The Woerpel Group and colleagues at Columbia have examined the structure–activity–distribution relationship of ferroptosis-modulating compounds. The study, entitled, "Identification of essential sites of lipid peroxidation in ferroptosis" appears in Nature Chemical Biology. NYU Chemistry authors include researchers Ryan Robson and Verna M. Estes, and Margaret and Herman Sokol Professor of Medicinal Chemistry Keith Woerpel.
Abstract: Ferroptosis, an iron-dependent form of cell death driven by lipid peroxidation, provides a potential treatment avenue for drug-resistant cancers and may play a role in the pathology of some degenerative diseases. Identifying the subcellular membranes essential for ferroptosis and the sequence of their peroxidation will illuminate drug discovery strategies and ferroptosis-relevant disease mechanisms. In this study, we employed fluorescence and stimulated Raman scattering imaging to examine the structure–activity–distribution relationship of ferroptosis-modulating compounds. We found that, although lipid peroxidation in various subcellular membranes can induce ferroptosis, the endoplasmic reticulum (ER) membrane is a key site of lipid peroxidation. Our results suggest an ordered progression model of membrane peroxidation during ferroptosis that accumulates initially in the ER membrane and later in the plasma membrane. Thus, the design of ER-targeted inhibitors and inducers of ferroptosis may be used to optimally control the dynamics of lipid peroxidation in cells undergoing ferroptosis.
This research was supported by the National Institutes of Health, including the National Cancer Institute, the National Institute of General Medical Sciences and the National Institute of Biomedical Imaging and Bioengineering.