Ferroptosis Induction and Cisplatin Chemoresistance Reversal by MASTL Inhibition in Ovarian Cancer

Ovarian cancer remains the leading cause of mortality among gynecologic malignancies, posing a significant threat to women’s health worldwide. Although cytoreductive surgery combined with platinum-based chemotherapy constitutes the standard treatment for epithelial ovarian cancer, therapeutic efficacy is markedly limited in patients with platinum-resistant recurrent disease. Microtubule-associated serine/threonine kinase-like (MASTL), a key regulator of mitotic progression, has recently garnered increasing attention due to its association with poor prognosis and chemotherapy resistance in various cancers. However, the precise role of MASTL deregulation in ovarian cancer progression and chemoresistance remains poorly understood. In this study, in vitro experiments demonstrated that MASTL is aberrantly overexpressed in ovarian cancer cells, particularly in cisplatin-resistant cell lines (CoC1/DDP). Genetic silencing of MASTL significantly sensitized resistant cells to cisplatin, induced apoptosis, and enhanced chemotherapy-induced cell death, potentially through the modulation of ferroptosis-related pathways. Further, treatment with a small-molecule MASTL inhibitor potentiated cisplatin-induced DNA damage and apoptosis in vitro. To our knowledge, this is the first study to demonstrate that pharmacological inhibition of MASTL enhances cisplatin sensitivity in ovarian cancer by ferroptosis. These findings suggest a promising therapeutic strategy targeting MASTL to overcome chemoresistance and improve clinical outcomes in patients with ovarian cancer.