DHODH-mediated mitochondrial redox homeostasis: a novel ferroptosis regulator and promising therapeutic target
Ferroptosis is a distinct form of regulated cell death characterized by iron-dependent lipid peroxidation, which plays a critical role in the pathogenesis of various diseases, including ischemic tissue injury, infectious diseases, neurodegenerative disorders, and cancer. The regulatory mechanisms un...
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| Format: | Article |
| Language: | English |
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Elsevier
2025-09-01
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| Series: | Redox Biology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213231725003015 |
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| author | Jinghao Cao Xi Chen Lulu Chen Yajuan Lu Yunyi Wu Aoli Deng Feifan Pan Hangqi Huang Yingchao Liu Yanchun Li Xiangmin Tong Jing Du |
| author_facet | Jinghao Cao Xi Chen Lulu Chen Yajuan Lu Yunyi Wu Aoli Deng Feifan Pan Hangqi Huang Yingchao Liu Yanchun Li Xiangmin Tong Jing Du |
| author_sort | Jinghao Cao |
| collection | DOAJ |
| description | Ferroptosis is a distinct form of regulated cell death characterized by iron-dependent lipid peroxidation, which plays a critical role in the pathogenesis of various diseases, including ischemic tissue injury, infectious diseases, neurodegenerative disorders, and cancer. The regulatory mechanisms underlying ferroptosis involve a complex interplay of multiple subcellular organelles, orchestrating iron homeostasis, lipid metabolism, and the generation of reactive oxygen species (ROS) that drive peroxidation processes, ultimately leading to membrane damage and cell death. Numerous antioxidant systems play pivotal roles in regulating and preventing ferroptosis, among which the recently identified mitochondrial inner membrane enzyme dihydroorotate dehydrogenase (DHODH) represents a novel therapeutic target for ferroptosis intervention. This systematic review comprehensively elucidates several key cellular defense mechanisms against ferroptosis that counteract ROS-driven peroxidation and operate through distinct subcellular localizations. We particularly focus on delineating the molecular mechanisms by which DHODH regulates ferroptosis, with special emphasis on its role in suppressing mitochondrial lipid peroxidation. Furthermore, we systematically evaluate the therapeutic potential of DHODH inhibitors in oncology, virology, and immune-inflammatory disorders. By integrating ferroptosis biology with DHODH-mediated cytoprotective networks, this review aims to provide mechanistic insights and novel therapeutic strategies for cancer and oxidative stress-related disorders. |
| format | Article |
| id | doaj-art-d4d21d0d71244d939f0eb7af3279cce8 |
| institution | Kabale University |
| issn | 2213-2317 |
| language | English |
| publishDate | 2025-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Redox Biology |
| spelling | doaj-art-d4d21d0d71244d939f0eb7af3279cce82025-08-24T05:12:40ZengElsevierRedox Biology2213-23172025-09-018510378810.1016/j.redox.2025.103788DHODH-mediated mitochondrial redox homeostasis: a novel ferroptosis regulator and promising therapeutic targetJinghao Cao0Xi Chen1Lulu Chen2Yajuan Lu3Yunyi Wu4Aoli Deng5Feifan Pan6Hangqi Huang7Yingchao Liu8Yanchun Li9Xiangmin Tong10Jing Du11Laboratory Medicine Center, Department of Clinical Laboratory, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, 310014, ChinaLaboratory Medicine Center, Department of Clinical Laboratory, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, 310014, ChinaLaboratory Medicine Center, Department of Clinical Laboratory, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, 310014, ChinaLaboratory Medicine Center, Department of Clinical Laboratory, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, 310014, ChinaLaboratory Medicine Center, Department of Clinical Laboratory, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, 310014, ChinaLaboratory Medicine Center, Department of Clinical Laboratory, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, 310014, ChinaLaboratory Medicine Center, Department of Clinical Laboratory, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, 310014, ChinaLaboratory Medicine Center, Department of Clinical Laboratory, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, 310014, ChinaLaboratory Medicine Center, Department of Clinical Laboratory, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, 310014, ChinaDepartment of Clinical Laboratory, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, Zhejiang, 310006, China; Corresponding author.Department of Clinical Laboratory, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, Zhejiang, 310006, China; Corresponding author.Laboratory Medicine Center, Department of Clinical Laboratory, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, 310014, China; Corresponding author.Ferroptosis is a distinct form of regulated cell death characterized by iron-dependent lipid peroxidation, which plays a critical role in the pathogenesis of various diseases, including ischemic tissue injury, infectious diseases, neurodegenerative disorders, and cancer. The regulatory mechanisms underlying ferroptosis involve a complex interplay of multiple subcellular organelles, orchestrating iron homeostasis, lipid metabolism, and the generation of reactive oxygen species (ROS) that drive peroxidation processes, ultimately leading to membrane damage and cell death. Numerous antioxidant systems play pivotal roles in regulating and preventing ferroptosis, among which the recently identified mitochondrial inner membrane enzyme dihydroorotate dehydrogenase (DHODH) represents a novel therapeutic target for ferroptosis intervention. This systematic review comprehensively elucidates several key cellular defense mechanisms against ferroptosis that counteract ROS-driven peroxidation and operate through distinct subcellular localizations. We particularly focus on delineating the molecular mechanisms by which DHODH regulates ferroptosis, with special emphasis on its role in suppressing mitochondrial lipid peroxidation. Furthermore, we systematically evaluate the therapeutic potential of DHODH inhibitors in oncology, virology, and immune-inflammatory disorders. By integrating ferroptosis biology with DHODH-mediated cytoprotective networks, this review aims to provide mechanistic insights and novel therapeutic strategies for cancer and oxidative stress-related disorders.http://www.sciencedirect.com/science/article/pii/S2213231725003015Dihydroorotate dehydrogenase (DHODH)FerroptosisCancer therapyDHODH inhibitors |
| spellingShingle | Jinghao Cao Xi Chen Lulu Chen Yajuan Lu Yunyi Wu Aoli Deng Feifan Pan Hangqi Huang Yingchao Liu Yanchun Li Xiangmin Tong Jing Du DHODH-mediated mitochondrial redox homeostasis: a novel ferroptosis regulator and promising therapeutic target Redox Biology Dihydroorotate dehydrogenase (DHODH) Ferroptosis Cancer therapy DHODH inhibitors |
| title | DHODH-mediated mitochondrial redox homeostasis: a novel ferroptosis regulator and promising therapeutic target |
| title_full | DHODH-mediated mitochondrial redox homeostasis: a novel ferroptosis regulator and promising therapeutic target |
| title_fullStr | DHODH-mediated mitochondrial redox homeostasis: a novel ferroptosis regulator and promising therapeutic target |
| title_full_unstemmed | DHODH-mediated mitochondrial redox homeostasis: a novel ferroptosis regulator and promising therapeutic target |
| title_short | DHODH-mediated mitochondrial redox homeostasis: a novel ferroptosis regulator and promising therapeutic target |
| title_sort | dhodh mediated mitochondrial redox homeostasis a novel ferroptosis regulator and promising therapeutic target |
| topic | Dihydroorotate dehydrogenase (DHODH) Ferroptosis Cancer therapy DHODH inhibitors |
| url | http://www.sciencedirect.com/science/article/pii/S2213231725003015 |
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