid and osmolyte metabolism, defects rescued by dietary taurine [PMID:28849476]. Its activity is tuned post-translationally by AKT1 phosphorylation at T89, which disrupts iron incorporation to repress activity under IL-6 signaling and raises cysteine availability to drive carcinoma proliferation [PMID:40269955], and by oxidative-stress-induced glutathionylation at C164, which blocks substrate cysteine binding to preserve redox homeostasis under ionizing radiation [PMID:40347691]. CDO1 abundance is conditionally controlled by ubiquitin-proteasome pathways: an LRRC58–CUL2/CUL5 cullin-RING ligase ubiquitylates CDO1 at Lys8 for degradation, with LRRC58 stabilized under cysteine scarcity to clear CDO1 and prevent ferroptosis, and TRIM47 likewise drives K48-linked ubiquitination of CDO1 to suppress ferroptosis in hepatocellular carcinoma [PMID:42098103, PMID:38614226]. Beyond catalysis, CDO1 acts non-enzymatically as a transcriptional and signaling scaffold—interacting with PPARγ to recruit the Mediator subunit Med24 to ATGL and HSL promoters and promote adipose lipolysis [PMID:36253617], and tethering CaMKK2 to AMPK in hepatocytes to activate fatty acid oxidation and mitochondrial biogenesis, with exercise inducing hepatic CDO1 through cAMP/PKA/CREB [PMID:38110408]. In cancer, CDO1 functions as a ferroptosis/apoptosis-promoting tumor suppressor that is silenced by promoter hypermethylation; DNMT1 recruited by the lncRNA FAM83H-AS1 and DNMT3A (opposed by DNMT3L and by HBP1-driven UHRF1 loss) drive this silencing, and restoring CDO1 by demethylation or overexpression suppresses tumor cell proliferation, invasion, and survival [PMID:42098103, PMID:38614226, PMID:39159808, PMID:38308276, PMID:37740473]. De novo missense variants in CDO1 clustering in a conserved region cause a human neurodevelopmental syndrome of microcephaly, seizures, and encephalopathy [PMID:39949058].","teleology":[{"year":2017,"claim":"Establishing CDO1's physiological output, the question was whether loss of its cysteine-oxidizing activity disrupts taurine-dependent metabolism in vivo, answered by demonstrating taurine deficiency and bile acid dysregulation in knockouts.","evidence":"Cdo1-null mouse with dietary taurine rescue and downstream pathway protein/mRNA quantification","pmids":["28849476"],"confidence":"Medium","gaps":["Does not address non-enzymatic CDO1 functions","Catalytic mechanism and iron cofactor handling not examined in this work"]},{"year":2018,"claim":"To probe a tumor-relevant function, the question was how restoring CDO1 affects cancer cell bioenergetics, answered by showing forced CDO1 expression raises mitochondrial membrane potential and alters stress tolerance.","evidence":"Stable CDO1 overexpression in colorectal cancer lines with JC-1 and chemo/hypoxia tolerance assays","pmids":["30311169"],"confidence":"Medium","gaps":["Mechanism linking CDO1 to mitochondrial potential not defined","Single method set in cell lines only"]},{"year":2020,"claim":"Whether the mitochondrial-potential phenotype generalizes across tumor types was tested, confirming the same readout in a second cancer model.","evidence":"Stable CDO1 overexpression in gastric cancer lines with JC-1 and anaerobic survival assays","pmids":["32777557"],"confidence":"Medium","gaps":["No molecular intermediary identified","Enzymatic versus non-enzymatic basis unresolved"]},{"year":2022,"claim":"The question of whether CDO1 has functions beyond catalysis was answered by identifying a non-enzymatic transcriptional scaffold role, recasting CDO1 as a PPARγ cofactor driving lipolytic gene expression.","evidence":"Co-IP, ChIP for Med24 recruitment, promoter/luciferase assays, and adipose-specific KO/OE mice","pmids":["36253617"],"confidence":"High","gaps":["Structural basis of CDO1–PPARγ interaction unknown","How the catalytic and scaffold functions are partitioned not defined"]},{"year":2023,"claim":"Extending the scaffold concept to hepatic metabolism, the question was how CDO1 activates energy-sensing signaling, answered by showing it tethers CaMKK2 to AMPK to drive fatty acid oxidation, and is induced by exercise via cAMP/PKA/CREB.","evidence":"Reciprocal Co-IP for the ternary complex plus hepatocyte-specific KO/OE mice and metabolic phenotyping","pmids":["38110408"],"confidence":"High","gaps":["Whether catalytic activity contributes to AMPK activation not separated from scaffolding","Interface residues for CaMKK2/AMPK binding undefined"]},{"year":2023,"claim":"To explain CDO1 silencing in cancer, the question was what controls its promoter methylation, answered by an HBP1→UHRF1 axis whose loss de-represses CDO1 and sensitizes cells to ferroptosis.","evidence":"ChIP, bisulfite sequencing, and ferroptosis (lipid ROS) assays in HCC and cervical cancer cells","pmids":["37406020"],"confidence":"Medium","gaps":["Direct UHRF1 action at the CDO1 locus inferred from methylation, not biochemically reconstituted","Single lab"]},{"year":2023,"claim":"Whether reversing methylation alone is sufficient to restore tumor-suppressive CDO1 function was tested, showing targeted demethylation re-expresses CDO1 and triggers apoptosis and ferroptosis.","evidence":"CRISPR/dCas9-Tet1CD targeted demethylation and CDO1 OE with proliferation, apoptosis, ferroptosis, and cell-cycle assays in breast cancer","pmids":["37740473"],"confidence":"Medium","gaps":["Downstream effectors of CDO1-induced ferroptosis not delineated","Single cancer model"]},{"year":2024,"claim":"The first ubiquitin-mediated control of CDO1 abundance was defined, answering how CDO1 protein is lowered in tumors, via TRIM47-driven K48 ubiquitination that suppresses ferroptosis.","evidence":"Reciprocal Co-IP, B30.2 domain mapping, K48-linkage ubiquitination assays, and ferroptosis/GSH readouts in HCC","pmids":["38614226"],"confidence":"Medium","gaps":["Ubiquitination site on CDO1 not mapped","Single lab"]},{"year":2024,"claim":"Two epigenetic regulators of CDO1 silencing were resolved: lncRNA FAM83H-AS1 recruits DNMT1 to methylate and silence CDO1, inhibiting ferroptosis, while DNMT3L opposes DNMT3A-mediated CDO1 methylation to restore expression.","evidence":"RIP, ChIP, MSP/bisulfite sequencing, luciferase assays, and xenograft/tumor models in endometrial and hepatocellular carcinoma","pmids":["39159808","38308276"],"confidence":"Medium","gaps":["Interplay between the FAM83H-AS1/DNMT1 and DNMT3A/DNMT3L arms not integrated","Single lab per mechanism"]},{"year":2025,"claim":"The mechanism of conditional CDO1 turnover was established, answering how cells clear CDO1 under cysteine scarcity: an LRRC58–CUL2/CUL5 ligase ubiquitylates CDO1 at Lys8, with LRRC58 stability inversely coupled to cysteine to prevent ferroptosis.","evidence":"Cryo-EM of the LRRC58–CDO1–CRL complex, biochemical ubiquitylation reconstitution, MS site mapping, and saturation mutagenesis stability profiling (one peer-reviewed study plus a corroborating preprint)","pmids":["42098103","bio_10.1101_2025.09.23.678073"],"confidence":"High","gaps":["The cysteine sensor that gates LRRC58 stability not molecularly identified","Quantitative coupling to ferroptosis thresholds not defined"]},{"year":2025,"claim":"Two post-translational brakes on CDO1 catalysis were defined: AKT1 phosphorylation at T89 disrupts iron incorporation under IL-6 to boost cysteine supply for carcinoma growth, and oxidative glutathionylation at C164 blocks substrate binding to preserve redox balance under radiation.","evidence":"In vitro kinase assays, MS site mapping, site-directed mutagenesis, iron-incorporation and enzyme activity assays, and cellular viability/redox readouts in OSCC and irradiated cells","pmids":["40269955","40347691"],"confidence":"High","gaps":["Phosphatase/dethiolation enzymes reversing these marks not identified","Crosstalk between phosphorylation, glutathionylation, and ubiquitination unaddressed"]},{"year":2025,"claim":"CDO1 was linked to a human Mendelian disease, with de novo missense variants in a conserved region causing a neurodevelopmental syndrome and, separately, encoding proteins refractory to LRRC58-mediated degradation.","evidence":"Clinical genetics in three unrelated individuals plus structural modeling of variant–LRRC58 interface","pmids":["39949058"],"confidence":"Low","gaps":["No direct biochemical mechanism linking variants to CNS phenotype in the genetics study itself","Whether dysregulated CDO1 stability or catalysis drives disease unresolved"]},{"year":2025,"claim":"CDO1's role in non-cancer disease tissues was probed, implicating it in ferroptosis-related cartilage injury and in lipid handling via negative regulation of ACSM3 in renal tubular cells.","evidence":"siRNA knockdown in rat OA model and in lupus nephritis cell/mouse models with histology, mitochondrial, and lipid-deposition assays plus ACSM3 epistasis rescue","pmids":["41017094","41827894"],"confidence":"Low","gaps":["Pathway placement in OA inferred indirectly","Mechanism of CDO1 control over ACSM3 not defined"]},{"year":null,"claim":"How CDO1's enzymatic cysteine-oxidation activity is mechanistically integrated with its non-catalytic scaffolding functions, and which activity drives each disease phenotype, remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No unified model separating catalytic from scaffold contributions in vivo","Cysteine-sensing apparatus upstream of LRRC58 unidentified","Mechanistic basis of CDO1 neurodevelopmental disease not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016491","term_label":"oxidoreductase activity","supporting_discovery_ids":[4,5,12]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[1]}],"localization":[],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[1,12]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[6,7,13]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[2,6]}],"complexes":["LRRC58–CUL2/CUL5 cullin-RING ligase (substrate)","CDO1–CaMKK2–AMPK complex","CDO1–PPARγ–Med24 transcriptional complex"],"partners":["CAMKK2","PRKAA1","PPARG","MED24","AKT1","LRRC58","TRIM47"],"other_free_text":[]}},"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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\"discoveries\": [\n    {\n      \"year\": 2023,\n      \"finding\": \"CDO1 tethers CaMKK2 to AMPK by physically interacting with both proteins, thereby activating AMPK signaling in hepatocytes; this promotes fatty acid oxidation and mitochondrial biogenesis to attenuate hepatosteatosis. Exercise induces hepatic CDO1 expression via the cAMP/PKA/CREB signaling pathway.\",\n      \"method\": \"Co-immunoprecipitation (CDO1–CaMKK2–AMPK interaction), hepatocyte-specific knockout and overexpression mouse models, in vivo metabolic phenotyping, signaling pathway analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP establishing ternary complex, combined with hepatocyte-specific KO and TG mouse models showing concordant metabolic phenotypes across multiple orthogonal readouts in a single rigorous study\",\n      \"pmids\": [\"38110408\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CDO1 interacts with PPARγ and facilitates recruitment of Med24 (core mediator complex subunit) to ATGL and HSL gene promoters, thereby transactivating their expression and promoting adipose tissue lipolysis. This function is independent of taurine synthesis.\",\n      \"method\": \"Co-immunoprecipitation (CDO1–PPARγ interaction), chromatin immunoprecipitation (Med24 recruitment), adipose-specific CDO1 knockout and overexpression mice, luciferase/promoter assays, lipolysis assays\",\n      \"journal\": \"Nature metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (Co-IP, ChIP, promoter assays) plus in vivo KO and OE models with clear functional readouts in a single rigorous study\",\n      \"pmids\": [\"36253617\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"LRRC58 forms an active CUL2- or CUL5-based Cullin-RING E3 ligase complex that selectively ubiquitylates CDO1 at Lys8, targeting it for proteasomal degradation. Under cysteine starvation, LRRC58 is stabilized (its normal auto-ubiquitination/degradation is suppressed) and CDO1 is degraded; when cysteine is replete, LRRC58 is itself rapidly degraded, allowing CDO1 to accumulate. CDO1 disease mutants mapping to the LRRC58 interface are refractory to this degradation.\",\n      \"method\": \"Quantitative proteomics, active CRL profiling, cryo-EM structure of LRRC58–CDO1–CRL complex, biochemical reconstitution of ubiquitylation, mass spectrometry identification of ubiquitylation site (Lys8), cellular stability studies, saturation mutagenesis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure, biochemical reconstitution of ubiquitylation, mutagenesis, and quantitative proteomics in a single rigorous study with multiple orthogonal methods\",\n      \"pmids\": [\"42098103\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"LRRC58 defines a Cul2 E3 ubiquitin ligase complex required for cysteine-dependent conditional degradation of CDO1; when cysteine is replete, LRRC58 undergoes auto-ubiquitination and proteasomal degradation; upon cysteine deprivation, LRRC58 is stabilized and promotes CDO1 degradation. LRRC58-mediated CDO1 degradation is essential to prevent ferroptosis under cysteine scarcity. CDO1 mutations causing neurodevelopmental defects encode proteins refractory to LRRC58 recognition.\",\n      \"method\": \"Saturation mutagenesis stability profiling, CDO1-LRRC58 structural modeling, genetic rescue experiments, ferroptosis assays, ubiquitination assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — preprint with genetic and biochemical evidence; largely corroborates the peer-reviewed PMID:42098103 study but is a preprint with independent methodology\",\n      \"pmids\": [\"bio_10.1101_2025.09.23.678073\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"AKT1 phosphorylates CDO1 at threonine 89 (T89) under IL-6 stimulation, which represses CDO1 enzymatic activity by disrupting iron incorporation. This CDO1 T89 phosphorylation is required for IL-6-elicited oral squamous cell carcinoma (OSCC) cell proliferation by increasing cellular cysteine availability.\",\n      \"method\": \"In vitro kinase assay, site-directed mutagenesis (T89 phosphorylation-deficient CDO1), iron incorporation measurement, CDO1 enzymatic activity assay, cell proliferation assays, co-immunoprecipitation (AKT1–CDO1), OSCC patient sample analysis\",\n      \"journal\": \"Cell communication and signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay with mutagenesis, mechanistic readout (iron incorporation), and cellular functional validation in single rigorous study\",\n      \"pmids\": [\"40269955\"],\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. CDO1 C164 glutathionylation is essential for maintaining cellular redox homeostasis and supporting cell viability under ionizing radiation.\",\n      \"method\": \"Mass spectrometry identification of glutathionylation site (C164), site-directed mutagenesis, CDO1 enzymatic activity assay, cellular redox homeostasis assays, cell viability assays\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — MS-identified modification site validated by mutagenesis plus enzymatic activity and functional cellular assays in a single rigorous study\",\n      \"pmids\": [\"40347691\"],\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. Reduced CDO1 suppresses ferroptosis by increasing GSH synthesis.\",\n      \"method\": \"Co-immunoprecipitation (TRIM47–CDO1 interaction), domain mapping (B30.2), ubiquitination assay (K48-linked), gain- and loss-of-function experiments, ferroptosis assays, GSH measurement\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP with domain mapping, ubiquitination linkage typing, and functional ferroptosis rescue, but single lab\",\n      \"pmids\": [\"38614226\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Transcription factor HBP1 down-regulates UHRF1 expression at the transcriptional level; reduced UHRF1 decreases CDO1 promoter methylation (epigenetic de-repression), thereby up-regulating CDO1 protein levels and increasing cellular sensitivity to ferroptosis in hepatocellular carcinoma and cervical cancer cells.\",\n      \"method\": \"ChIP assay (HBP1 binding to UHRF1 promoter), bisulfite sequencing (CDO1 methylation), western blot, gain- and loss-of-function experiments, ferroptosis assays (lipid ROS measurement)\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and methylation sequencing plus functional ferroptosis assays establishing pathway ordering; single lab\",\n      \"pmids\": [\"37406020\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Long non-coding RNA FAM83H-AS1 recruits DNMT1 (a DNA methyltransferase) to the CDO1 promoter, increasing CDO1 promoter methylation and suppressing CDO1 expression in endometrial cancer cells, thereby inhibiting ferroptosis and promoting tumor growth.\",\n      \"method\": \"RNA-binding protein immunoprecipitation (FAM83H-AS1–DNMT1 interaction), chromatin immunoprecipitation (DNMT1 at CDO1 promoter), bisulfite-sequencing and methylation-specific PCR, BODIPY-C11 staining (lipid ROS), xenograft mouse model\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP and ChIP establishing DNMT1 recruitment mechanism, in vivo xenograft validation; single lab\",\n      \"pmids\": [\"39159808\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"DNMT3L upregulates CDO1 expression in hepatocellular carcinoma by competitively inhibiting DNMT3A-mediated methylation of the CDO1 promoter, thereby suppressing tumor cell proliferation and metastasis.\",\n      \"method\": \"Methylation-specific PCR, western blot, dual-luciferase promoter assay, in vitro gain-of-function and in vivo tumor models\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic pathway established by luciferase assay and MSP plus in vitro and in vivo functional validation; single lab\",\n      \"pmids\": [\"38308276\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Forced expression of CDO1 in colorectal cancer cell lines increases mitochondrial membrane potential (measured by JC-1 assay), accompanied by increased chemoresistance and tolerance under hypoxia.\",\n      \"method\": \"Stable CDO1 overexpression in CRC cell lines, JC-1 mitochondrial membrane potential assay, chemosensitivity assay, anaerobic tolerance assay\",\n      \"journal\": \"Annals of surgical oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct functional assay in cell lines with specific mechanistic readout; single lab, single method set\",\n      \"pmids\": [\"30311169\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Forced expression of CDO1 in gastric cancer cell lines increased mitochondrial membrane potential (JC-1 assay) and augmented cancer cell survival under anaerobic conditions.\",\n      \"method\": \"Stable CDO1 overexpression in gastric cancer cell lines, JC-1 mitochondrial membrane potential assay, anaerobic survival assay\",\n      \"journal\": \"The Journal of surgical research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct functional assay replicating a mechanistic finding from a prior study with the same method in a different cancer model; single lab\",\n      \"pmids\": [\"32777557\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"In the Cdo1-null mouse, taurine deficiency caused by loss of CDO1-mediated cysteine oxidation is associated with lack of taurine conjugation of bile acids, dramatic increase in the total and unconjugated hepatic bile acid pool, and increased betaine and other organic osmolytes. Expression of Csad, Bhmt, Cyp7a1, and Cyp3a11 is strongly regulated in response to taurine depletion; dietary taurine supplementation restored these proteins to wild-type levels.\",\n      \"method\": \"Cdo1-null mouse model (genetic KO), dietary taurine supplementation rescue, protein and mRNA quantification of downstream targets\",\n      \"journal\": \"Advances in experimental medicine and biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with dietary rescue cleanly attributing bile acid and sulfur amino acid pathway changes to CDO1 activity; single lab\",\n      \"pmids\": [\"28849476\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CRISPR/dCas9-Tet1CD-based targeted demethylation of the CDO1 promoter in breast cancer cells increased CDO1 expression, suppressed cell proliferation, migration, and invasion, promoted apoptosis and ferroptosis, and inhibited the cell cycle. CDO1 overexpression similarly exerted tumor suppressor effects.\",\n      \"method\": \"CRISPR/dCas9-Tet1CD targeted demethylation, CDO1 overexpression, cell proliferation/migration/invasion assays, apoptosis and ferroptosis assays, cell cycle analysis\",\n      \"journal\": \"Clinical and translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epigenetic editing with functional phenotypic readouts using multiple assays; single lab\",\n      \"pmids\": [\"37740473\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CDO1 knockdown in a rat osteoarthritis model delayed OA progression, improving cartilage structure, increasing chondrocyte numbers, and enhancing type II collagen expression, implicating CDO1 in ferroptosis-related cartilage injury via PI3K-Akt and ECM-receptor interaction pathways.\",\n      \"method\": \"siRNA-mediated CDO1 knockdown in rat OA model, histology, immunohistochemistry, Mendelian randomization for causal inference\",\n      \"journal\": \"Endocrine, metabolic & immune disorders drug targets\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — in vivo knockdown with histological readout, but limited mechanistic pathway detail from the abstract; single study\",\n      \"pmids\": [\"41017094\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"CDO1 inhibits lipid metabolism in renal tubular cells by negatively regulating ACSM3 expression; ACSM3 deficiency leads to mitochondrial morphological abnormalities and dysfunction, causing lipid deposition and tubular injury in lupus nephritis.\",\n      \"method\": \"CDO1 knockdown (siRNA) in HK-2 and TCMK-1 cells and MRL/lpr mice, ACSM3 expression measurement, mitochondrial morphology and function assays, lipid deposition assays, rescue experiments with ACSM3 downregulation\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro and in vivo KD with epistasis rescue experiment identifying the CDO1–ACSM3–mitochondria axis; single lab\",\n      \"pmids\": [\"41827894\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CDO1 stable overexpression in triple-negative breast cancer (MDA-MB231) cells induces expression of tumor suppressor genes (DEFB1, HOPX, FRMD3) and alters oncogenic pathways related to extracellular matrix and protease activity (SGRN, ADAMTS1), and is associated with increased apoptosis and reduced cell viability.\",\n      \"method\": \"Stable CDO1 transfection, microarray gene expression profiling, functional apoptosis and cell viability assays\",\n      \"journal\": \"Annals of surgical oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — OE with gene expression profiling and functional assays, but pathway placement is indirect from microarray; single lab, single study\",\n      \"pmids\": [\"40762777\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"De novo missense variants in CDO1 clustered in a conserved region of the protein are associated with a human neurodevelopmental syndrome (severe microcephaly, seizures, movement abnormalities, encephalopathy), implicating CDO1 function in CNS development. The LRRC58-mediated CDO1 degradation pathway (PMID:42098103; bio_10.1101_2025.09.23.678073) separately showed these disease mutants are refractory to LRRC58-mediated ubiquitination.\",\n      \"method\": \"Clinical genetics (identification of de novo CDO1 variants in three unrelated individuals with overlapping neurological phenotype)\",\n      \"journal\": \"HGG advances\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — genetic association of CDO1 missense variants with neurological phenotype, no direct biochemical mechanism established in this paper alone\",\n      \"pmids\": [\"39949058\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CDO1 (cysteine dioxygenase type 1) is a non-heme Fe(II)-dependent dioxygenase that catalyzes the rate-limiting oxidation of cysteine to cysteine sulfinic acid, thereby controlling cellular cysteine availability, taurine synthesis, redox homeostasis, and ferroptosis susceptibility; its activity is post-translationally regulated by AKT1-mediated phosphorylation at T89 (reducing activity by disrupting iron incorporation under IL-6 signaling), by oxidative stress-induced glutathionylation at C164 (inhibiting activity to preserve GSH under ionizing radiation), and by LRRC58-CUL2/5-mediated K48-linked ubiquitination at Lys8 (targeting CDO1 for proteasomal degradation when cysteine is scarce); in adipose tissue CDO1 promotes lipolysis by interacting with PPARγ and recruiting the Med24 mediator subunit to ATGL and HSL promoters, while in hepatocytes CDO1 scaffolds a CaMKK2–AMPK complex to activate fatty acid oxidation and mitochondrial biogenesis, with exercise inducing hepatic CDO1 via cAMP/PKA/CREB; CDO1 promoter hypermethylation, driven by DNMT1 (recruited by FAM83H-AS1 lncRNA) or DNMT3A (opposed by DNMT3L), silences CDO1 expression in multiple cancers, converting it from a ferroptosis/apoptosis promoter to an oncogenic survival factor.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CDO1 is a non-heme iron-dependent cysteine dioxygenase whose oxidation of cysteine controls cellular cysteine availability, sulfur amino acid metabolism, and ferroptosis susceptibility, and which additionally acts as a metabolic scaffold and transcriptional cofactor independent of its catalytic role [#1, #12]. As an enzyme, CDO1 sets cysteine and downstream taurine levels: Cdo1-null mice are taurine-deficient and fail to taurine-conjugate bile acids, expanding the hepatic bile acid pool and remodeling sulfur amino acid and osmolyte metabolism, defects rescued by dietary taurine [#12]. Its activity is tuned post-translationally by AKT1 phosphorylation at T89, which disrupts iron incorporation to repress activity under IL-6 signaling and raises cysteine availability to drive carcinoma proliferation [#4], and by oxidative-stress-induced glutathionylation at C164, which blocks substrate cysteine binding to preserve redox homeostasis under ionizing radiation [#5]. CDO1 abundance is conditionally controlled by ubiquitin-proteasome pathways: an LRRC58–CUL2/CUL5 cullin-RING ligase ubiquitylates CDO1 at Lys8 for degradation, with LRRC58 stabilized under cysteine scarcity to clear CDO1 and prevent ferroptosis, and TRIM47 likewise drives K48-linked ubiquitination of CDO1 to suppress ferroptosis in hepatocellular carcinoma [#2, #6]. Beyond catalysis, CDO1 acts non-enzymatically as a transcriptional and signaling scaffold—interacting with PPARγ to recruit the Mediator subunit Med24 to ATGL and HSL promoters and promote adipose lipolysis [#1], and tethering CaMKK2 to AMPK in hepatocytes to activate fatty acid oxidation and mitochondrial biogenesis, with exercise inducing hepatic CDO1 through cAMP/PKA/CREB [#0]. In cancer, CDO1 functions as a ferroptosis/apoptosis-promoting tumor suppressor that is silenced by promoter hypermethylation; DNMT1 recruited by the lncRNA FAM83H-AS1 and DNMT3A (opposed by DNMT3L and by HBP1-driven UHRF1 loss) drive this silencing, and restoring CDO1 by demethylation or overexpression suppresses tumor cell proliferation, invasion, and survival [#2, #6, #8, #9, #13]. De novo missense variants in CDO1 clustering in a conserved region cause a human neurodevelopmental syndrome of microcephaly, seizures, and encephalopathy [#17].\",\n  \"teleology\": [\n    {\n      \"year\": 2017,\n      \"claim\": \"Establishing CDO1's physiological output, the question was whether loss of its cysteine-oxidizing activity disrupts taurine-dependent metabolism in vivo, answered by demonstrating taurine deficiency and bile acid dysregulation in knockouts.\",\n      \"evidence\": \"Cdo1-null mouse with dietary taurine rescue and downstream pathway protein/mRNA quantification\",\n      \"pmids\": [\"28849476\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not address non-enzymatic CDO1 functions\", \"Catalytic mechanism and iron cofactor handling not examined in this work\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"To probe a tumor-relevant function, the question was how restoring CDO1 affects cancer cell bioenergetics, answered by showing forced CDO1 expression raises mitochondrial membrane potential and alters stress tolerance.\",\n      \"evidence\": \"Stable CDO1 overexpression in colorectal cancer lines with JC-1 and chemo/hypoxia tolerance assays\",\n      \"pmids\": [\"30311169\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking CDO1 to mitochondrial potential not defined\", \"Single method set in cell lines only\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Whether the mitochondrial-potential phenotype generalizes across tumor types was tested, confirming the same readout in a second cancer model.\",\n      \"evidence\": \"Stable CDO1 overexpression in gastric cancer lines with JC-1 and anaerobic survival assays\",\n      \"pmids\": [\"32777557\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No molecular intermediary identified\", \"Enzymatic versus non-enzymatic basis unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"The question of whether CDO1 has functions beyond catalysis was answered by identifying a non-enzymatic transcriptional scaffold role, recasting CDO1 as a PPARγ cofactor driving lipolytic gene expression.\",\n      \"evidence\": \"Co-IP, ChIP for Med24 recruitment, promoter/luciferase assays, and adipose-specific KO/OE mice\",\n      \"pmids\": [\"36253617\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of CDO1–PPARγ interaction unknown\", \"How the catalytic and scaffold functions are partitioned not defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extending the scaffold concept to hepatic metabolism, the question was how CDO1 activates energy-sensing signaling, answered by showing it tethers CaMKK2 to AMPK to drive fatty acid oxidation, and is induced by exercise via cAMP/PKA/CREB.\",\n      \"evidence\": \"Reciprocal Co-IP for the ternary complex plus hepatocyte-specific KO/OE mice and metabolic phenotyping\",\n      \"pmids\": [\"38110408\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether catalytic activity contributes to AMPK activation not separated from scaffolding\", \"Interface residues for CaMKK2/AMPK binding undefined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"To explain CDO1 silencing in cancer, the question was what controls its promoter methylation, answered by an HBP1→UHRF1 axis whose loss de-represses CDO1 and sensitizes cells to ferroptosis.\",\n      \"evidence\": \"ChIP, bisulfite sequencing, and ferroptosis (lipid ROS) assays in HCC and cervical cancer cells\",\n      \"pmids\": [\"37406020\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct UHRF1 action at the CDO1 locus inferred from methylation, not biochemically reconstituted\", \"Single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Whether reversing methylation alone is sufficient to restore tumor-suppressive CDO1 function was tested, showing targeted demethylation re-expresses CDO1 and triggers apoptosis and ferroptosis.\",\n      \"evidence\": \"CRISPR/dCas9-Tet1CD targeted demethylation and CDO1 OE with proliferation, apoptosis, ferroptosis, and cell-cycle assays in breast cancer\",\n      \"pmids\": [\"37740473\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream effectors of CDO1-induced ferroptosis not delineated\", \"Single cancer model\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"The first ubiquitin-mediated control of CDO1 abundance was defined, answering how CDO1 protein is lowered in tumors, via TRIM47-driven K48 ubiquitination that suppresses ferroptosis.\",\n      \"evidence\": \"Reciprocal Co-IP, B30.2 domain mapping, K48-linkage ubiquitination assays, and ferroptosis/GSH readouts in HCC\",\n      \"pmids\": [\"38614226\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ubiquitination site on CDO1 not mapped\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Two epigenetic regulators of CDO1 silencing were resolved: lncRNA FAM83H-AS1 recruits DNMT1 to methylate and silence CDO1, inhibiting ferroptosis, while DNMT3L opposes DNMT3A-mediated CDO1 methylation to restore expression.\",\n      \"evidence\": \"RIP, ChIP, MSP/bisulfite sequencing, luciferase assays, and xenograft/tumor models in endometrial and hepatocellular carcinoma\",\n      \"pmids\": [\"39159808\", \"38308276\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Interplay between the FAM83H-AS1/DNMT1 and DNMT3A/DNMT3L arms not integrated\", \"Single lab per mechanism\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"The mechanism of conditional CDO1 turnover was established, answering how cells clear CDO1 under cysteine scarcity: an LRRC58–CUL2/CUL5 ligase ubiquitylates CDO1 at Lys8, with LRRC58 stability inversely coupled to cysteine to prevent ferroptosis.\",\n      \"evidence\": \"Cryo-EM of the LRRC58–CDO1–CRL complex, biochemical ubiquitylation reconstitution, MS site mapping, and saturation mutagenesis stability profiling (one peer-reviewed study plus a corroborating preprint)\",\n      \"pmids\": [\"42098103\", \"bio_10.1101_2025.09.23.678073\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The cysteine sensor that gates LRRC58 stability not molecularly identified\", \"Quantitative coupling to ferroptosis thresholds not defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Two post-translational brakes on CDO1 catalysis were defined: AKT1 phosphorylation at T89 disrupts iron incorporation under IL-6 to boost cysteine supply for carcinoma growth, and oxidative glutathionylation at C164 blocks substrate binding to preserve redox balance under radiation.\",\n      \"evidence\": \"In vitro kinase assays, MS site mapping, site-directed mutagenesis, iron-incorporation and enzyme activity assays, and cellular viability/redox readouts in OSCC and irradiated cells\",\n      \"pmids\": [\"40269955\", \"40347691\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phosphatase/dethiolation enzymes reversing these marks not identified\", \"Crosstalk between phosphorylation, glutathionylation, and ubiquitination unaddressed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"CDO1 was linked to a human Mendelian disease, with de novo missense variants in a conserved region causing a neurodevelopmental syndrome and, separately, encoding proteins refractory to LRRC58-mediated degradation.\",\n      \"evidence\": \"Clinical genetics in three unrelated individuals plus structural modeling of variant–LRRC58 interface\",\n      \"pmids\": [\"39949058\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No direct biochemical mechanism linking variants to CNS phenotype in the genetics study itself\", \"Whether dysregulated CDO1 stability or catalysis drives disease unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"CDO1's role in non-cancer disease tissues was probed, implicating it in ferroptosis-related cartilage injury and in lipid handling via negative regulation of ACSM3 in renal tubular cells.\",\n      \"evidence\": \"siRNA knockdown in rat OA model and in lupus nephritis cell/mouse models with histology, mitochondrial, and lipid-deposition assays plus ACSM3 epistasis rescue\",\n      \"pmids\": [\"41017094\", \"41827894\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Pathway placement in OA inferred indirectly\", \"Mechanism of CDO1 control over ACSM3 not defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CDO1's enzymatic cysteine-oxidation activity is mechanistically integrated with its non-catalytic scaffolding functions, and which activity drives each disease phenotype, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unified model separating catalytic from scaffold contributions in vivo\", \"Cysteine-sensing apparatus upstream of LRRC58 unidentified\", \"Mechanistic basis of CDO1 neurodevelopmental disease not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [4, 5, 12]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [1, 12]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [6, 7, 13]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [2, 6]}\n    ],\n    \"complexes\": [\"LRRC58–CUL2/CUL5 cullin-RING ligase (substrate)\", \"CDO1–CaMKK2–AMPK complex\", \"CDO1–PPARγ–Med24 transcriptional complex\"],\n    \"partners\": [\"CaMKK2\", \"PRKAA1\", \"PPARG\", \"MED24\", \"AKT1\", \"LRRC58\", \"TRIM47\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}