Abstract 361: Targeting the suppressor of ferroptosis to improve the treament effeciency of glioblastoma

Abstract Glioma is the most frequent tumor in central nervous system (CNS), which makes up about 30% of CNS tumors. The current standard strategy for glioma treatment is surgery plus adjuvant chemotherapy and concurrent radiotherapy. Even though, the prognosis of glioma is still poor. It’s encouraging that temozolomide (TMZ) prolongs the overall survival of glioma patients, but the following TMZ resistance is really frustrating. It’s urgent to figure out efficient ways to improve the long term prognosis of patients, such as antagonizing the TMZ resistance. Ferroptosis was a newly discovered type of regulated cell death characterized by iron-dependent aberrant lipid peroxidation and membrane damage in the last decade. Ferroptosis-associated iron transport proteins modulate the process precisely through controlling the iron content. ZIP14, also known as SLC39A14, is an eight-transmembrane protein which could transport divalent metal ion like Mn2+, Zn2+ and Fe2+. Our preliminary data showed that the expression level of ZIP14 was higher in tumor tissues than paired normal tissue, which was corelated with poor prognosis of glioma. Knock down ZIP14 could induce cell death, and which could be rescued by inhibitors for ferroptosis but not for apoptosis or necrosis. Knock down ZIP14 decreased the ferroptosis inhibition by Ferroptosis suppress protein 1 (FSP1) which through reduction of lipid peroxidation, and sensitized cells to TMZ. Furthermore, we found that ZIP14 formed a complex with Ubiquinone. And it was known that FSP1 is critical in the switch of ubiquinone to ubiquinol. Therefore, we propose that ZIP14 suppress lipid peroxidation through blockage of the transition of ubiquinone to ubiquinol. While ZIP14 was knocked down, the complex with Ubiquinone wad damaged, and could not further change to Ubiquinol, so the suppression to lipid peroxidation was released, and then, ferroptosis was upregulated. In this study, we are going to figure out the molecular mechanism about how ZIP14 suppress ferroptosis and find out efficient small molecule inhibitors to activate ferroptosis by abolishing ZIP14 and improve the prognosis of glioma patients. Citation Format: Jing Wang. Targeting the suppressor of ferroptosis to improve the treament effeciency of glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 361.