DLL1-mediated ferroptosis resistance via the Notch-Nrf2/GPX4 axis drives cisplatin resistance in ovarian cancer

BACKGROUND: Ovarian cancer (OV) is a leading cause of cancer-related mortality, with cisplatin resistance being a major clinical challenge. This study investigates the role of the Notch ligand DLL1 in mediating ferroptosis resistance and its impact on cisplatin sensitivity in OV. METHODS: Multi-omics data, clinical samples, and OV cell lines were used to assess DLL1 expression, its link to prognosis, and its effect on the Nrf2/GPX4 axis. CCK-8, clone formation, and ferroptosis assays evaluated the impact of DLL1 on cell behavior and cisplatin sensitivity. RESULTS: DLL1 was upregulated in OV tissues and correlated with poor prognosis. Its knockdown inhibited cell proliferation, migration, and EMT, while inducing ferroptosis, evidenced by increased lipid peroxidation and mitochondrial dysfunction. Mechanistically, DLL1 activated the Nrf2/GPX4 antioxidant axis. DLL1 depletion sensitized OV cells to cisplatin. In vivo, combining DLL1-targeted therapy with a ferroptosis inducer significantly reduced tumor growth in cisplatin-resistant models. CONCLUSION: DLL1 drives cisplatin resistance in OV by enhancing ferroptosis resistance via the Notch-Nrf2/GPX4 axis. Targeting DLL1 alongside ferroptosis induction represents a promising therapeutic strategy, positioning DLL1 as a potential biomarker and target in drug-resistant OV.