CDO1

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).

1. 2017 Medium

   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

   PMID:28849476

   Open questions at the time

   • Does not address non-enzymatic CDO1 functions
   • Catalytic mechanism and iron cofactor handling not examined in this work
2. 2018 Medium

   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

   PMID:30311169

   Open questions at the time

   • Mechanism linking CDO1 to mitochondrial potential not defined
   • Single method set in cell lines only
3. 2020 Medium

   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

   PMID:32777557

   Open questions at the time

   • No molecular intermediary identified
   • Enzymatic versus non-enzymatic basis unresolved
4. 2022 High

   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

   PMID:36253617

   Open questions at the time

   • Structural basis of CDO1–PPARγ interaction unknown
   • How the catalytic and scaffold functions are partitioned not defined
5. 2023 High

   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

   PMID:38110408

   Open questions at the time

   • Whether catalytic activity contributes to AMPK activation not separated from scaffolding
   • Interface residues for CaMKK2/AMPK binding undefined
6. 2023 Medium

   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

   PMID:37406020

   Open questions at the time

   • Direct UHRF1 action at the CDO1 locus inferred from methylation, not biochemically reconstituted
   • Single lab
7. 2023 Medium

   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

   PMID:37740473

   Open questions at the time

   • Downstream effectors of CDO1-induced ferroptosis not delineated
   • Single cancer model
8. 2024 Medium

   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

   PMID:38614226

   Open questions at the time

   • Ubiquitination site on CDO1 not mapped
   • Single lab
9. 2024 Medium

   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

   PMID:38308276 PMID:39159808

   Open questions at the time

   • Interplay between the FAM83H-AS1/DNMT1 and DNMT3A/DNMT3L arms not integrated
   • Single lab per mechanism
10. 2025 High

    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)

    PMID:42098103 PMID:bio_10.1101_2025.09.23.678073

    Open questions at the time

    • The cysteine sensor that gates LRRC58 stability not molecularly identified
    • Quantitative coupling to ferroptosis thresholds not defined
11. 2025 High

    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

    PMID:40269955 PMID:40347691

    Open questions at the time

    • Phosphatase/dethiolation enzymes reversing these marks not identified
    • Crosstalk between phosphorylation, glutathionylation, and ubiquitination unaddressed
12. 2025 Low

    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

    PMID:39949058

    Open questions at the time

    • No direct biochemical mechanism linking variants to CNS phenotype in the genetics study itself
    • Whether dysregulated CDO1 stability or catalysis drives disease unresolved
13. 2025 Low

    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

    PMID:41017094 PMID:41827894

    Open questions at the time

    • Pathway placement in OA inferred indirectly
    • Mechanism of CDO1 control over ACSM3 not defined

• 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.
• 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