Prof. Dr. Marcus Conrad
Helmholtz Zentrum München
Institute of Metabolism and Cell Death
Ingolstädter Landstr. 1, 85764 Neuherberg, Germany
&
Technical University of Munich (TUM)
Translational Redox Biology
TUM Natural School of Sciences, Garching, Germany
https://www.conradlaboratory.com
https://www.helmholtz-munich.de/en/mcd
TITLE
Modulating Ferroptosis for Disease Prevention
ABSTRACT
Ferroptosis is a metabolic form of regulated cell death characterized by iron-dependent oxidative destruction of cellular membranes. Ferroptosis emerges as the underlying cause of several degenerative diseases and represents a pharmacologically tractable vulnerability for eradicating difficult-to-treat cancers, including therapy-resistant and metastatic cancer cells. Years before the term “ferroptosis” was coined, we had shown that glutathione peroxidase 4 (GPX4) acts as the guardian of ferroptosis due to its ability to directly scavenge phospholipid hydroperoxides. We further identified ferroptosis suppressor protein-1 (FSP1) as a second critical surveillance system for ferroptosis. Remarkably, FSP1 also serves as the long-sought-after, warfarin-resistant vitamin K reductase in the canonical vitamin K cycle and maintains a non-canonical vitamin K cycle efficiently protecting against ferroptosis. We further reported the first in vivo active FSP1 inhibitor, called icFSP1, which induces phase separation of FSP1 prior to cancer cell death induction. Ongoing studies are thus geared towards understanding the in vivo relevance of these systems in ferroptosis control and their pharmacological tractability as the basis for developing new pharmacotherapies for ferroptosis-related diseases including cancer.