Abstract 6795: Cystine deprivation overcomes protective effects of hypoxia on ferroptosis in high-grade serous ovarian cancer

Abstract Iron is known to be crucial for high-grade serous ovarian cancer (HGSC) proliferation. HGSC tumors exhibit elevated iron levels compared to normal tissues, making it more susceptible to ferroptosis. Previous studies have shown that ferroptosis inducers can reduce both tumor growth and metastasis in ovarian cancer mouse models. Hypoxia is a prevalent feature of the tumor microenvironment and may protect HGSC from ferroptosis. Induction of ferroptosis can be triggered by inhibitors of GPX4 (GPX4i) or xCT (xCTi), prompting us to consider whether hypoxia may abrogate the induction of ferroptosis in HGSC cells. We tested multiple ovarian cancer cell lines (e.g., OVCAR3, OVCAR4, and OVCAR8) under normoxia and hypoxia. We used both hypoxia chamber (1% oxygen) and CoCl2 to mimic hypoxic conditions and found that both methods significantly inhibited GPX4i-induced ferroptosis by more than twofold (e.g. 5uM RSL3 decreased OVCAR4 cell viability by 80% under normoxia but only 50% under hypoxia), while only having a minimal effect on xCTi-induced ferroptosis. Given that xCTi blocks cystine import, we also examined whether hypoxia affects cystine deprivation-induced ferroptosis. Hypoxia did not protect HGSC cells from cystine deprivation-induced ferroptosis. In conclusion, our study suggests that hypoxia selectively blocks GPX4i-induced ferroptosis in HGSC, while cystine deprivation-induced ferroptosis remains effective, highlighting the potential of targeting cystine import as a more robust approach for treating HGSC. Citation Format: Zonghao Tang, Anil Sood. Cystine deprivation overcomes protective effects of hypoxia on ferroptosis in high-grade serous ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6795.