FDFT1 Suppresses Ovarian Tumorigenesis and Overcomes Cisplatin Resistance by Activating Ferroptosis Through the NRF2/GPX4/SLC7A11 Axis.

INTRODUCTION

Ovarian cancer's lethality stems from late-stage diagnosis and chemoresistance. Ferroptosis induction represents a promising strategy to overcome platinum resistance. Farnesyl diphosphate farnesyltransferase 1(FDFT1), a cholesterol metabolism enzyme with paradoxical roles in cancer, remains relatively underexplored in ovarian carcinogenesis and therapeutic resistance.

METHOD: Multi-omics analyses of public datasets identified FDFT1's clinical relevance. Functional studies employed FDFT1-overexpressing ovarian cancer cells (SKOV3/ES-2) and cisplatin-resistant SKOV3/DDP models. Mechanistic evaluations included ferroptosis markers (Fe²⁺, MDA, GSH), NRF2/GPX4/SLC7A11 axis analysis, and xenograft experiments.

RESULTS

FDFT1 showed recurrent genomic loss and downregulation in ovarian tumors. Overexpression suppressed proliferation, migration, and invasion, while increasing apoptosis. FDFT1 activated ferroptosis via NRF2/GPX4/SLC7A11 axis suppression, elevating Fe²⁺, MDA, and ROS while depleting GSH. Cisplatin-resistant tumors exhibited FDFT1 downregulation, and overexpression of FDFT1 reversed drug resistance. Xenografts confirmed tumor growth suppression with ferroptosis activation.

DISCUSSION: Our findings establish FDFT1 as a tumor suppressor that induces ferroptosis via NRF2/GPX4/SLC7A11 inhibition in ovarian cancer. Restoring FDFT1 reverses cisplatin resistance, linking its downregulation to chemoresistance. This contrasts with its oncogenic roles in other cancers, highlighting context-dependent metabolic regulation. These findings position FDFT1 as a novel regulator of ferroptosis and a promising therapeutic target for overcoming chemoresistance in ovarian cancer.

CONCLUSION

FDFT1 functions as a tumor suppressor by inducing iron-dependent lipid peroxidation through NRF2 pathway inhibition. Its restoration overcomes cisplatin resistance, positioning FDFT1 as both a promising biomarker and therapeutic target for chemoresistant ovarian cancer.