Uncovering a BMP2 Ferroptosis Axis Driving Chemoresistance in Ovarian Cancer

Platinum-based chemotherapy is the standard treatment for ovarian cancer, yet over 70% of advanced cases ultimately develop resistance.1 Impaired ferroptosis, an iron-dependent, lipid-peroxidation driven cell death pathway, has recently emerged as a contributor to this resistance. 2-3 BMP2 signaling, which is frequently upregulated in ovarian cancer and promotes proliferation, EMT, and post-chemotherapy survival, activates SMAD1/5/8 transcriptional programs that enhance antioxidant capacity.4 These antioxidant effects may indirectly stabilize GPX4, a key ferroptosis suppressor, however, the mechanistic connection between BMP2-SMAD signaling and ferroptotic dysregulation in ovarian cancer remains unexplored. We propose that dysregulated BMP2-SMAD1/5/8 signaling suppresses ferroptosis and contributes to cisplatin resistance in ovarian tumors. Enhancing ferroptotic sensitivity using erastin, a system Xc- inhibitor that depletes glutathione and reduces GPX4 activity, will resensitize tumors to cisplatin and clarify whether BMP2 pathway activity governs ferroptotic tone.2-3 Female C57BL/6 mice (n=60) will receive intraperitoneal ID8 ovarian cancer cells and be randomized into four groups (n=15): saline control, cisplatin alone, erastin alone, and combined cisplatin+erastin. Treatments will be administered for 21 days. Tumors will be evaluated for burden, BMP2-SMAD pathway activation, GPX4 expression, lipid ROS accumulation, and ferroptosis biomarkers. Combination therapy is expected to reduce tumor burden, increase lipid peroxidation, and suppress GPX4 expression more effectively than cisplatin alone, supporting a mechanistic role for BMP2-SMAD activity in maintaining ferroptosis resistance. This study addresses a previously untested biochemical link between BMP2 signaling and ferroptosis in ovarian cancer while evaluating a targeted therapeutic strategy. Findings may reveal a novel mechanism of platinum resistance and support ferroptosis-based combination therapy as a promising future direction.