The deubiquitinase USP24 suppresses ferroptosis in triple-negative breast cancer by stabilizing DHODH protein
Abstract Triple-negative breast cancer (TNBC) is an aggressive subtype of invasive breast cancer characterized by limited treatment options and a poor prognosis. While ferroptosis, an iron-dependent form of regulated cell death, plays a role in tumor suppression, its specific molecular mechanisms in...
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Nature Publishing Group
2025-07-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-025-07895-4 |
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| author | Li Yang Xiaoqin An Shangzhu Yang Xiaowen Lin Ziyuan Chen Qian Xue Xi Chen Yuan Wang Ding Yan Shirui Chen Yuqing Fan Daolin Tang Wenfeng Yu Jinbao Liu Xin Chen |
| author_facet | Li Yang Xiaoqin An Shangzhu Yang Xiaowen Lin Ziyuan Chen Qian Xue Xi Chen Yuan Wang Ding Yan Shirui Chen Yuqing Fan Daolin Tang Wenfeng Yu Jinbao Liu Xin Chen |
| author_sort | Li Yang |
| collection | DOAJ |
| description | Abstract Triple-negative breast cancer (TNBC) is an aggressive subtype of invasive breast cancer characterized by limited treatment options and a poor prognosis. While ferroptosis, an iron-dependent form of regulated cell death, plays a role in tumor suppression, its specific molecular mechanisms in TNBC remain largely unexplored. In this study, we identify deubiquitinase USP24 as the most significantly altered enzyme among key deubiquitinating enzymes during ferroptosis in human TNBC cells. Silencing USP24 enhances ferroptosis-mediated tumor suppression in TNBC cells. Mechanistically, USP24 interacts directly with dihydroorotate dehydrogenase (DHODH) and deubiquitinates it, a process critical for maintaining coenzyme Q reduction and protecting cells from lipid peroxidation. Consistently, pharmacological inhibition of USP24 synergizes strongly with ferroptosis inducers in both in vitro and in vivo models via a DHODH-dependent pathway. These findings highlight USP24 as a potential therapeutic target to enhance ferroptosis sensitivity in TNBC. |
| format | Article |
| id | doaj-art-0dcf1a8a50c74291942c4b8f72064188 |
| institution | Kabale University |
| issn | 2041-4889 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj-art-0dcf1a8a50c74291942c4b8f720641882025-08-20T04:02:41ZengNature Publishing GroupCell Death and Disease2041-48892025-07-0116111510.1038/s41419-025-07895-4The deubiquitinase USP24 suppresses ferroptosis in triple-negative breast cancer by stabilizing DHODH proteinLi Yang0Xiaoqin An1Shangzhu Yang2Xiaowen Lin3Ziyuan Chen4Qian Xue5Xi Chen6Yuan Wang7Ding Yan8Shirui Chen9Yuqing Fan10Daolin Tang11Wenfeng Yu12Jinbao Liu13Xin Chen14Department of Physiology, School of Basic Medical Sciences, Guizhou Medical UniversityDepartment of Physiology, School of Basic Medical Sciences, Guizhou Medical UniversityDepartment of Physiology, School of Basic Medical Sciences, Guizhou Medical UniversityKey Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, The Fifth Affiliated Hospital, Guangzhou Medical UniversityKey Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, The Fifth Affiliated Hospital, Guangzhou Medical UniversityGuangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Disease, School of Basic Medical Sciences, Guangzhou Medical UniversityGuangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Disease, School of Basic Medical Sciences, Guangzhou Medical UniversityKey Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, The Fifth Affiliated Hospital, Guangzhou Medical UniversityKey Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, The Fifth Affiliated Hospital, Guangzhou Medical UniversityDepartment of Physiology, School of Basic Medical Sciences, Guizhou Medical UniversityDepartment of Physiology, School of Basic Medical Sciences, Guizhou Medical UniversityDepartment of Surgery, UT Southwestern Medical CenterDepartment of Physiology, School of Basic Medical Sciences, Guizhou Medical UniversityGuangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Disease, School of Basic Medical Sciences, Guangzhou Medical UniversityKey Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, The Fifth Affiliated Hospital, Guangzhou Medical UniversityAbstract Triple-negative breast cancer (TNBC) is an aggressive subtype of invasive breast cancer characterized by limited treatment options and a poor prognosis. While ferroptosis, an iron-dependent form of regulated cell death, plays a role in tumor suppression, its specific molecular mechanisms in TNBC remain largely unexplored. In this study, we identify deubiquitinase USP24 as the most significantly altered enzyme among key deubiquitinating enzymes during ferroptosis in human TNBC cells. Silencing USP24 enhances ferroptosis-mediated tumor suppression in TNBC cells. Mechanistically, USP24 interacts directly with dihydroorotate dehydrogenase (DHODH) and deubiquitinates it, a process critical for maintaining coenzyme Q reduction and protecting cells from lipid peroxidation. Consistently, pharmacological inhibition of USP24 synergizes strongly with ferroptosis inducers in both in vitro and in vivo models via a DHODH-dependent pathway. These findings highlight USP24 as a potential therapeutic target to enhance ferroptosis sensitivity in TNBC.https://doi.org/10.1038/s41419-025-07895-4 |
| spellingShingle | Li Yang Xiaoqin An Shangzhu Yang Xiaowen Lin Ziyuan Chen Qian Xue Xi Chen Yuan Wang Ding Yan Shirui Chen Yuqing Fan Daolin Tang Wenfeng Yu Jinbao Liu Xin Chen The deubiquitinase USP24 suppresses ferroptosis in triple-negative breast cancer by stabilizing DHODH protein Cell Death and Disease |
| title | The deubiquitinase USP24 suppresses ferroptosis in triple-negative breast cancer by stabilizing DHODH protein |
| title_full | The deubiquitinase USP24 suppresses ferroptosis in triple-negative breast cancer by stabilizing DHODH protein |
| title_fullStr | The deubiquitinase USP24 suppresses ferroptosis in triple-negative breast cancer by stabilizing DHODH protein |
| title_full_unstemmed | The deubiquitinase USP24 suppresses ferroptosis in triple-negative breast cancer by stabilizing DHODH protein |
| title_short | The deubiquitinase USP24 suppresses ferroptosis in triple-negative breast cancer by stabilizing DHODH protein |
| title_sort | deubiquitinase usp24 suppresses ferroptosis in triple negative breast cancer by stabilizing dhodh protein |
| url | https://doi.org/10.1038/s41419-025-07895-4 |
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