Affinage

DHODH

Dihydroorotate dehydrogenase (quinone), mitochondrial · UniProt Q02127

Length
395 aa
Mass
42.9 kDa
Annotated
2026-06-09
100 papers in source corpus 28 papers cited in narrative 28 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/7 claims corpus-supported (86%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

DHODH is a flavin-dependent mitochondrial inner-membrane enzyme that catalyzes the oxidation of dihydroorotate to orotate in de novo pyrimidine biosynthesis, coupling this reaction to the reduction of ubiquinone to ubiquinol; its activity functions as a metabolic node linking nucleotide supply to redox defense, differentiation, and immune signaling (PMID:33981038, PMID:22692683). Beyond supplying pyrimidines, the ubiquinol generated by DHODH acts as a radical-trapping antioxidant that suppresses mitochondrial lipid peroxidation and ferroptosis in parallel with mitochondrial GPX4 but independently of cytosolic GPX4 or FSP1 (PMID:33981038). Inhibitors bind competitively at the ubiquinone site, and high-resolution structures define their binding modes and chiral specificity (PMID:16480261, PMID:29549331, PMID:27994748). Biallelic loss-of-function mutations that reduce DHOdehase activity cause Miller syndrome, consistent with strong embryonic expression in pharyngeal arch and limb bud (PMID:22692683). DHODH activity is tuned post-translationally: HERC4-mediated ubiquitination at K306 (antagonized by PRR11) and USP24-mediated deubiquitination control DHODH stability and ferroptosis sensitivity, while SIRT3-regulated acetylation modulates its function under stress (PMID:38838551, PMID:40715045, PMID:39303219). Pyrimidine depletion downstream of DHODH inhibition arrests cells in S phase and drives differentiation, p53 induction, and antitumor responses through ATR/Chk1 and MYC-dependent programs, and is also exploited as an antiviral mechanism against SARS-CoV-2 and other RNA viruses (PMID:29549331, PMID:33496740, PMID:35790845, PMID:32754890). DHODH additionally influences transcriptional elongation and antigen presentation via P-TEFb, supports tumor macropinocytosis through NRP1 O-GlcNAcylation, and binds β-catenin to regulate Wnt signaling independently of its catalytic activity (PMID:21430780, PMID:38973593, PMID:40816268, PMID:33060568).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2006 High

    Establishing where inhibitors act on DHODH was needed for rational drug design; structures showed inhibitors occupy the ubiquinone binding pocket.

    Evidence High-resolution X-ray crystallography of DHODH-inhibitor complexes with enzymatic correlation

    PMID:16480261

    Open questions at the time
    • Does not address non-catalytic functions
    • Single-lab structural study
  2. 2007 Medium

    Whether human DHODH function depends on mitochondrial targeting was unresolved; complementation showed a functional mitochondrial targeting signal and conserved enzymatic role.

    Evidence Genetic complementation of auxotrophic U. maydis pyr4 mutants with humanized DHODH and brequinar sensitivity

    PMID:17369345

    Open questions at the time
    • Heterologous system
    • Does not address regulation in human cells
  3. 2011 High

    It was unknown whether DHODH had functions beyond pyrimidine synthesis; inhibition was shown to suppress transcriptional elongation of neural crest and melanoma genes.

    Evidence Chemical genetic screen in zebrafish, mammalian stem cell assays, melanoma xenografts

    PMID:21430780

    Open questions at the time
    • Molecular link between DHODH and elongation machinery not fully defined
    • Catalytic vs non-catalytic contribution unclear
  4. 2012 High

    The cause of Miller syndrome was unknown; biallelic DHODH loss-of-function mutations reducing enzymatic activity were shown to be causative.

    Evidence Yeast complementation, in vitro enzymatic assays of 11 missense mutations, urine metabolomics, mouse embryo in situ hybridization

    PMID:22692683

    Open questions at the time
    • Tissue-specific basis of craniofacial/limb defects not mechanistically resolved
  5. 2016 High

    Whether DHODH inhibition could overcome AML differentiation blockade was untested; ML390 directly inhibited DHODH and induced differentiation in HoxA9 AML.

    Evidence Phenotypic HTS, genetic resistance mapping, X-ray crystallography of DHODH-ML390

    PMID:27994748

    Open questions at the time
    • Downstream differentiation signaling not detailed in this study
  6. 2018 High

    How DHODH inhibition triggers tumor suppression was incompletely understood; (R)-HZ05 was shown to cause S-phase accumulation, pyrimidine depletion, and increased p53 synthesis.

    Evidence Target deconvolution, crystal structure, cell cycle and p53 synthesis assays, in vivo tumor models

    PMID:29549331

    Open questions at the time
    • Generality across p53-mutant contexts not established
  7. 2020 Medium

    Whether DHODH-driven pyrimidine supply is required for RNA virus replication and inflammatory cytokine production was tested; inhibition blocked SARS-CoV-2 replication DHODH-dependently and suppressed cytokines.

    Evidence DHODH inhibitors, knockout cells, uridine rescue, cytokine ELISA, in vivo antiviral efficacy

    PMID:32754890 PMID:33249060

    Open questions at the time
    • Host-vs-viral target specificity in vivo limited
    • Cytokine effects mechanistically indirect
  8. 2020 Medium

    Whether DHODH has catalysis-independent signaling roles was unknown; DHODH was shown to bind β-catenin and stabilize it by blocking GSK3β interaction, independent of enzymatic activity.

    Evidence Co-IP, proximity ligation, catalytically inactive mutant, nuclear fractionation, downstream gene expression

    PMID:33060568

    Open questions at the time
    • Single lung/esophageal context
    • Structural basis of binding undefined
    • No reciprocal in vivo genetic validation
  9. 2021 High

    A non-pyrimidine role for DHODH in cell death was unresolved; DHODH was shown to suppress ferroptosis via ubiquinol generation in the mitochondrial inner membrane, parallel to mitochondrial GPX4.

    Evidence DHODH KO, brequinar, dihydroorotate/orotate rescue, fractionation, lipid peroxidation assays, in vivo tumor models

    PMID:33981038

    Open questions at the time
    • Relative contribution vs GPX4 across tissues
    • Coupling of catalytic flux to local CoQH2 pool not quantified
  10. 2021 Medium

    Mechanisms of DHODH inhibition in MDS and metabolic disease were sought; pyrimidine depletion was shown to induce S-phase arrest with MYC suppression and to reprogram metabolism toward glycolysis with p53/GDF15 activation.

    Evidence RNA-seq, MYC overexpression rescue, decitabine incorporation, Seahorse, GLUT4 imaging, db/db and xenograft models

    PMID:33496740 PMID:34113829

    Open questions at the time
    • Single-lab studies
    • Direct vs indirect link to p53/GDF15 not fully dissected
  11. 2022 Medium

    How DHODH inhibition drives differentiation and affects nuclear RNA was probed; pyrimidine depletion activated ATR/Chk1-dependent differentiation and caused ATM-dependent nuclear poly(A)+ RNA accumulation.

    Evidence Immunoblotting, Chk1 genetic inactivation, FISH for poly(A)+ RNA, ATM inhibition, uridine rescue

    PMID:35790845 PMID:36412986

    Open questions at the time
    • Mechanistic link between pyrimidine pools and RNA export incomplete
    • Single-lab findings
  12. 2024 Medium

    Post-translational control of DHODH stability and its ferroptosis output was clarified; PRR11/HERC4 ubiquitination at K306, SIRT3-dependent acetylation, and CIRBP-dependent expression were shown to govern DHODH-mediated antioxidant defense.

    Evidence Co-IP, ubiquitination assays, K306 mutagenesis, SIRT3 KO, CoQH2 measurement, in vivo xenograft/AKI/heart-transplant models

    PMID:38690728 PMID:38838551 PMID:39303219

    Open questions at the time
    • Each regulator validated in a single disease context
    • Crosstalk between modifications unexplored
  13. 2024 Medium

    How DHODH influences immune visibility of tumors was unknown; it was shown to repress MHC-I via P-TEFb-dependent elongation, sustain NRP1 O-GlcNAcylation to drive macropinocytosis and MHC-II repression, and reshape phospholipids to modulate ferroptosis and T-cell killing.

    Evidence CRISPR screen, gene expression profiling, P-TEFb inhibition, O-GlcNAcylation and glutarylation assays, lipidomics, CD8+ T-cell co-culture, in vivo immunocompetent models with checkpoint blockade

    PMID:38973593 PMID:40274823 PMID:40816268

    Open questions at the time
    • Distinct mechanistic arms not integrated
    • Each demonstrated in single model systems
  14. 2025 Medium

    Upstream control of DHODH abundance in therapy resistance was further defined; USP24 deubiquitinates and stabilizes DHODH to protect against ferroptosis, and an OTUB1–DDX3X axis stabilizes DHODH mRNA to confer gemcitabine resistance.

    Evidence Co-IP, ubiquitination assays, mRNA stability assays, genetic silencing/rescue, in vivo tumoroid and ferroptosis models

    PMID:40715045 PMID:41053036

    Open questions at the time
    • Single-lab studies
    • Tissue specificity of regulators unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • How DHODH's catalytic ubiquinol output is mechanistically partitioned among pyrimidine synthesis, ferroptosis defense, transcriptional elongation, and its catalysis-independent protein-binding roles remains unresolved.
  • No unified model coupling enzymatic flux to non-canonical functions
  • Structural basis of β-catenin and signaling interactions undefined
  • Tissue-specific weighting of these roles unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016491 oxidoreductase activity 3 GO:0016209 antioxidant activity 1 GO:0016787 hydrolase activity 1
Localization
GO:0005739 mitochondrion 2
Pathway
R-HSA-1430728 Metabolism 3 R-HSA-1640170 Cell Cycle 3 R-HSA-168256 Immune System 3 R-HSA-5357801 Programmed Cell Death 3 R-HSA-1643685 Disease 1
Partners
CTNNB1DDX3XHERC4NRP1PRR11SIRT3USP24

Evidence

Reading pass · 28 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2021 DHODH operates in parallel to mitochondrial GPX4 (but independently of cytosolic GPX4 or FSP1) to inhibit ferroptosis in the mitochondrial inner membrane by reducing ubiquinone to ubiquinol, a radical-trapping antioxidant that suppresses mitochondrial lipid peroxidation. Genetic inactivation (DHODH KO), pharmacological inhibition (brequinar), metabolite supplementation (dihydroorotate/orotate), subcellular fractionation, lipid peroxidation assays, in vitro and in vivo tumor models Nature High 33981038
2011 DHODH inhibition (e.g., leflunomide) suppresses transcriptional elongation of genes required for neural crest development and melanoma growth, distinct from its pyrimidine synthesis function. Chemical genetic screen in zebrafish, mammalian neural crest stem cell self-renewal assays, transcriptional elongation assays, melanoma xenograft studies, BRAF(V600E) transgenic zebrafish model Nature High 21430780
2006 Human DHODH inhibitors bind competitively at the ubiquinone (CoQ) binding site; X-ray crystal structures revealed a dual binding mode of inhibitors within the same cocrystal, dependent on chemical substitution, with in vitro activity correlating with binding mode. High-resolution X-ray crystallography of DHODH-inhibitor complexes, in vitro enzymatic inhibition assays Journal of medicinal chemistry High 16480261
2018 DHODH inhibition by (R)-HZ05 (a chiral tetrahydroindazole) increases p53 synthesis by causing S-phase accumulation and pyrimidine depletion; the crystal structure of the (R)-HZ05/DHODH complex confirmed binding mode and chiral specificity. Target deconvolution, X-ray crystal structure of DHODH/(R)-HZ05 complex, cell cycle analysis, p53 synthesis measurement, in vivo tumor growth assays Nature communications High 29549331
2016 ML390 binds directly to DHODH and inhibits it, inducing differentiation in HoxA9-overexpressing AML cells; the X-ray crystal structure of ML390 bound to DHODH elucidated binding interactions. Phenotypic high-throughput screen, genetic resistance mapping, X-ray crystallography of DHODH-ML390 complex ACS medicinal chemistry letters High 27994748
2012 Biallelic DHODH loss-of-function mutations cause Miller syndrome by reducing pyrimidine biosynthesis (DHOdehase activity); complementation in auxotrophic yeast confirmed reduced pyrimidine synthesis, and in vitro enzymatic assays confirmed reduced DHOdehase activity for 11 disease-associated missense mutations. Mouse embryo in situ analysis showed Dhodh is strongly expressed in pharyngeal arch and limb bud, consistent with the developmental defects. Yeast complementation assay, in vitro enzymatic activity assay, urine metabolite analysis (orotic acid and dihydroorotate levels), in situ hybridization in mouse embryos Human molecular genetics High 22692683
2007 Human DHODH contains a functional mitochondrial targeting signal; expression of human DHODH fused to the U. maydis mitochondrial targeting signal complements pyr4 (DHODH) deletion auxotrophy in U. maydis, confirming mitochondrial localization and functional conservation. Genetic complementation of auxotrophic yeast pyr4 mutants, functional brequinar sensitivity assay in humanized U. maydis strains Applied and environmental microbiology Medium 17369345
2020 DHODH is an essential host factor for SARS-CoV-2 and other RNA virus replication; DHODH inhibition blocks viral replication in a DHODH-dependent manner (confirmed by DHODH knockout cells showing low viral replication and by uridine rescue experiments). DHODH inhibitor treatment (S312/S416/leflunomide/teriflunomide), DHODH knockout cell lines, in vivo antiviral efficacy, EC50 determination Protein & cell Medium 32754890
2020 PTC299 (a DHODH inhibitor) inhibits SARS-CoV-2 replication in a DHODH-dependent and dose-dependent manner, and also suppresses IL-6, IL-17A, IL-17F, and VEGF production in tissue culture, consistent with DHODH's requirement for immunomodulatory cytokine production. Tissue culture SARS-CoV-2 replication assay, cytokine measurement by ELISA, selectivity index determination Virus research Medium 33249060
2019 DHODH inhibition with leflunomide substantially impairs colorectal cancer liver metastatic colonization and hypoxic growth by blocking pyrimidine nucleotide biosynthesis driven by gluconeogenic enzyme PCK1 under hypoxia. Patient-derived xenograft (PDX) in vivo selection, metabolite profiling, leflunomide pharmacological inhibition, in vivo metastasis models eLife Medium 31841108
2017 DHODH inactivation/deficiency in melanoma cells induces S-phase cell cycle arrest, autophagy via the AMPK-Ulk1 axis, and apoptosis in BCL-2-deficient cells; JNK phosphorylation of BCL-2 abrogates BCL-2/Beclin1 interaction to permit autophagy. BCL-2 rescues apoptosis but promotes cell cycle arrest and inhibits autophagy. DHODH siRNA knockdown, leflunomide treatment, Western blot for AMPK/Ulk1/JNK/BCL-2/Beclin1, flow cytometry for cell cycle and apoptosis, autophagy assays Oncotarget Medium 29348830
2020 DHODH directly binds the NH2-terminal of β-catenin, interrupting the GSK3β–β-catenin interaction, preventing β-catenin degradation and causing its nuclear accumulation and activation of downstream genes (CCND1, E2F3, Nanog, OCT4) in esophageal squamous cell carcinoma; this regulation is independent of DHODH catalytic activity. Co-immunoprecipitation, proximity ligation assay, catalytically inactive DHODH mutant expression, β-catenin nuclear fractionation, downstream gene expression analysis Cell death & disease Medium 33060568
2022 ATM (ataxia telangiectasia mutated) kinase is required for DHODH-inhibition-induced poly(A)+ RNA nuclear accumulation adjacent to nuclear speckles; this phenomenon is abrogated by exogenous uridine, linking intracellular pyrimidine depletion to nuclear poly(A)+ RNA metabolism via the mitochondrial respiratory chain complex III. Original mRNA metabolic screening, fluorescence in situ hybridization for poly(A)+ RNA, ATM inhibitor/genetic knockdown, uridine rescue experiments RNA biology Medium 36412986
2024 DHODH inhibition reduces CDP-choline levels and attenuates phosphatidylcholine synthesis via the CDP-choline-dependent Kennedy pathway; compensatory increased phospholipid methylation from phosphatidylethanolamine produces very long chain PUFA-containing PCs, promoting ferroptosis and enhancing cancer cell sensitivity to T cell cytotoxicity. DHODH genetic inactivation, lipidomic and metabolomic analyses, Kennedy pathway inhibitor studies, CD8+ T cell co-culture assays, in vivo mouse tumor models with PD-1 blockade Nature communications Medium 40274823
2024 PRR11 directly binds and stabilizes DHODH protein by suppressing E3 ubiquitin ligase HERC4-mediated polyubiquitination and degradation of DHODH at the K306 site, conferring ferroptosis resistance in glioblastoma in a DHODH-dependent manner. Co-immunoprecipitation, ubiquitination assay, site-directed mutagenesis (K306), DHODH knockdown/overexpression, lipid peroxidation assays, in vivo xenograft models Redox biology Medium 38838551
2024 Mitochondrial dysfunction during cisplatin-induced AKI causes SIRT3 reduction and subsequent DHODH acetylation; SIRT3 overexpression or NMN supplementation attenuates DHODH acetylation and reduces ferroptosis, while Sirt3 knockout aggravates DHODH acetylation and ferroptosis. MitoQ pretreatment alleviated mitochondrial dysfunction, SIRT3 SUMOylation, and DHODH acetylation. Targeted metabolomics, DHODH overexpression/knockdown, SIRT3 overexpression/KO, CoQH2 measurement, lipid peroxidation assays, in vivo mouse AKI model, NMN supplementation Advanced science Medium 39303219
2025 USP24 deubiquitinase directly interacts with DHODH and deubiquitinates it, stabilizing DHODH protein and protecting cells from lipid peroxidation and ferroptosis; pharmacological USP24 inhibition synergizes with ferroptosis inducers via a DHODH-dependent pathway. Co-immunoprecipitation, ubiquitination assay, USP24 silencing, DHODH rescue experiments, in vitro and in vivo ferroptosis assays Cell death & disease Medium 40715045
2024 DHODH sustains O-GlcNAcylation of neuropilin-1 (NRP1) and its membrane localization, mediating tumor cell macropinocytosis; DHODH-NRP1-driven macropinocytosis increases intracellular lysine and tryptophan, which promotes glutarylation of CIITA transcription factor to repress MHC class II expression and enable immune evasion. Genome-wide CRISPR-Cas9 screen, metabolic compound library screen, NRP1 O-GlcNAcylation assay, membrane localization studies, amino acid metabolomics, CIITA glutarylation assay, in vivo immune cell infiltration analysis Immunity Medium 40816268
2024 DHODH inhibition (brequinar) causes upregulation of MHC class I antigen presentation pathway genes and cell surface MHC class I expression in cancer cells; this effect is strictly dependent on pyrimidine nucleotide depletion and is mediated by RNA polymerase II elongation control via positive transcription elongation factor B (P-TEFb), independent of canonical antigen presentation pathway transcriptional regulators. Gene expression profiling, pyrimidine nucleotide depletion rescue experiments, P-TEFb inhibitor studies, flow cytometry for MHC class I, in vivo immunocompetent melanoma model with immune checkpoint blockade eLife Medium 38973593
2021 DHODH inhibition (PTC299) induces intra-S-phase arrest and apoptotic cell death in MDS cells, and enhances incorporation of decitabine (a cytidine analog) into DNA by inhibiting pyrimidine production, synergizing with hypomethylating agents; MYC target gene sets are markedly downregulated, and MYC overexpression largely attenuates growth inhibitory effects of PTC299. Cell viability assays with uridine rescue, RNA-seq, MYC overexpression rescue, decitabine incorporation assay, xenograft mouse models Blood advances Medium 33496740
2022 DHODH inhibition (brequinar) induces differentiation of myeloid leukemia cells by activating the ATR/Chk1 signaling pathway via pyrimidine depletion; this mechanism is shared with low-dose cytarabine-induced differentiation, and Chk1 genetic inactivation abolishes differentiation. Immunoblotting for ATR/Chk1 activation, flow cytometry for differentiation markers, pharmacologic Chk1 inhibition, genetic Chk1 inactivation, primary AML sample ex vivo assays, uridine rescue Scientific reports Medium 35790845
2024 DHODH inhibition reduces mitochondrial respiration and CoQH2 production; DHODH upregulation by E2 (estradiol) protects cardiomyocytes from ferroptosis in heart failure via CoQ-related biological processes; CoQ siRNA knockdown abolishes the protective effect of DHODH upregulation. TAC mouse heart failure model, E2 treatment, siRNA knockdown of CoQ, DHODH overexpression/knockdown, ferroptosis marker assays, echocardiography, mitochondrial membrane potential measurement Frontiers in bioscience Medium 39082362
2019 DHODH inhibition (brequinar/leflunomide) exerts anti-rotavirus activity through targeting DHODH to deplete the pyrimidine nucleotide pool, confirmed by restoration of viral replication with exogenous uridine supplementation. DHODH inhibitor treatment, uridine rescue experiment, Caco2 cell line and primary human intestinal organoids, clinical rotavirus strain testing Antiviral research Medium 30974126
2021 DHODH inhibition reduces mitochondrial respiration, promotes glycolysis, enhances GLUT4 translocation to the cytoplasmic membrane, and activates p53 to increase GDF15 expression; in db/db mice, DHODH inhibitors elevate circulating GDF15, reduce food intake, delay pancreatic β cell death, and improve metabolic balance. Seahorse metabolic assay, GLUT4 translocation imaging, p53 activation assay, GDF15 ELISA, db/db mouse model iScience Medium 34113829
2024 PACS2 downregulation upregulates DHODH expression and reverses high-glucose/palmitic acid-induced ferroptosis in cardiomyocytes by modulating mitochondrial function; this effect is mediated through CPT1A, as a CPT1A agonist with PACS2 silencing exacerbates ferroptosis. PACS2 siRNA knockdown, CPT1A agonist treatment, ferroptosis marker measurement (iron ions, lipid peroxides, ROS), mitochondrial function assays, streptozotocin/HFD mouse model Cardiovascular diabetology Low 39633391
2025 OTUB1 deubiquitylase stabilizes DDX3X RNA-binding protein by suppressing its polyubiquitination; DDX3X in turn stabilizes DHODH mRNA, thereby upregulating DHODH protein and de novo pyrimidine synthesis to confer gemcitabine resistance in pancreatic cancer. Co-immunoprecipitation (OTUB1-DDX3X), ubiquitination assay, DDX3X knockdown, DHODH mRNA stability assay, in vivo murine tumoroid model with OTUB1 inhibitor Cell death & disease Medium 41053036
2023 MK-4 (menaquinone-4/vitamin K2) attenuates ferroptosis after subarachnoid hemorrhage by upregulating DHODH through activation of SIRT1 and promoting SIRT1 nuclear entry; DHODH inhibitor (brequinar) or SIRT1 inhibitor (selisistat) partially abolished MK-4's protective effects. SAH mouse model, Western blot for DHODH and SIRT1, immunofluorescence for SIRT1 localization, DHODH/SIRT1 inhibitor rescue experiments, ferroptosis marker assays Free radical biology & medicine Low 38042225
2024 CIRBP (cold-inducible RNA-binding protein) regulates DHODH protein expression; Cirbp-KO donor hearts show decreased DHODH expression during transplantation, compromising DHODH-mediated ubiquinone reduction, exacerbating lipid peroxidation and triggering ferroptosis. Cirbp-KO rat heart transplantation model, RNA-Seq, cardiac proteomics, DHODH expression analysis, lipid peroxidation measurement, CIRBP overexpression rescue The Journal of clinical investigation Medium 38690728

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2021 DHODH-mediated ferroptosis defence is a targetable vulnerability in cancer. Nature 1535 33981038
2011 DHODH modulates transcriptional elongation in the neural crest and melanoma. Nature 389 21430780
2019 The novel dihydroorotate dehydrogenase (DHODH) inhibitor BAY 2402234 triggers differentiation and is effective in the treatment of myeloid malignancies. Leukemia 197 30940908
2020 Novel and potent inhibitors targeting DHODH are broad-spectrum antivirals against RNA viruses including newly-emerged coronavirus SARS-CoV-2. Protein & cell 170 32754890
2021 DHODH and cancer: promising prospects to be explored. Cancer & metabolism 137 33971967
2019 Identification of DHODH as a therapeutic target in small cell lung cancer. Science translational medicine 119 31694929
2011 Recent developments in the medicinal chemistry and therapeutic potential of dihydroorotate dehydrogenase (DHODH) inhibitors. Mini reviews in medicinal chemistry 109 21861807
2018 Dependence on the Pyrimidine Biosynthetic Enzyme DHODH Is a Synthetic Lethal Vulnerability in Mutant KRAS-Driven Cancers. Cell chemical biology 103 29628435
2006 Dual binding mode of a novel series of DHODH inhibitors. Journal of medicinal chemistry 90 16480261
2017 Dihydroorotate dehydrogenase (DHODH) inhibitors affect ATP depletion, endogenous ROS and mediate S-phase arrest in breast cancer cells. Biochimie 82 28196676
2019 PCK1 and DHODH drive colorectal cancer liver metastatic colonization and hypoxic growth by promoting nucleotide synthesis. eLife 81 31841108
2018 A DHODH inhibitor increases p53 synthesis and enhances tumor cell killing by p53 degradation blockage. Nature communications 74 29549331
2020 The DHODH inhibitor PTC299 arrests SARS-CoV-2 replication and suppresses induction of inflammatory cytokines. Virus research 60 33249060
2016 Development of ML390: A Human DHODH Inhibitor That Induces Differentiation in Acute Myeloid Leukemia. ACS medicinal chemistry letters 58 27994748
2023 The Warburg effect modulates DHODH role in ferroptosis: a review. Cell communication and signaling : CCS 55 37147673
2022 A Broad Antiviral Strategy: Inhibitors of Human DHODH Pave the Way for Host-Targeting Antivirals against Emerging and Re-Emerging Viruses. Viruses 50 35632670
2020 IMU-838, a Developmental DHODH Inhibitor in Phase II for Autoimmune Disease, Shows Anti-SARS-CoV-2 and Broad-Spectrum Antiviral Efficacy In Vitro. Viruses 50 33291455
2012 Miller (Genee-Wiedemann) syndrome represents a clinically and biochemically distinct subgroup of postaxial acrofacial dysostosis associated with partial deficiency of DHODH. Human molecular genetics 50 22692683
2020 Vidofludimus calcium, a next generation DHODH inhibitor for the Treatment of relapsing-remitting multiple sclerosis. Multiple sclerosis and related disorders 49 32428844
2023 Depletion of SOD2 enhances nasopharyngeal carcinoma cell radiosensitivity via ferroptosis induction modulated by DHODH inhibition. BMC cancer 45 36737723
2019 Suppression of pyrimidine biosynthesis by targeting DHODH enzyme robustly inhibits rotavirus replication. Antiviral research 43 30974126
2023 17β-oestradiol inhibits ferroptosis in the hippocampus by upregulating DHODH and further improves memory decline after ovariectomy. Redox biology 42 37116254
2024 DHODH inhibition enhances the efficacy of immune checkpoint blockade by increasing cancer cell antigen presentation. eLife 40 38973593
2015 Benzimidazole derivatives as potential dual inhibitors for PARP-1 and DHODH. Bioorganic & medicinal chemistry 36 26088338
2021 Efficacy and safety of dihydroorotate dehydrogenase (DHODH) inhibitors "leflunomide" and "teriflunomide" in Covid-19: A narrative review. European journal of pharmacology 35 34111397
2023 DHODH Inhibition Exerts Synergistic Therapeutic Effect with Cisplatin to Induce Ferroptosis in Cervical Cancer through Regulating mTOR Pathway. Cancers 32 36672495
2020 Elevated DHODH expression promotes cell proliferation via stabilizing β-catenin in esophageal squamous cell carcinoma. Cell death & disease 32 33060568
2024 A targetable PRR11-DHODH axis drives ferroptosis- and temozolomide-resistance in glioblastoma. Redox biology 31 38838551
2024 Mitochondrial Dysfunction-Evoked DHODH Acetylation is Involved in Renal Cell Ferroptosis during Cisplatin-Induced Acute Kidney Injury. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 31 39303219
2024 PACS2/CPT1A/DHODH signaling promotes cardiomyocyte ferroptosis in diabetic cardiomyopathy. Cardiovascular diabetology 31 39633391
2021 DHODH inhibition synergizes with DNA-demethylating agents in the treatment of myelodysplastic syndromes. Blood advances 31 33496740
2025 DHODH-mediated mitochondrial redox homeostasis: a novel ferroptosis regulator and promising therapeutic target. Redox biology 30 40716151
2021 Effective deploying of a novel DHODH inhibitor against herpes simplex type 1 and type 2 replication. Antiviral research 30 33716051
2022 DHODH inhibition impedes glioma stem cell proliferation, induces DNA damage, and prolongs survival in orthotopic glioblastoma xenografts. Oncogene 29 36344676
2017 Inactivation/deficiency of DHODH induces cell cycle arrest and programed cell death in melanoma. Oncotarget 28 29348830
2015 Original 2-(3-Alkoxy-1H-pyrazol-1-yl)azines Inhibitors of Human Dihydroorotate Dehydrogenase (DHODH). Journal of medicinal chemistry 28 26079043
2023 Exploiting Cancer Vulnerabilities by Blocking of the DHODH and GPX4 Pathways: A Multifunctional Bodipy/PROTAC Nanoplatform for the Efficient Synergistic Ferroptosis Therapy. Advanced healthcare materials 27 37204046
2022 Iron-dependent ferroptosis participated in benzene-induced anemia of inflammation through IRP1-DHODH-ALOX12 axis. Free radical biology & medicine 27 36244588
2021 The Synergism between DHODH Inhibitors and Dipyridamole Leads to Metabolic Lethality in Acute Myeloid Leukemia. Cancers 27 33670894
2015 Original 2-(3-alkoxy-1H-pyrazol-1-yl)pyrimidine derivatives as inhibitors of human dihydroorotate dehydrogenase (DHODH). Journal of medicinal chemistry 25 25558988
2022 ENT1 blockade by CNX-774 overcomes resistance to DHODH inhibition in pancreatic cancer. Cancer letters 24 36341997
2007 Functional expression of human dihydroorotate dehydrogenase (DHODH) in pyr4 mutants of ustilago maydis allows target validation of DHODH inhibitors in vivo. Applied and environmental microbiology 24 17369345
2012 Association of DHODH haplotype variants and response to leflunomide treatment in rheumatoid arthritis. Pharmacogenomics 23 22966891
2023 Menaquinone-4 attenuates ferroptosis by upregulating DHODH through activation of SIRT1 after subarachnoid hemorrhage. Free radical biology & medicine 20 38042225
2024 Cirbp suppression compromises DHODH-mediated ferroptosis defense and attenuates hypothermic cardioprotection in an aged donor transplantation model. The Journal of clinical investigation 19 38690728
2021 A Combined Chemical, Computational, and In Vitro Approach Identifies SBL-105 as Novel DHODH Inhibitor in Acute Myeloid Leukemia Cells. Oncology research 19 34353411
2019 UVB-induced DHODH upregulation, which is driven by STAT3, is a promising target for chemoprevention and combination therapy of photocarcinogenesis. Oncogenesis 19 31551419
2021 DHODH inhibition modulates glucose metabolism and circulating GDF15, and improves metabolic balance. iScience 18 34113829
2025 DHODH modulates immune evasion of cancer cells via CDP-Choline dependent regulation of phospholipid metabolism and ferroptosis. Nature communications 17 40274823
2024 Antirheumatic drug leflunomide attenuates atherosclerosis by regulating lipid metabolism and endothelial dysfunction via DHODH/AMPK signaling pathway. International journal of biological sciences 17 39113703
2018 Intraocular DHODH-inhibitor PP-001 suppresses relapsing experimental uveitis and cytokine production of human lymphocytes, but not of RPE cells. Journal of neuroinflammation 17 29467002
2025 Ferroptosis and PANoptosis under hypoxia pivoting on the crosstalk between DHODH and GPX4 in corneal epithelium. Free radical biology & medicine 16 39761766
2024 DHODH inhibition represents a therapeutic strategy and improves abiraterone treatment in castration-resistant prostate cancer. Oncogene 16 38480915
2024 Ginsenoside Rd alleviates early brain injury by inhibiting ferroptosis through cGAS/STING/DHODH pathway after subarachnoid hemorrhage. Free radical biology & medicine 16 39746578
2022 Caffeic Acid Phenethyl Ester as a DHODH Inhibitor and Its Synergistic Anticancer Properties in Combination with 5-Fluorouracil in a Breast Cancer Cell Line. Journal of experimental pharmacology 15 35910085
2009 A study of the effects of substituents on the selectivity of the binding of N-arylaminomethylene malonate inhibitors to DHODH. Bioorganic & medicinal chemistry letters 15 20034791
2020 Exploitation of dihydroorotate dehydrogenase (DHODH) and p53 activation as therapeutic targets: A case study in polypharmacology. The Journal of biological chemistry 14 32900849
2012 CoMFA and CoMSIA studies on aryl carboxylic acid amide derivatives as dihydroorotate dehydrogenase (DHODH) inhibitors. Current computer-aided drug design 14 22242798
2022 Mitochondrial DHODH regulates hypoxia-inducible factor 1 expression in OTSCC. American journal of cancer research 13 35141004
2022 N-Heterocyclic 3-Pyridyl Carboxamide Inhibitors of DHODH for the Treatment of Acute Myelogenous Leukemia. Journal of medicinal chemistry 12 35925768
2025 DHODH inhibitors: What will it take to get them into the clinic as antivirals? Antiviral research 11 39938808
2024 DHODH Alleviates Heart Failure via the Modulation of CoQ-Related Ferroptotic Inhibition. Frontiers in bioscience (Landmark edition) 11 39082362
2023 Characterisation of putative class 1A DHODH-like proteins from Mucorales and dematiaceous mould species. PloS one 11 37531380
2023 DHODH: a promising target in the treatment of T-cell acute lymphoblastic leukemia. Blood advances 11 37648673
2025 The deubiquitinase USP24 suppresses ferroptosis in triple-negative breast cancer by stabilizing DHODH protein. Cell death & disease 10 40715045
2022 Cytarabine-induced differentiation of AML cells depends on Chk1 activation and shares the mechanism with inhibitors of DHODH and pyrimidine synthesis. Scientific reports 10 35790845
2021 DHODH Hot Spots: An Underexplored Source to Guide Drug Development Efforts. Current topics in medicinal chemistry 9 34348625
2025 Inhibition of tumor cell macropinocytosis driver DHODH reverses immunosuppression and overcomes anti-PD1 resistance. Immunity 8 40816268
2020 The DHODH Inhibitor PTC299 Arrests SARS-CoV-2 Replication and Suppresses Induction of Inflammatory Cytokines. bioRxiv : the preprint server for biology 8 32793904
2024 Synthesis and Characterization of DHODH Inhibitors Based on the Vidofludimus Scaffold with Pronounced Anti-SARS-CoV-2 Activity. ChemMedChem 7 38887198
2022 Virtual screening and molecular dynamic simulations of the antimalarial derivatives of 2-anilino 4-amino substituted quinazolines docked against a Pf-DHODH protein target. The Egyptian journal of medical human genetics 7 37521844
2020 A carboxylic acid isostere screen of the DHODH inhibitor Brequinar. Bioorganic & medicinal chemistry letters 7 33007394
2020 Selective eradication of pluripotent stem cells by inhibiting DHODH activity. Stem cells (Dayton, Ohio) 7 33038285
2025 Akt mitigates ER stress-instigated cardiac dysfunction via regulation of ferroptosis and mitochondrial integrity in a DHODH-dependent manner. Life sciences 6 40164331
2024 Discovery of JNJ-74856665: A Novel Isoquinolinone DHODH Inhibitor for the Treatment of AML. Journal of medicinal chemistry 6 38889244
2023 Deciphering Interactions between Potential Inhibitors and the Plasmodium falciparum DHODH Enzyme: A Computational Perspective. The journal of physical chemistry. B 6 37897437
2022 In vitro metabolism, pharmacokinetics and drug interaction potentials of emvododstat, a DHODH inhibitor. Xenobiotica; the fate of foreign compounds in biological systems 6 34846990
2025 The long non-coding RNA RSDR protects against acute kidney injury in mice by interacting with hnRNPK to regulate DHODH-mediated ferroptosis. Nature communications 5 40796740
2024 Targeted inhibition of DHODH is synergistic with BCL2 blockade in HGBCL with concurrent MYC and BCL2 rearrangement. BMC cancer 5 38918775
2024 Metabolic Plasticity of Glioblastoma Cells in Response to DHODH Inhibitor BAY2402234 Treatment. Metabolites 5 39195509
2023 Assessment of a novel variation in DHODH gene causing Miller syndrome: The first report in Chinese population. Molecular genetics & genomic medicine 5 37120754
2023 Inhibition of DHODH Enhances Replication-Associated Genomic Instability and Promotes Sensitivity in Endometrial Cancer. Cancers 5 38136273
2022 A new small molecule DHODH-inhibitor [KIO-100 (PP-001)] targeting activated T cells for intraocular treatment of uveitis - A phase I clinical trial. Frontiers in medicine 5 36325389
2024 Orally bioavailable RORγ/DHODH dual host-targeting small molecules with broad-spectrum antiviral activity. Antiviral research 4 39306285
2022 Inhibition of mitochondrial complex III or dihydroorotate dehydrogenase (DHODH) triggers formation of poly(A)+ RNA foci adjacent to nuclear speckles following activation of ATM (ataxia telangiectasia mutated). RNA biology 4 36412986
2017 Effects of dihydroorotate dehydrogenase (DHODH) inhibitors on the growth of Theileria equi and Babesia caballi in vitro. Experimental parasitology 4 28286324
2017 Liquid phase combinatorial synthesis of 1,2,5-trisubstituted benzimidazole derivatives as human DHODH inhibitors. Bioorganic chemistry 4 28941392
2025 Intrinsic Natural Resistance of Various Plant Pathogens to Ipflufenoquin, a New DHODH (Dihydroorotate Dehydrogenase)-Inhibiting Fungicide, in Relation to an Unaltered Amino Acid Sequence of the Target Site. Plant disease 3 39475586
2025 DHODH Blockade Induces Ferroptosis in Neuroblastoma by Modulating the Mevalonate Pathway. Molecular & cellular proteomics : MCP 3 40513779
2025 The VDAC3/DHODH Axis Ameliorates Sepsis-induced Myocardial Injury by Regulating Ferroptosis. Frontiers in bioscience (Landmark edition) 3 40613295
2025 The deubiquitylase OTUB1 drives gemcitabine resistance in pancreatic cancer by enhancing pyrimidine metabolism through modulating DHODH mRNA stability. Cell death & disease 3 41053036
2024 DHODH inhibition enhances the efficacy of immune checkpoint blockade by increasing cancer cell antigen presentation. bioRxiv : the preprint server for biology 3 37066260
2024 Virtual screening and molecular dynamics studies of novel small molecules targeting Schistosoma mansoni DHODH: identification of potential inhibitors. In silico pharmacology 3 39620199
2024 DHODH Inhibition Suppresses MYC and Inhibits the Growth of Medulloblastoma in a Novel In Vivo Zebrafish Model. Cancers 3 39766063
2023 Kinetic and structural studies of Mycobacterium tuberculosis dihydroorotate dehydrogenase reveal new insights into class 2 DHODH inhibition. Biochimica et biophysica acta. General subjects 3 37150227
2023 Cloning and Characterization of Yak DHODH Gene and Its Functional Studies in a Bisphenol S-Induced Ferroptosis Model of Fetal Fibroblasts. Animals : an open access journal from MDPI 3 38136869
2022 SAR studies toward discovery of emvododstat (PTC299), a potent dihydroorotate dehydrogenase (DHODH) inhibitor. European journal of medicinal chemistry 3 36242990
2025 Flubendazole inhibits cervical carcinoma by targeting DHODH to induce ferroptosis and mitophagy. Biochemical pharmacology 2 40885318
2025 An immunometabolic prodrug strategy overcomes DHODH inhibitor resistance in refractory melanoma. Journal of experimental & clinical cancer research : CR 2 41239499
2024 The DHODH inhibitor teriflunomide impedes cell proliferation and enhances chemosensitivity to daunorubicin (DNR) in T-cell acute lymphoblastic leukemia. Annals of hematology 2 39377943

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