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Nat Rev Drug Discov. 2016 May;15(5):348-66. doi: 10.1038/nrd.2015.6. Epub 2016 Jan 18.

Regulated necrosis: disease relevance and therapeutic opportunities.

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Helmholtz Zentrum München, Institute of Developmental Genetics, 85764 Neuherberg, Germany.
Molecular Signaling and Cell Death Unit, Inflammation Research Center, Flanders Institute for Biotechnology, 9052 Ghent, Belgium.
Molecular Signaling and Cell Death Unit, Department of Biomedical Molecular Biology, Ghent University, 9000 Ghent, Belgium.
Methusalem Program, Ghent University, 9000 Ghent, Belgium.
Department of Biological Sciences and Department of Chemistry, Howard Hughes Medical Institute, Columbia University, 550 West 120th Street, Northwest Corner Building, MC 4846, New York, New York 10027, USA.


The discovery of regulated cell death presents tantalizing possibilities for gaining control over the life-death decisions made by cells in disease. Although apoptosis has been the focus of drug discovery for many years, recent research has identified regulatory mechanisms and signalling pathways for previously unrecognized, regulated necrotic cell death routines. Distinct critical nodes have been characterized for some of these alternative cell death routines, whereas other cell death routines are just beginning to be unravelled. In this Review, we describe forms of regulated necrotic cell death, including necroptosis, the emerging cell death modality of ferroptosis (and the related oxytosis) and the less well comprehended parthanatos and cyclophilin D-mediated necrosis. We focus on small molecules, proteins and pathways that can induce and inhibit these non-apoptotic forms of cell death, and discuss strategies for translating this understanding into new therapeutics for certain disease contexts.

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