General Information of the Ferroptosis Regulator (ID: REG10193)
Regulator Name Dihydroorotate dehydrogenase (quinone), mitochondrial (DHODH)
Synonyms
Dihydroorotate oxidase
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Gene Name DHODH
Gene ID 1723
Regulator Type Protein coding
Uniprot ID Q02127
Sequence
MAWRHLKKRAQDAVIILGGGGLLFASYLMATGDERFYAEHLMPTLQGLLDPESAHRLAVR
FTSLGLLPRARFQDSDMLEVRVLGHKFRNPVGIAAGFDKHGEAVDGLYKMGFGFVEIGSV
TPKPQEGNPRPRVFRLPEDQAVINRYGFNSHGLSVVEHRLRARQQKQAKLTEDGLPLGVN
LGKNKTSVDAAEDYAEGVRVLGPLADYLVVNVSSPNTAGLRSLQGKAELRRLLTKVLQER
DGLRRVHRPAVLVKIAPDLTSQDKEDIASVVKELGIDGLIVTNTTVSRPAGLQGALRSET
GGLSGKPLRDLSTQTIREMYALTQGRVPIIGVGGVSSGQDALEKIRAGASLVQLYTALTF
WGPPVVGKVKRELEALLKEQGFGGVTDAIGADHRR

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Family Dihydroorotate dehydrogenase family
Function
Catalyzes the conversion of dihydroorotate to orotate with quinone as electron acceptor. Required for UMP biosynthesis via de novo pathway.

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HGNC ID
HGNC:2867
KEGG ID hsa:1723
Full List of the Ferroptosis Target of This Regulator and Corresponding Disease/Drug Response(s)
DHODH can regulate the following target(s), and cause disease/drug response(s). You can browse detail information of target(s) or disease/drug response(s).
Browse Target
Browse Disease
Polyunsaturated fatty acid lipoxygenase ALOX15 (ALOX15) [Driver]
In total 2 item(s) under this target
Experiment 1 Reporting the Ferroptosis Target of This Regulator [1]
Target for Ferroptosis Driver
Responsed Disease Spinal cord injury ICD-11: ND51
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model
PC12 cells Adrenal gland pheochromocytoma Rattus norvegicus CVCL_0481
In Vivo Model
Forty female Sprague-Dawley rats (200-300 g, 8 weeks old) were purchased from the Animal Experiment Center of Fudan University. Forty rats were randomly divided into four groups: sham operation group (n = 10), SCI group (n = 10), SCI + ferroptosis inhibitor group (SCI + ferrostatin1) (n = 10), and SCI + DHODH Inhibitor group (SCI + teriflunomide) (n = 10). Ten rats in the sham group only received laminectomy without SCI. To induce spinal cord injury, spinal cord injury surgery was performed in the middle thoracic region of rats (T8-T9).

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Response regulation The application of DHODH is a potential treatment for spinal cord injury (SCI). DHODH can reduce the ferroptosis of neurons after spinal cord injury by regulating the P53/ALOX15 signaling pathway, thereby alleviating spinal cord injury.
Experiment 2 Reporting the Ferroptosis Target of This Regulator [1]
Target for Ferroptosis Driver
Responsed Disease Spinal cord injury ICD-11: ND51
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model
PC12 cells Adrenal gland pheochromocytoma Rattus norvegicus CVCL_0481
In Vivo Model
Forty female Sprague-Dawley rats (200-300 g, 8 weeks old) were purchased from the Animal Experiment Center of Fudan University. Forty rats were randomly divided into four groups: sham operation group (n = 10), SCI group (n = 10), SCI + ferroptosis inhibitor group (SCI + ferrostatin1) (n = 10), and SCI + DHODH Inhibitor group (SCI + teriflunomide) (n = 10). Ten rats in the sham group only received laminectomy without SCI. To induce spinal cord injury, spinal cord injury surgery was performed in the middle thoracic region of rats (T8-T9).

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Response regulation The application of DHODH is a potential treatment for spinal cord injury (SCI). DHODH can reduce the ferroptosis of neurons after spinal cord injury by regulating the P53/ALOX15 signaling pathway, thereby alleviating spinal cord injury.
Polyunsaturated fatty acid lipoxygenase ALOX12 (ALOX12) [Driver]
In total 1 item(s) under this target
Experiment 1 Reporting the Ferroptosis Target of This Regulator [2]
Target for Ferroptosis Driver
Responsed Disease Anemia ICD-11: 3A9Z
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model
AHH-1 cells Normal Homo sapiens CVCL_3640
In Vivo Model
4-week male C57BL/6J mice (20-22 g) were obtained from the vital river and preconditioned for one week. Mice were divided into two groups, either exposed to benzene or fresh air in the exposure system for 6 h/day, 6 days/week, for two months. In the last exposure day, the mice were fast for 10 h. Subsequently, the mice were injected with tribromoethanol (T48402, Sigma, USA) (300 mg/kg).

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Response regulation The iron-regulatory system IRP1, ferroptosis regulator DHODH, and fatty acids metabolism rate-limiting enzyme ALOX12 were the crucial influencers in regulating ferroptosis, this provides the potential target in attenuating benzene-induced anemia of inflammation.
Phospholipid hydroperoxide glutathione peroxidase (GPX4) [Suppressor]
In total 1 item(s) under this target
Experiment 1 Reporting the Ferroptosis Target of This Regulator [3]
Target for Ferroptosis Suppressor
Responsed Disease Hereditary Leiomyomatosis ICD-11: 2C90
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model
UM-RC-2 cells Clear cell renal carcinoma Homo sapiens CVCL_2739
UM-RC-6 cells Renal cell carcinoma Homo sapiens CVCL_2741
RCC4 cells Clear cell renal cell carcinoma Homo sapiens CVCL_0498
TK-10 cells Renal carcinoma Homo sapiens CVCL_1773
HT-1080 cells Fibrosarcoma Homo sapiens CVCL_0317
NCI-H226 cells Pleural epithelioid mesothelioma Homo sapiens CVCL_1544
In Vivo Model
5 x 106 HT-1080 or 1 x 107 NCI-H226 cells were injected into mice subcutaneously. When the tumor reached 50-100 mm3, the mice were assigned randomly into different treatment groups. Brequinar or sulfasalazine was dissolved in dimethyl sulfoxide (DMSO) and diluted in PBS. Brequinar was intraperitoneally injected into mice at a dose of 30 mg/kg every three days. Sulfasalazine was intraperitoneally injected daily at a dose of 100 mg/kg. Liproxstatin-1 diluted in PBS was intraperitoneally injected daily at a dose of 10 mg/kg. The daily injection of brequinar, sulfasalazine, or liproxstatin-1 was continued until the endpoint as indicated in the corresponding figures.

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Response regulation 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 with anti-ferroptosis activity) in Clear cell renal carcinoma.
Hereditary Leiomyomatosis [ICD-11: 2C90]
In total 1 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response [3]
Target Regulator Dihydroorotate dehydrogenase (quinone), mitochondrial (DHODH) Protein coding
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model
UM-RC-2 cells Clear cell renal carcinoma Homo sapiens CVCL_2739
UM-RC-6 cells Renal cell carcinoma Homo sapiens CVCL_2741
RCC4 cells Clear cell renal cell carcinoma Homo sapiens CVCL_0498
TK-10 cells Renal carcinoma Homo sapiens CVCL_1773
HT-1080 cells Fibrosarcoma Homo sapiens CVCL_0317
NCI-H226 cells Pleural epithelioid mesothelioma Homo sapiens CVCL_1544
In Vivo Model
5 x 106 HT-1080 or 1 x 107 NCI-H226 cells were injected into mice subcutaneously. When the tumor reached 50-100 mm3, the mice were assigned randomly into different treatment groups. Brequinar or sulfasalazine was dissolved in dimethyl sulfoxide (DMSO) and diluted in PBS. Brequinar was intraperitoneally injected into mice at a dose of 30 mg/kg every three days. Sulfasalazine was intraperitoneally injected daily at a dose of 100 mg/kg. Liproxstatin-1 diluted in PBS was intraperitoneally injected daily at a dose of 10 mg/kg. The daily injection of brequinar, sulfasalazine, or liproxstatin-1 was continued until the endpoint as indicated in the corresponding figures.

    Click to Show/Hide
Response regulation 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 with anti-ferroptosis activity) in Clear cell renal carcinoma.
Anemia [ICD-11: 3A9Z]
In total 1 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response [2]
Target Regulator Dihydroorotate dehydrogenase (quinone), mitochondrial (DHODH) Protein coding
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model
AHH-1 cells Normal Homo sapiens CVCL_3640
In Vivo Model
4-week male C57BL/6J mice (20-22 g) were obtained from the vital river and preconditioned for one week. Mice were divided into two groups, either exposed to benzene or fresh air in the exposure system for 6 h/day, 6 days/week, for two months. In the last exposure day, the mice were fast for 10 h. Subsequently, the mice were injected with tribromoethanol (T48402, Sigma, USA) (300 mg/kg).

    Click to Show/Hide
Response regulation The iron-regulatory system IRP1, ferroptosis regulator DHODH, and fatty acids metabolism rate-limiting enzyme ALOX12 were the crucial influencers in regulating ferroptosis, this provides the potential target in attenuating benzene-induced anemia of inflammation.
Spinal cord injury [ICD-11: ND51]
In total 2 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response [1]
Target Regulator Dihydroorotate dehydrogenase (quinone), mitochondrial (DHODH) Protein coding
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model
PC12 cells Adrenal gland pheochromocytoma Rattus norvegicus CVCL_0481
In Vivo Model
Forty female Sprague-Dawley rats (200-300 g, 8 weeks old) were purchased from the Animal Experiment Center of Fudan University. Forty rats were randomly divided into four groups: sham operation group (n = 10), SCI group (n = 10), SCI + ferroptosis inhibitor group (SCI + ferrostatin1) (n = 10), and SCI + DHODH Inhibitor group (SCI + teriflunomide) (n = 10). Ten rats in the sham group only received laminectomy without SCI. To induce spinal cord injury, spinal cord injury surgery was performed in the middle thoracic region of rats (T8-T9).

    Click to Show/Hide
Response regulation The application of DHODH is a potential treatment for spinal cord injury (SCI). DHODH can reduce the ferroptosis of neurons after spinal cord injury by regulating the P53/ALOX15 signaling pathway, thereby alleviating spinal cord injury.
Experiment 2 Reporting the Ferroptosis-centered Disease Response [1]
Target Regulator Dihydroorotate dehydrogenase (quinone), mitochondrial (DHODH) Protein coding
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model
PC12 cells Adrenal gland pheochromocytoma Rattus norvegicus CVCL_0481
In Vivo Model
Forty female Sprague-Dawley rats (200-300 g, 8 weeks old) were purchased from the Animal Experiment Center of Fudan University. Forty rats were randomly divided into four groups: sham operation group (n = 10), SCI group (n = 10), SCI + ferroptosis inhibitor group (SCI + ferrostatin1) (n = 10), and SCI + DHODH Inhibitor group (SCI + teriflunomide) (n = 10). Ten rats in the sham group only received laminectomy without SCI. To induce spinal cord injury, spinal cord injury surgery was performed in the middle thoracic region of rats (T8-T9).

    Click to Show/Hide
Response regulation The application of DHODH is a potential treatment for spinal cord injury (SCI). DHODH can reduce the ferroptosis of neurons after spinal cord injury by regulating the P53/ALOX15 signaling pathway, thereby alleviating spinal cord injury.
References
Ref 1 Dihydroorotate dehydrogenase regulates ferroptosis in neurons after spinal cord injury via the P53-ALOX15 signaling pathway. CNS Neurosci Ther. 2023 Jul;29(7):1923-1939. doi: 10.1111/cns.14150. Epub 2023 Mar 21.
Ref 2 Iron-dependent ferroptosis participated in benzene-induced anemia of inflammation through IRP1-DHODH-ALOX12 axis. Free Radic Biol Med. 2022 Nov 20;193(Pt 1):122-133. doi: 10.1016/j.freeradbiomed.2022.10.273. Epub 2022 Oct 13.
Ref 3 DHODH-mediated ferroptosis defence is a targetable vulnerability in cancer. Nature. 2021 May;593(7860):586-590. doi: 10.1038/s41586-021-03539-7. Epub 2021 May 12.