Redox-triggered USP18 confers cisplatin resistance in ovarian cancer by selectively activating a non-canonical FSP1-dependent ferroptosis escape pathway

  • Redox Biol. 2026 Jun:93:104179. doi: 10.1016/j.redox.2026.104179.
Zitong Zhao  1 ,  Ge Ge  1 ,  Menghan Gong  1 ,  Yi Liu  2 ,  Liying Ma  1 ,  Dongdong Zhang  3 ,  Li Sun  4 ,  Yongmei Song  5
Affiliations
  • 1. State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
  • 2. National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, 518116, China.
  • 3. State Key Laboratory of Epigenetic Regulation and Intervention, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China. Electronic address: [email protected].
  • 4. National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, 518116, China. Electronic address: [email protected].
  • 5. State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China. Electronic address: [email protected].
PMID: 42030646 DOI: 10.1016/j.redox.2026.104179
Abstract

Background: Cisplatin resistance is a primary cause of treatment failure in ovarian Cancer (OC), partly due to enhanced antioxidant defenses that counteract cisplatin-induced DNA damage and Reactive Oxygen Species (ROS). Beyond the classic Glutathione Peroxidase 4 (GPX4) pathway, evidence suggests that non-canonical pathways like those mediated by Ferroptosis Suppressor Protein 1 (FSP1) may drive resistance. This study aims to elucidate how such alternative pathways facilitate resistance under cisplatin-induced ROS stress.

Methods: Ubiquitin Specific Peptidase 18 (USP18) was identified from a deubiquitination library. Protein/RNA interaction and m6A analyses revealed its regulation of downstream effectors Insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) and FSP1. The combination of cisplatin with the FSP1 inhibitor (iFSP1) was evaluated in vitro and in vivo models.

Results: Cisplatin-induced ROS upregulates the expression of the USP18 through the transcription factor c-Jun, establishing the ROS-c-JUN-USP18 signaling axis. This axis stabilizes the IGF2BP2 protein via USP18-mediated deubiquitination, which in turn enhances the stability of FSP1 mRNA in an m6A methylation-dependent manner, thereby driving the selective activation of the FSP1-mediated pathway over the canonical GPX4 pathway. The predictive efficacy of models derived from the ROS-c-JUN-USP18-IGF2BP2-FSP1 axis was demonstrated by ROC curves and nomograms, confirming their utility in identifying patients with cisplatin-resistant OC. Importantly, the combination of iFSP1 with cisplatin produces a significant synergistic effect, effectively overcoming drug resistance in USP18-high tumors.

Conclusion: This study elucidates the mechanism by which the ROS-c-JUN-USP18-IGF2BP2-FSP1 axis regulates cisplatin resistance and proposes a novel iFSP1-cisplatin combination therapy, offering a promising new strategy for OC treatment.

Keywords
Cisplatin resistance; Non-canonical ferroptosis; Ovarian cancer; Reactive oxygen species; USP18.
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