Nature Chemical Biology 14 (2018) features a study called "FINO2 initiates ferroptosis through GPX4 inactivation and iron oxidation" by Sokol Professor of Medicinal Chemistry Keith Woerpel, his group members and collaborators. Among the NYU authors are: graduate students Alex Andia (first author), Dan Heindel, Brisa Hurlocker, Chris Vaiana, Dylan Zuckerman, researchers Amy Chan and Eveliz Peguero-Pereira, and Professor Lara Mahal.
Abstract: Ferroptosis is a non-apoptotic form of regulated cell death caused by the failure of the glutathione-dependent lipid-peroxide-scavenging network. FINO2 is an endoperoxide-containing 1,2-dioxolane that can initiate ferroptosis selectively in engineered cancer cells. We investigated the mechanism and structural features necessary for ferroptosis initiation by FINO2. We found that FINO2 requires both an endoperoxide moiety and a nearby hydroxyl head group to initiate ferroptosis. In contrast to previously described ferroptosis inducers, FINO2 does not inhibit system xc– or directly target the reducing enzyme GPX4, as do erastin and RSL3, respectively, nor does it deplete GPX4 protein, as does FIN56. Instead, FINO2 both indirectly inhibits GPX4 enzymatic function and directly oxidizes iron, ultimately causing widespread lipid peroxidation. These findings suggest that endoperoxides such as FINO2 can initiate a multipronged mechanism of ferroptosis.
Click here for a complete list of authors and to read the entire article, FINO2 initiates ferroptosis through GPX4 inactivation and iron oxidation.
This work was supported by the the National Science Foundation (NSF), through its Materials Research Science and Engineering Center (MRSEC) program and instrumentation grants, the National Cancer Institute, the National Institute of General Medical Sciences, the National Heart, Lung, and Blood Institute, the National Institute of Allergy and Infectious Diseases.