Knockdown of TOP2A reverses cisplatin resistance in ovarian cancer by inhibiting EMT via ferroptosis mediated by the TP53/GPX4/SLC7A11 axis.

INTRODUCTION: Cisplatin resistance is a major challenge in ovarian cancer therapy, particularly for high-grade serous ovarian cancer (HGSOC). DNA topoisomerase IIα (TOP2A) relates to cancer drug resistance, yet its role and molecular mechanisms in ovarian cancer cisplatin resistance remain unclear. METHODS: TOP2A expression was detected in HGSOC tissues and cisplatin-resistant cells (SKOV3-DDP, OVCAR3-DDP). Functional assays combined with TOP2A knockdown evaluated cisplatin sensitivity and malignant phenotypes (proliferation, invasion, migration) in resistant cells. RNA-seq and GEO cisplatin resistance dataset (GSE214302) validated TOP2A's role in cisplatin resistance, prognostic value, and associations with TP53, GPX4, SLC7A11. Molecular docking/Co-IP confirmed TOP2A-TP53 interaction. Fer-1 and TP53 knockdown clarified TP53/GPX4/SLC7A11 axis regulation of ferroptosis and EMT, and an in vivo xenograft tumor model validated these findings. RESULTS: TOP2A is highly expressed in HGSOC tissues and cisplatin-resistant cells, with high levels strongly associated with tumor progression (advanced stage, high grade, lymph node metastasis) and poor prognosis. RNA-seq shows TOP2A correlates with TP53, GPX4, SLC7A11.GEO dataset analysis confirms all four associate with cisplatin resistance. SLC7A11 and TOP2A are effective resistance biomarkers, and high TOP2A predicts shorter progression-free survival. Molecular assays verify direct TOP2A-TP53 interaction. Functional experiments reveal TOP2A knockdown enhances cisplatin sensitivity, inhibits malignancy, activates ferroptosis, and suppresses EMT via the TP53/GPX4/SLC7A11 axis. This effect is reversed by Fer-1 or TP53 knockdown, with mechanisms validated in vivo. CONCLUSION: TOP2A represents a potential prognostic biomarker and therapeutic target for cisplatin resistance in ovarian cancer (OC), as it regulates ferroptosis and EMT via the TP53/GPX4/SLC7A11 axis, which is mediated by its direct interaction with TP53. This thus provides a novel direction for treating cisplatin-resistant OC.