The deubiquitinase USP24 suppresses ferroptosis in triple-negative breast cancer by stabilizing DHODH protein
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.
Authors
- Yan Ding (ORCID: https://orcid.org/0000-0002-4269-9476)
- Xiaoqin An (ORCID: https://orcid.org/0009-0000-4877-9998)
- Xiaowen Lin (ORCID: https://orcid.org/0000-0001-5096-7066)
- Daolin Tang (ORCID: https://orcid.org/0000-0002-1903-6180)
- Yunpeng Fan (ORCID: https://orcid.org/0000-0003-2374-3627)
- Su‐Jin Yang (ORCID: https://orcid.org/0000-0001-5200-0991)
- Yuan Wang (ORCID: https://orcid.org/0009-0005-1515-2036)
- Xi Chen (ORCID: https://orcid.org/0000-0003-2171-3141)
- Xin Chen (ORCID: https://orcid.org/0000-0003-3668-4830)
- Qian Xue (ORCID: https://orcid.org/0009-0003-5737-8311)
- Xin Yang (ORCID: https://orcid.org/0000-0003-3428-3806)
- Wenfeng Yu
- Ziyuan Chen (ORCID: https://orcid.org/0000-0003-2832-945X)
- Shirui Chen (ORCID: https://orcid.org/0000-0002-4280-7027)
- Jinbao Liu (ORCID: https://orcid.org/0000-0003-2220-2407)
Institutions
- Guiyang Medical University (CN)
- Second Affiliated Hospital of Guangzhou Medical University (CN)
- Southwestern Medical Center (US)
- First Affiliated Hospital of Guangzhou Medical University (CN)
- Affiliated Hospital of Guizhou Medical University (CN)
- State Key Laboratory of Respiratory Disease (CN)
- Southwestern Medical Center (US)
- The University of Texas Southwestern Medical Center (US)
- Guangzhou Medical University (CN)
Publication Details
- Journal
- Cell Death and Disease
- Published
- 2025-07-26
- DOI
- https://doi.org/10.1038/s41419-025-07895-4
- Citations
- 7
- Primary Topic
- RNA modifications and cancer
- Type
- article
- Field-Weighted Citation Impact
- 5.64
Funders
- Guangzhou Medical University
- State Key Laboratory of Respiratory Disease
- National Natural Science Foundation of China
- Guizhou Medical University