Abstract SY11-01: Ferroptosis and cancer metabolism: History, mechanisms, and therapeutic applications

Abstract Ferroptosis is form of cell death tightly integrated with metabolism and driven by peroxidation of specific lipids. I will discuss the history, key regulators, recent emerging mechanisms, and therapeutic applications of controlling ferroptosis. We identified an unusual species of lipid that is a key driver of ferroptosis; our studies linking ferroptosis to metabolism have enabled design of precision, therapeutic diets that promote ferroptosis in some cancer models. We found that we can promote ferroptosis in specific cancers by making dietary changes that enhance lipid peroxidation and limit the repair capacity of cancer cells. In addition, we found that these ferroptosis-promoting dietary changes enhance the response of cancer cells to pro-ferroptosis small molecule drug candidates, such as GPX4 inhibitors. We have this found that specific pairing of drugs with rationally designed dietary changes can substantially improve therapeutic effects in animal models. Citation Format: Brent R. Stockwell. Ferroptosis and cancer metabolism: History, mechanisms, and therapeutic applications [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr SY11-01.