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.