FERROPTOSIS: MECHANISMS AND THERAPEUTIC APPLICATIONS

Cell death is involved in diseases such as cancer and neurodegeneration, and also has a natural role in the development of multicellular organisms. Although apoptosis has been well defined, alternative forms of cell death have been less explored. My lab performed a global analysis of pharmacologically accessible cell death mechanisms using a strategy we refer to as modulatory profiling. We tested lethal compounds in the presence of chemical and genetic modulators of cell death, and categorized the cell death mechanisms based on the pattern of responses to modulators. Using this approach, we found compounds that induce apoptosis, necrosis, and a distinct form of iron-dependent oxidative cell death that we refer to as ferroptosis. We found that ferroptosis is distinct from apoptosis and necrosis on the basis of morphological, biochemical, genetic and inhibitor sensitivity data. In addition, we elucidated mechanisms regulating ferroptosis, and examined the relevance of ferroptosis to a variety of diseases and therapeutic applications. We discovered that ferroptosis represents death by lipoxygenase-driven peroxidation of polyunsaturated fatty acid moieties in phospholipids, due to loss of activity of the lipid repair enzyme GPX4, which can occur in a number of different ways. Most recently, we explored the cellular membranes that under lipid peroxidation during ferroptosis using novel imaging tools, and discovered specific organelle membranes that are dispensable for ferroptosis.