title: Global survey of cell death mechanisms reveals metabolic regulation of ferroptosis.
abstract: Apoptosis is one type of programmed cell death. Increasingly, non-apoptotic cell death is recognized as being genetically controlled, or 'regulated'. However, the full extent and diversity of alternative cell death mechanisms remain uncharted. Here we surveyed the landscape of pharmacologically accessible cell death mechanisms. In an examination of 56 caspase-independent lethal compounds, modulatory profiling showed that 10 compounds induced three different types of regulated non-apoptotic cell death. Optimization of one of those ten resulted in the discovery of FIN56, a specific inducer of ferroptosis. Ferroptosis has been found to occur when the lipid-repair enzyme GPX4 is inhibited. FIN56 promoted degradation of GPX4. FIN56 also bound to and activated squalene synthase, an enzyme involved in isoprenoid biosynthesis, independent of GPX4 degradation. These discoveries show that dysregulation of lipid metabolism is associated with ferroptosis. This systematic approach is a means to discover and characterize novel cell death phenotypes.
authors.affiliation: Department of Biological Sciences, Columbia University, New York, New York, USA.
authors.forename: Kenichi
authors.identifier: 0000-0001-8540-9785
authors.initials: K
authors.lastname: Shimada
authors.affiliation: Department of Biological Sciences, Columbia University, New York, New York, USA.
authors.forename: Rachid
authors.initials: R
authors.lastname: Skouta
authors.affiliation: Department of Biological Sciences, Columbia University, New York, New York, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Kaplan
authors.affiliation: Department of Biological Sciences, Columbia University, New York, New York, USA.
authors.forename: Wan Seok
authors.initials: WS
authors.lastname: Yang
authors.affiliation: Department of Pharmacology, Columbia University, New York, New York, USA.
authors.forename: Miki
authors.initials: M
authors.lastname: Hayano
authors.affiliation: Department of Biological Sciences, Columbia University, New York, New York, USA.
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Dixon
authors.affiliation: Quantitative Proteomics Center, Columbia University, New York, New York, USA.
authors.forename: Lewis M
authors.initials: LM
authors.lastname: Brown
authors.affiliation: Department of Biological Sciences, Columbia University, New York, New York, USA.
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Valenzuela
authors.affiliation: Department of Biological Sciences, Columbia University, New York, New York, USA.
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Wolpaw
authors.affiliation: Department of Biological Sciences, Columbia University, New York, New York, USA.|Department of Chemistry, Columbia University, New York, New York, USA.
authors.forename: Brent R
authors.identifier: 0000-0002-3532-3868
authors.initials: BR
authors.lastname: Stockwell
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007501:Iron / Q000378:metabolism*; D050356:Lipid Metabolism / Q000187:drug effects; D010091:Oximes / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*
chemical_list: C000618760:FIN56 compound; D010091:Oximes; D013449:Sulfonamides; D007501:Iron