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  • Review Article
  • Published:

Regulated necrosis: disease relevance and therapeutic opportunities

Nature Reviews Drug Discovery volume 15, pages 348–366 (2016)Cite this article

Subjects

Key Points

  • Recent research has identified a series of previously unrecognized regulated cell death modalities beyond apoptosis, including necroptosis, parthanatos, ferroptosis and oxytosis.

  • Several genetic approaches in model systems have implicated these forms of regulated cell death in diverse pathologically relevant conditions.

  • Targeted and phenotypic screening approaches have led to the identification of small molecules that can modulate these pathways.

  • Some of these regulated forms of cell death appear to be intertwined with the innate immune response, thus possibly affecting treatment outcomes with cell-death inducers or inhibitors.

  • Strategies aiming to interfere with multiple cell death pathways might represent the optimal treatment paradigm for translational settings.

  • Owing to their recent discovery, small-molecule modulators of regulated cell death are still in their infancy and therefore require further chemical optimization to reach clinical testing.

Abstract

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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Figure 1: The main signalling events downstream of TNFR activation.
Figure 2: Chemical structures of inhibitors of non-apoptotic cell death.
Figure 3: Chemical structures of ferroptosis inducers and inhibitors.
Figure 4: Upstream events in the control of ferroptosis.
Figure 5: Key signalling events in parthanatos.

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References

  1. Laster, S. M., Wood, J. G. & Gooding, L. R. Tumor necrosis factor can induce both apoptic and necrotic forms of cell lysis. J. Immunol. 141, 2629–2634 (1988).

    CAS  PubMed  Google Scholar 

  2. Vanden Berghe, T., Linkermann, A., Jouan-Lanhouet, S., Walczak, H. & Vandenabeele, P. Regulated necrosis: the expanding network of non-apoptotic cell death pathways. Nat. Rev. Mol. Cell Biol. 15, 135–147 (2014).

    Article  CAS  PubMed  Google Scholar 

  3. Green, D. R. & Levine, B. To be or not to be? How selective autophagy and cell death govern cell fate. Cell 157, 65–75 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Galluzzi, L., Pietrocola, F., Levine, B. & Kroemer, G. Metabolic control of autophagy. Cell 159, 1263–1276 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Brinkmann, V. & Zychlinsky, A. Neutrophil extracellular traps: is immunity the second function of chromatin? J. Cell Biol. 198, 773–783 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Lupfer, C., Malik, A. & Kanneganti, T. D. Inflammasome control of viral infection. Curr. Opin. Virol. 12, 38–46 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Mohammad, R. M. et al. Broad targeting of resistance to apoptosis in cancer. Semin. Cancer Biol. 35, S78–S103 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Vandenabeele, P., Galluzzi, L., Vanden Berghe, T. & Kroemer, G. Molecular mechanisms of necroptosis: an ordered cellular explosion. Nat. Rev. Mol. Cell Biol. 11, 700–714 (2010).

    Article  CAS  PubMed  Google Scholar 

  9. Sun, L. & Wang, X. A new kind of cell suicide: mechanisms and functions of programmed necrosis. Trends Biochem. Sci. 39, 587–593 (2014).

    Article  CAS  PubMed  Google Scholar 

  10. Degterev, A. et al. Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury. Nat. Chem. Biol. 1, 112–119 (2005).

    Article  CAS  PubMed  Google Scholar 

  11. Degterev, A. et al. Identification of RIP1 kinase as a specific cellular target of necrostatins. Nat. Chem. Biol. 4, 313–321 (2008). References 10 and 11 describe the first series of small molecules able to prevent necrotic TNF-induced cell death via RIPK1 inhibition.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Pasparakis, M. & Vandenabeele, P. Necroptosis and its role in inflammation. Nature 517, 311–320 (2015).

    Article  CAS  PubMed  Google Scholar 

  13. Kim, S. K. et al. Upregulated RIP3 expression potentiates MLKL phosphorylation-mediated programmed necrosis in toxic epidermal necrolysis. J. Invest. Dermatol. 135, 2021–2030 (2015).

    Article  CAS  PubMed  Google Scholar 

  14. Ofengeim, D. et al. Activation of necroptosis in multiple sclerosis. Cell Rep. 10, 1836–1849 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Gunther, C. et al. Caspase-8 regulates TNF-α-induced epithelial necroptosis and terminal ileitis. Nature 477, 335–339 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Linkermann, A., Stockwell, B. R., Krautwald, S. & Anders, H. J. Regulated cell death and inflammation: an auto-amplification loop causes organ failure. Nat. Rev. Immunol. 14, 759–767 (2014).

    Article  CAS  PubMed  Google Scholar 

  17. He, S. et al. Receptor interacting protein kinase-3 determines cellular necrotic response to TNF-α. Cell 137, 1100–1111 (2009).

    Article  CAS  PubMed  Google Scholar 

  18. Linkermann, A. et al. Dichotomy between RIP1- and RIP3-mediated necroptosis in tumor necrosis factor-α-induced shock. Mol. Med. 18, 577–586 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Newton, K. et al. Activity of protein kinase RIPK3 determines whether cells die by necroptosis or apoptosis. Science 343, 1357–1360 (2014).

    Article  CAS  PubMed  Google Scholar 

  20. Jouan-Lanhouet, S. et al. Necroptosis, in vivo detection in experimental disease models. Semin. Cell Dev. Biol. 35, 2–13 (2014).

    Article  CAS  PubMed  Google Scholar 

  21. Dondelinger, Y. et al. NF-κB-independent role of IKKα/IKKβ in preventing RIPK1 kinase-dependent apoptotic and necroptotic cell death during TNF signaling. Mol. Cell 60, 63–76 (2015).

    Article  CAS  PubMed  Google Scholar 

  22. Micheau, O. & Tschopp, J. Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes. Cell 114, 181–190 (2003).

    Article  CAS  PubMed  Google Scholar 

  23. Wang, L., Du, F. & Wang, X. TNF-α induces two distinct caspase-8 activation pathways. Cell 133, 693–703 (2008).

    Article  CAS  PubMed  Google Scholar 

  24. Dondelinger, Y. et al. RIPK3 contributes to TNFR1-mediated RIPK1 kinase-dependent apoptosis in conditions of cIAP1/2 depletion or TAK1 kinase inhibition. Cell Death Differ. 20, 1381–1392 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Legarda-Addison, D., Hase, H., O'Donnell, M. A. & Ting, A. T. NEMO/IKKγ regulates an early NF-κB-independent cell-death checkpoint during TNF signaling. Cell Death Differ. 16, 1279–1288 (2009).

    Article  CAS  PubMed  Google Scholar 

  26. Oberst, A. et al. Catalytic activity of the caspase-8-FLIPL complex inhibits RIPK3-dependent necrosis. Nature 471, 363–367 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Cai, Z. et al. Plasma membrane translocation of trimerized MLKL protein is required for TNF-induced necroptosis. Nat. Cell Biol. 16, 55–65 (2014).

    Article  CAS  PubMed  Google Scholar 

  28. Chen, X. et al. Translocation of mixed lineage kinase domain-like protein to plasma membrane leads to necrotic cell death. Cell Res. 24, 105–121 (2014).

    Article  CAS  PubMed  Google Scholar 

  29. Dondelinger, Y. et al. MLKL compromises plasma membrane integrity by binding to phosphatidylinositol phosphates. Cell Rep. 7, 971–981 (2014).

    Article  CAS  PubMed  Google Scholar 

  30. Wang, H. et al. Mixed lineage kinase domain-like protein MLKL causes necrotic membrane disruption upon phosphorylation by RIP3. Mol. Cell 54, 133–146 (2014).

    Article  CAS  PubMed  Google Scholar 

  31. Tenev, T. et al. The Ripoptosome, a signaling platform that assembles in response to genotoxic stress and loss of IAPs. Mol. Cell 43, 432–448 (2011).

    Article  CAS  PubMed  Google Scholar 

  32. Feoktistova, M. et al. cIAPs block Ripoptosome formation, a RIP1/caspase-8 containing intracellular cell death complex differentially regulated by cFLIP isoforms. Mol. Cell 43, 449–463 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Mandal, P. et al. RIP3 induces apoptosis independent of pronecrotic kinase activity. Mol. Cell 56, 481–495 (2014). This paper demonstrates how small-molecule drugs targeting RIPK3 kinase activity indeed block necroptosis induction, but in some cases induce RIPK3-platform-mediated apoptosis involving caspase 8 and RIPK1 kinase activity.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Hildebrand, J. M. et al. Activation of the pseudokinase MLKL unleashes the four-helix bundle domain to induce membrane localization and necroptotic cell death. Proc. Natl Acad. Sci. USA 111, 15072–15077 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Teng, X. et al. Structure–activity relationship study of novel necroptosis inhibitors. Bioorg. Med. Chem. Lett. 15, 5039–5044 (2005).

    Article  CAS  PubMed  Google Scholar 

  36. Vandenabeele, P., Grootjans, S., Callewaert, N. & Takahashi, N. Necrostatin-1 blocks both RIPK1 and IDO: consequences for the study of cell death in experimental disease models. Cell Death Differ. 20, 185–187 (2013).

    Article  CAS  PubMed  Google Scholar 

  37. Takahashi, N. et al. Necrostatin-1 analogues: critical issues on the specificity, activity and in vivo use in experimental disease models. Cell Death Dis. 3, e437 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Degterev, A., Maki, J. L. & Yuan, J. Activity and specificity of necrostatin-1, small-molecule inhibitor of RIP1 kinase. Cell Death Differ. 20, 366 (2013).

    Article  CAS  PubMed  Google Scholar 

  39. Prendergast, G. C., Chang, M. Y., Mandik-Nayak, L., Metz, R. & Muller, A. J. Indoleamine 2,3-dioxygenase as a modifier of pathogenic inflammation in cancer and other inflammation-associated diseases. Curr. Med. Chem. 18, 2257–2262 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Xie, T. et al. Structural basis of RIP1 inhibition by necrostatins. Structure 21, 493–499 (2013).

    Article  CAS  PubMed  Google Scholar 

  41. Harris, P. A. et al. Discovery of small molecule RIP1 kinase inhibitors for the treatment of pathologies associated with necroptosis. ACS Med. Chem. Lett. 4, 1238–1243 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Najjar, M. et al. Structure guided design of potent and selective ponatinib-based hybrid inhibitors for RIPK1. Cell Rep. 10, 1850–1860 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Fauster, A. et al. A cellular screen identifies ponatinib and pazopanib as inhibitors of necroptosis. Cell Death Dis. 6, e1767 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Newton, K., Sun, X. & Dixit, V. M. Kinase RIP3 is dispensable for normal NF-κBs, signaling by the B-cell and T-cell receptors, tumor necrosis factor receptor 1, and Toll-like receptors 2 and 4. Mol. Cell. Biol. 24, 1464–1469 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Wang, Q. et al. Receptor-interacting protein kinase 3 contributes to abdominal aortic aneurysms via smooth muscle cell necrosis and inflammation. Circ. Res. 116, 600–611 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Kaiser, W. J. et al. Toll-like receptor 3-mediated necrosis via TRIF, RIP3, and MLKL. J. Biol. Chem. 288, 31268–31279 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Upton, J. W., Kaiser, W. J. & Mocarski, E. S. DAI/ZBP1/DLM-1 complexes with RIP3 to mediate virus-induced programmed necrosis that is targeted by murine cytomegalovirus vIRA. Cell Host Microbe 11, 290–297 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Vitner, E. B. et al. RIPK3 as a potential therapeutic target for Gaucher's disease. Nat. Med. 20, 204–208 (2014).

    Article  CAS  PubMed  Google Scholar 

  49. Sun, L. et al. Mixed lineage kinase domain-like protein mediates necrosis signaling downstream of RIP3 kinase. Cell 148, 213–227 (2012). In this paper, a pharmacoproteomics approach based on a necroptosis-inhibiting drug (NSA) led to the successful identification of the execution protein MLKL, which is regulated by RIPK3-dependent phosphorylation.

    Article  CAS  PubMed  Google Scholar 

  50. Li, J. et al. The RIP1/RIP3 necrosome forms a functional amyloid signaling complex required for programmed necrosis. Cell 150, 339–350 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Cauwels, A., Janssen, B., Waeytens, A., Cuvelier, C. & Brouckaert, P. Caspase inhibition causes hyperacute tumor necrosis factor-induced shock via oxidative stress and phospholipase A2. Nat. Immunol. 4, 387–393 (2003).

    Article  CAS  PubMed  Google Scholar 

  52. Duprez, L. et al. RIP kinase-dependent necrosis drives lethal systemic inflammatory response syndrome. Immunity 35, 908–918 (2011).

    Article  CAS  PubMed  Google Scholar 

  53. Wu, J. et al. Mlkl knockout mice demonstrate the indispensable role of Mlkl in necroptosis. Cell Res. 23, 994–1006 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Polykratis, A. et al. Cutting edge: RIPK1 kinase inactive mice are viable and protected from TNF-induced necroptosis in vivo. J. Immunol. 193, 1539–1543 (2014).

    Article  CAS  PubMed  Google Scholar 

  55. Yang, W. S. & Stockwell, B. R. Synthetic lethal screening identifies compounds activating iron-dependent, nonapoptotic cell death in oncogenic-RAS-harboring cancer cells. Chem. Biol. 15, 234–245 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Dixon, S. J. et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 149, 1060–1072 (2012). In this paper, the term ferroptosis is coined, and it is shown that a functional system X c− is required to maintain glutathione levels to inhibit this form of cell death in a subset of cancer cell lines.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Sato, H., Tamba, M., Ishii, T. & Bannai, S. Cloning and expression of a plasma membrane cystine/glutamate exchange transporter composed of two distinct proteins. J. Biol. Chem. 274, 11455–11458 (1999).

    Article  CAS  PubMed  Google Scholar 

  58. Conrad, M. & Sato, H. The oxidative stress-inducible cystine/glutamate antiporter, system Xc−: cystine supplier and beyond. Amino Acids 42, 231–246 (2012).

    Article  CAS  PubMed  Google Scholar 

  59. Ursini, F., Maiorino, M., Valente, M., Ferri, L. & Gregolin, C. Purification from pig liver of a protein which protects liposomes and biomembranes from peroxidative degradation and exhibits glutathione peroxidase activity on phosphatidylcholine hydroperoxides. Biochim. Biophys. Acta 710, 197–211 (1982).

    Article  CAS  PubMed  Google Scholar 

  60. Yang, W. S. et al. Regulation of ferroptotic cancer cell death by GPX4. Cell 156, 317–331 (2014). This paper shows that GPX4 is the limiting glutathione-utilizing enzyme required for the prevention of ferroptosis in cancer cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Friedmann Angeli, J. P. et al. Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice. Nat. Cell Biol. 16, 1180–1191 (2014). This paper shows that the ferroptosis inhibitor liproxstatin-1 protects mice from acute renal failure induced by inducible Gpx4 ablation as well as from hepatic IRI.

    Article  CAS  PubMed  Google Scholar 

  62. Linkermann, A. et al. Synchronized renal tubular cell death involves ferroptosis. Proc. Natl Acad. Sci. USA 111, 16836–16841 (2014). This paper indicates that in vivo inhibition of ferroptosis leads to a protective effect in a pathophysiological setting, such as IRI in the kidney.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Seiler, A. et al. Glutathione peroxidase 4 senses and translates oxidative stress into 12/15-lipoxygenase dependent- and AIF-mediated cell death. Cell. Metab. 8, 237–248 (2008). This paper describes the first conditional-knockout model of the ferroptosis regulator GPX4 in cells and mice, which were further used for the development of liproxstatin-1 and for assessing the importance of ferroptosis in different tissues.

    Article  CAS  PubMed  Google Scholar 

  64. Yoo, S. E. et al. Gpx4 ablation in adult mice results in a lethal phenotype accompanied by neuronal loss in brain. Free Radic. Biol. Med. 52, 1820–1827 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Chen, L., Na, R., Gu, M., Richardson, A. & Ran, Q. Lipid peroxidation up-regulates BACE1 expression in vivo: a possible early event of amyloidogenesis in Alzheimer's disease. J. Neurochem. 107, 197–207 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Yoo, M. H. et al. Delineating the role of glutathione peroxidase 4 in protecting cells against lipid hydroperoxide damage and in Alzheimer's disease. Antioxid. Redox Signal 12, 819–827 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Ufer, C. et al. Translational regulation of glutathione peroxidase 4 expression through guanine-rich sequence-binding factor 1 is essential for embryonic brain development. Genes Dev. 22, 1838–1850 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Hauser, D. N., Dukes, A. A., Mortimer, A. D. & Hastings, T. G. Dopamine quinone modifies and decreases the abundance of the mitochondrial selenoprotein glutathione peroxidase 4. Free Radic. Biol. Med. 65, 419–427 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Bellinger, F. P. et al. Changes in selenoprotein P in substantia nigra and putamen in Parkinson's disease. J. Parkinsons Dis. 2, 115–126 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Bellinger, F. P. et al. Glutathione peroxidase 4 is associated with neuromelanin in substantia nigra and dystrophic axons in putamen of Parkinson's brain. Mol. Neurodegener. 6, 8 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Skouta, R. et al. Ferrostatins inhibit oxidative lipid damage and cell death in diverse disease models. J. Am. Chem. Soc. 136, 4551–4556 (2014). Ferrostatins with improved properties are reported in this paper to be effective in several cellular disease models. These ferrostatins block lipid peroxidation, but not by inhibiting mitochondrial ROS production or preventing lysosomal membrane permeabilization.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Wirth, E. K. et al. Cerebellar hypoplasia in mice lacking selenoprotein biosynthesis in neurons. Biol. Trace Elem. Res. 158, 203–210 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Roth, T. L. et al. Transcranial amelioration of inflammation and cell death after brain injury. Nature 505, 223–228 (2014).

    Article  CAS  PubMed  Google Scholar 

  74. Korade, Z. et al. Antioxidant supplementation ameliorates molecular deficits in Smith–Lemli–Opitz syndrome. Biol. Psychiatry 75, 215–222 (2014).

    Article  CAS  PubMed  Google Scholar 

  75. Ueta, T. et al. Glutathione peroxidase 4 is required for maturation of photoreceptor cells. J. Biol. Chem. 287, 7675–7682 (2012).

    Article  CAS  PubMed  Google Scholar 

  76. Sengupta, A. et al. Targeted disruption of glutathione peroxidase 4 in mouse skin epithelial cells impairs postnatal hair follicle morphogenesis that is partially rescued through inhibition of COX-2. J. Invest. Dermatol. 133, 1731–1741 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Matsushita, M. et al. T cell lipid peroxidation induces ferroptosis and prevents immunity to infection. J. Exp. Med. 212, 555–568 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Wortmann, M. et al. Combined deficiency in glutathione peroxidase 4 and vitamin E causes multiorgan thrombus formation and early death in mice. Circ. Res. 113, 408–417 (2013).

    Article  CAS  PubMed  Google Scholar 

  79. Woo, J. H. et al. Elucidating compound mechanism of action by network perturbation analysis. Cell 162, 441–451 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Bannai, S. Exchange of cystine and glutamate across plasma membrane of human fibroblasts. J. Biol. Chem. 261, 2256–2263 (1986).

    CAS  PubMed  Google Scholar 

  81. Mandal, P. K. et al. System Xc− and thioredoxin reductase 1 cooperatively rescue glutathione deficiency. J. Biol. Chem. 285, 22244–22253 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Jiang, L. et al. Ferroptosis as a p53-mediated activity during tumour suppression. Nature 520, 57–62 (2015). This paper implicates ferroptosis as a non-canonical tumour suppressive function of p53 via p53-mediated transcriptional inhibition of system X c−.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Hayano, M., Yang, W. S., Corn, C. K., Pagano, N. C. & Stockwell, B. R. Loss of cysteinyl-tRNA synthetase (CARS) induces the transsulfuration pathway and inhibits ferroptosis induced by cystine deprivation. Cell Death Differ. http://dx.doi.org/10.1038/cdd.2015.93 (2015).

  84. Yant, L. J. et al. The selenoprotein GPX4 is essential for mouse development and protects from radiation and oxidative damage insults. Free Radic. Biol. Med. 34, 496–502 (2003).

    Article  CAS  PubMed  Google Scholar 

  85. Gao, M., Monian, P., Quadri, N., Ramasamy, R. & Jiang, X. Glutaminolysis and transferrin regulate ferroptosis. Mol. Cell 59, 298–308 (2015). This paper suggests that inhibiting glutaminolysis might be a putative anti-ferroptotic pharmacological approach and that cells that preferably use glutaminolysis for energy production are more sensitive to ferroptosis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Tretter, L. & Adam-Vizi, V. Generation of reactive oxygen species in the reaction catalyzed by α-ketoglutarate dehydrogenase. J. Neurosci. 24, 7771–7778 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Bae, Y. S. et al. Platelet-derived growth factor-induced H2O2 production requires the activation of phosphatidylinositol 3-kinase. J. Biol. Chem. 275, 10527–10531 (2000).

    Article  CAS  PubMed  Google Scholar 

  88. Han, C. Y. et al. NADPH oxidase-derived reactive oxygen species increases expression of monocyte chemotactic factor genes in cultured adipocytes. J. Biol. Chem. 287, 10379–10393 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Li, B. et al. Fructose-1,6-bisphosphatase opposes renal carcinoma progression. Nature 513, 251–255 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Dixon, S. J. et al. Human haploid cell genetics reveals roles for lipid metabolism genes in nonapoptotic cell death. ACS Chem. Biol. 10, 1604–1609 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Dixon, S. J. et al. Pharmacological inhibition of cystine–glutamate exchange induces endoplasmic reticulum stress and ferroptosis. eLife 3, e02523 (2014). Here, inhibition of system X c− by erastin or sorafenib is shown to be associated with endoplasmic reticulum stress and glutathione- specific γ-glutamylcyclotransferase 1 upregulation involved in glutathione degradation.

    Article  PubMed  PubMed Central  Google Scholar 

  92. Yagoda, N. et al. RAS–RAF–MEK-dependent oxidative cell death involving voltage-dependent anion channels. Nature 447, 864–868 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Louandre, C. et al. Iron-dependent cell death of hepatocellular carcinoma cells exposed to sorafenib. Int. J. Cancer 133, 1732–1742 (2013).

    Article  CAS  PubMed  Google Scholar 

  94. Chung, W. J. et al. Inhibition of cystine uptake disrupts the growth of primary brain tumors. J. Neurosci. 25, 7101–7110 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Chen, R. S. et al. Disruption of xCT inhibits cancer cell metastasis via the caveolin-1/β-catenin pathway. Oncogene 28, 599–609 (2009).

    Article  CAS  PubMed  Google Scholar 

  96. Nagano, O., Okazaki, S. & Saya, H. Redox regulation in stem-like cancer cells by CD44 variant isoforms. Oncogene 32, 5191–5198 (2013).

    Article  CAS  PubMed  Google Scholar 

  97. Timmerman, L. A. et al. Glutamine sensitivity analysis identifies the xCT antiporter as a common triple-negative breast tumor therapeutic target. Cancer Cell 24, 450–465 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Keldsen, N., Havsteen, H., Vergote, I., Bertelsen, K. & Jakobsen, A. Altretamine (hexamethylmelamine) in the treatment of platinum-resistant ovarian cancer: a phase II study. Gynecol. Oncol. 88, 118–122 (2003).

    Article  CAS  PubMed  Google Scholar 

  99. Lee, Y. et al. Parthanatos mediates AIMP2-activated age-dependent dopaminergic neuronal loss. Nat. Neurosci. 16, 1392–1400 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Virag, L., Robaszkiewicz, A., Rodriguez-Vargas, J. M. & Oliver, F. J. Poly(ADP-ribose) signaling in cell death. Mol. Aspects Med. 34, 1153–1167 (2013).

    Article  CAS  PubMed  Google Scholar 

  101. Curtin, N. J. & Szabo, C. Therapeutic applications of PARP inhibitors: anticancer therapy and beyond. Mol. Aspects Med. 34, 1217–1256 (2013).

    Article  CAS  PubMed  Google Scholar 

  102. Mashimo, M., Kato, J. & Moss, J. ADP-ribosyl-acceptor hydrolase 3 regulates poly (ADP-ribose) degradation and cell death during oxidative stress. Proc. Natl Acad. Sci. USA 110, 18964–18969 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Andrabi, S. A., Dawson, T. M. & Dawson, V. L. Mitochondrial and nuclear cross talk in cell death: parthanatos. Ann. NY Acad. Sci. 1147, 233–241 (2008).

    Article  CAS  PubMed  Google Scholar 

  104. Wang, Y. et al. Poly(ADP-ribose) (PAR) binding to apoptosis-inducing factor is critical for PAR polymerase-1-dependent cell death (parthanatos). Sci. Signal. 4, ra20 (2011).

    PubMed  PubMed Central  Google Scholar 

  105. Andrabi, S. A. et al. Iduna protects the brain from glutamate excitotoxicity and stroke by interfering with poly(ADP-ribose) polymer-induced cell death. Nat. Med. 17, 692–699 (2011). In this paper, the first endogenous inhibitor of parthanatos is described, indicating that interfering with PAR polymer signalling is a putative treatment for neurodegenerative disease.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Graziani, G. & Szabo, C. Clinical perspectives of PARP inhibitors. Pharmacol. Res. 52, 109–118 (2005).

    Article  CAS  PubMed  Google Scholar 

  107. del Moral, R. M. et al. PARP inhibition attenuates histopathological lesion in ischemia/reperfusion renal mouse model after cold prolonged ischemia. ScientificWorldJournal 2013, 486574 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Sahaboglu, A. et al. PARP1 gene knock-out increases resistance to retinal degeneration without affecting retinal function. PLoS ONE 5, e15495 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Jagtap, P. et al. Novel phenanthridinone inhibitors of poly (adenosine 5′-diphosphate-ribose) synthetase: potent cytoprotective and antishock agents. Crit. Care Med. 30, 1071–1082 (2002).

    Article  CAS  PubMed  Google Scholar 

  110. Jagtap, P. G. et al. The discovery and synthesis of novel adenosine substituted 2,3-dihydro-1H-isoindol-1-ones: potent inhibitors of poly(ADP-ribose) polymerase-1 (PARP-1). Bioorg. Med. Chem. Lett. 14, 81–85 (2004).

    Article  CAS  PubMed  Google Scholar 

  111. Jagtap, P. G. et al. Discovery of potent poly(ADP-ribose) polymerase-1 inhibitors from the modification of indeno[1,2-c]isoquinolinone. J. Med. Chem. 48, 5100–5103 (2005).

    Article  CAS  PubMed  Google Scholar 

  112. Morrow, D. A. et al. A randomized, placebo-controlled trial to evaluate the tolerability, safety, pharmacokinetics, and pharmacodynamics of a potent inhibitor of poly(ADP-ribose) polymerase (INO-1001) in patients with ST-elevation myocardial infarction undergoing primary percutaneous coronary intervention: results of the TIMI 37 trial. J. Thromb. Thrombolysis 27, 359–364 (2009).

    Article  CAS  PubMed  Google Scholar 

  113. US National Library of Medicine. ClinicalTrials.gov [online], (2013).

  114. Andrabi, S. A. et al. Poly(ADP-ribose) polymerase-dependent energy depletion occurs through inhibition of glycolysis. Proc. Natl Acad. Sci. USA 111, 10209–10214 (2014). Although parthanatos still lacks a clear core cell death pathway, this paper indicates that overactivation of PARP1 is caused by PAR-dependent inhibition of glycolysis through the inhibition of HK, explaining the bioenergetic collapse that results in necrotic cell death.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Devalaraja-Narashimha, K., Diener, A. M. & Padanilam, B. J. Cyclophilin D gene ablation protects mice from ischemic renal injury. Am. J. Physiol. Renal Physiol. 297, F749–F759 (2009).

    Article  CAS  PubMed  Google Scholar 

  116. Millay, D. P. et al. Genetic and pharmacologic inhibition of mitochondrial-dependent necrosis attenuates muscular dystrophy. Nat. Med. 14, 442–447 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Jobe, S. M. et al. Critical role for the mitochondrial permeability transition pore and cyclophilin D in platelet activation and thrombosis. Blood 111, 1257–1265 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Fujimoto, K., Chen, Y., Polonsky, K. S. & Dorn, G. W. 2nd. Targeting cyclophilin D and the mitochondrial permeability transition enhances β-cell survival and prevents diabetes in Pdx1 deficiency. Proc. Natl Acad. Sci. USA 107, 10214–10219 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  119. Forte, M. et al. Cyclophilin D inactivation protects axons in experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis. Proc. Natl Acad. Sci. USA 104, 7558–7563 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Javadov, S. & Kuznetsov, A. Mitochondrial permeability transition and cell death: the role of cyclophilin D. Front. Physiol. 4, 76 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Giorgio, V. et al. Dimers of mitochondrial ATP synthase form the permeability transition pore. Proc. Natl Acad. Sci. USA 110, 5887–5892 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Bonora, M., Bravo- San Pedro, J. M., Kroemer, G., Galluzzi, L. & Pinton, P. Novel insights into the mitochondrial permeability transition. Cell Cycle 13, 2666–2670 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Green, D. R., Galluzzi, L. & Kroemer, G. Cell biology. Metabolic control of cell death. Science 345, 1250256 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Vaseva, A. V. et al. p53 opens the mitochondrial permeability transition pore to trigger necrosis. Cell 149, 1536–1548 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Karch, J. & Molkentin, J. D. Is p53 the long-sought molecular trigger for cyclophilin D-regulated mitochondrial permeability transition pore formation and necrosis? Circ. Res. 111, 1258–1260 (2012).

    Article  CAS  PubMed  Google Scholar 

  126. Nakagawa, T. et al. Cyclophilin D-dependent mitochondrial permeability transition regulates some necrotic but not apoptotic cell death. Nature 434, 652–658 (2005).

    Article  CAS  PubMed  Google Scholar 

  127. Baines, C. P. et al. Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death. Nature 434, 658–662 (2005).

    Article  CAS  PubMed  Google Scholar 

  128. Schinzel, A. C. et al. Cyclophilin D is a component of mitochondrial permeability transition and mediates neuronal cell death after focal cerebral ischemia. Proc. Natl Acad. Sci. USA 102, 12005–12010 (2005). References 126–128 characterize the requirement of CypD for the formation of the MPTP, and its inhibition as a pharmacologically amenable approach.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Zhang, L. H., Youn, H. D. & Liu, J. O. Inhibition of cell cycle progression by the novel cyclophilin ligand sanglifehrin A is mediated through the NFκB-dependent activation of p53. J. Biol. Chem. 276, 43534–43540 (2001).

    Article  CAS  PubMed  Google Scholar 

  130. Clarke, S. J., McStay, G. P. & Halestrap, A. P. Sanglifehrin A acts as a potent inhibitor of the mitochondrial permeability transition and reperfusion injury of the heart by binding to cyclophilin-D at a different site from cyclosporin A. J. Biol. Chem. 277, 34793–34799 (2002).

    Article  CAS  PubMed  Google Scholar 

  131. Linkermann, A. et al. Two independent pathways of regulated necrosis mediate ischemia–reperfusion injury. Proc. Natl Acad. Sci. USA 110, 12024–12029 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  132. Nighoghossian, N. et al. Cyclosporine in acute ischemic stroke. Neurology 84, 2216–2223 (2015).

    Article  CAS  PubMed  Google Scholar 

  133. Keogh, A. Calcineurin inhibitors in heart transplantation. J. Heart Lung Transplant 23, S202–S206 (2004).

    Article  PubMed  Google Scholar 

  134. Zhao, H. et al. Necroptosis and parthanatos are involved in remote lung injury after receiving ischemic renal allografts in rats. Kidney Int. 87, 738–748 (2015).

    Article  CAS  PubMed  Google Scholar 

  135. Takahashi, N. et al. RIPK1 ensures intestinal homeostasis by protecting the epithelium against apoptosis. Nature 513, 95–99 (2014).

    Article  CAS  PubMed  Google Scholar 

  136. Dannappel, M. et al. RIPK1 maintains epithelial homeostasis by inhibiting apoptosis and necroptosis. Nature 513, 90–94 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Lamkanfi, M. & Dixit, V. M. Mechanisms and functions of inflammasomes. Cell 157, 1013–1022 (2014).

    Article  CAS  PubMed  Google Scholar 

  138. Bergsbaken, T., Fink, S. L. & Cookson, B. T. Pyroptosis: host cell death and inflammation. Nat. Rev. Microbiol. 7, 99–109 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Ch'en, I. L., Tsau, J. S., Molkentin, J. D., Komatsu, M. & Hedrick, S. M. Mechanisms of necroptosis in T cells. J. Exp. Med. 208, 633–641 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Moriwaki, K. & Chan, F. K. Necrosis-dependent and independent signaling of the RIP kinases in inflammation. Cytokine Growth Factor Rev. 25, 167–174 (2014).

    Article  CAS  PubMed  Google Scholar 

  141. Munoz-Planillo, R. et al. K+ efflux is the common trigger of NLRP3 inflammasome activation by bacterial toxins and particulate matter. Immunity 38, 1142–1153 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Misawa, T. et al. Microtubule-driven spatial arrangement of mitochondria promotes activation of the NLRP3 inflammasome. Nat. Immunol. 14, 454–460 (2013).

    Article  CAS  PubMed  Google Scholar 

  143. Zhou, R., Yazdi, A. S., Menu, P. & Tschopp, J. A role for mitochondria in NLRP3 inflammasome activation. Nature 469, 221–225 (2011).

    Article  CAS  PubMed  Google Scholar 

  144. Hornung, V. et al. Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization. Nat. Immunol. 9, 847–856 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Upton, J. W., Kaiser, W. J. & Mocarski, E. S. Virus inhibition of RIP3-dependent necrosis. Cell Host Microbe 7, 302–313 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Kang, T. B., Yang, S. H., Toth, B., Kovalenko, A. & Wallach, D. Caspase-8 blocks kinase RIPK3-mediated activation of the NLRP3 inflammasome. Immunity 38, 27–40 (2013). This study puts forward for the first time the possible and complex interaction between the necrosome and inflammasome machinery.

    Article  CAS  PubMed  Google Scholar 

  147. Moriwaki, K., Bertin, J., Gough, P. J. & Chan, F. K. A. RIPK3-caspase 8 complex mediates atypical pro-IL-1β processing. J. Immunol. 194, 1938–1944 (2015).

    Article  CAS  PubMed  Google Scholar 

  148. Lawlor, K. E. et al. RIPK3 promotes cell death and NLRP3 inflammasome activation in the absence of MLKL. Nat. Commun. 6, 6282 (2015).

    Article  CAS  PubMed  Google Scholar 

  149. Kayagaki, N. et al. Caspase-11 cleaves gasdermin D for non-canonical inflammasome signaling. 526, 666–671 Nature (2015).

    Article  CAS  PubMed  Google Scholar 

  150. Shi, J. et al. Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death. 526, 660–665 Nature (2015).

    Article  CAS  PubMed  Google Scholar 

  151. Coll, R. C. et al. A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases. Nat. Med. 21, 248–255 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Tan, S., Schubert, D. & Maher, P. Oxytosis: a novel form of programmed cell death. Curr. Top. Med. Chem. 1, 497–506 (2001).

    Article  CAS  PubMed  Google Scholar 

  153. Li, Y., Maher, P. & Schubert, D. A role for 12-lipoxygenase in nerve cell death caused by glutathione depletion. Neuron 19, 453–463 (1997).

    Article  CAS  PubMed  Google Scholar 

  154. Pallast, S. et al. Increased nuclear apoptosis-inducing factor after transient focal ischemia: a 12/15-lipoxygenase-dependent organelle damage pathway. J. Cereb. Blood Flow Metab. 30, 1157–1167 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Pallast, S., Arai, K., Wang, X., Lo, E. H. & van Leyen, K. 12/15-lipoxygenase targets neuronal mitochondria under oxidative stress. J. Neurochem. 111, 882–889 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Yigitkanli, K. et al. Inhibition of 12/15-lipoxygenase as therapeutic strategy to treat stroke. Ann. Neurol. 73, 129–135 (2013).

    Article  CAS  PubMed  Google Scholar 

  157. van Leyen, K. et al. Baicalein and 12/15-lipoxygenase in the ischemic brain. Stroke 37, 3014–3018 (2006). This study demonstrates that glutathione depletion leads to lipid peroxidation and cell death in neuronal cells — a phenomenon later termed as oxytosis, which is related to ferroptosis.

    Article  CAS  PubMed  Google Scholar 

  158. Jin, G. et al. Protecting against cerebrovascular injury: contributions of 12/15-lipoxygenase to edema formation after transient focal ischemia. Stroke 39, 2538–2543 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Oxler, E. M., Dolga, A. & Culmsee, C. AIF depletion provides neuroprotection through a preconditioning effect. Apoptosis 17, 1027–1038 (2012).

    Article  CAS  PubMed  Google Scholar 

  160. Mahoney, D. J. et al. Both cIAP1 and cIAP2 regulate TNFα-mediated NF-κB activation. Proc. Natl Acad. Sci. USA 105, 11778–11783 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  161. Haas, T. L. et al. Recruitment of the linear ubiquitin chain assembly complex stabilizes the TNF-R1 signaling complex and is required for TNF-mediated gene induction. Mol. Cell 36, 831–844 (2009).

    Article  CAS  PubMed  Google Scholar 

  162. Varfolomeev, E. et al. IAP antagonists induce autoubiquitination of c-IAPs, NF-κB activation, and TNFα-dependent apoptosis. Cell 131, 669–681 (2007).

    Article  CAS  PubMed  Google Scholar 

  163. Vince, J. E. et al. IAP antagonists target cIAP1 to induce TNFα-dependent apoptosis. Cell 131, 682–693 (2007).

    Article  CAS  PubMed  Google Scholar 

  164. Petersen, S. L. et al. Autocrine TNFα signaling renders human cancer cells susceptible to Smac-mimetic-induced apoptosis. Cancer Cell 12, 445–456 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Bertrand, M. J. et al. cIAP1 and cIAP2 facilitate cancer cell survival by functioning as E3 ligases that promote RIP1 ubiquitination. Mol. Cell 30, 689–700 (2008).

    Article  CAS  PubMed  Google Scholar 

  166. Lin, Y., Devin, A., Rodriguez, Y. & Liu, Z. G. Cleavage of the death domain kinase RIP by caspase-8 prompts TNF-induced apoptosis. Genes Dev. 13, 2514–2526 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Feng, S. et al. Cleavage of RIP3 inactivates its caspase-independent apoptosis pathway by removal of kinase domain. Cell Signal 19, 2056–2067 (2007).

    Article  CAS  PubMed  Google Scholar 

  168. O'Donnell, M. A. et al. Caspase 8 inhibits programmed necrosis by processing CYLD. Nat. Cell Biol. 13, 1437–1442 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Cho, Y. S. et al. Phosphorylation-driven assembly of the RIP1–RIP3 complex regulates programmed necrosis and virus-induced inflammation. Cell 137, 1112–1123 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Zhang, D. W. et al. RIP3, an energy metabolism regulator that switches TNF-induced cell death from apoptosis to necrosis. Science 325, 332–336 (2009).

    Article  CAS  PubMed  Google Scholar 

  171. Zhao, J. et al. Mixed lineage kinase domain-like is a key receptor interacting protein 3 downstream component of TNF-induced necrosis. Proc. Natl Acad. Sci. USA 109, 5322–5327 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  172. Fulda, S. Smac mimetics as IAP antagonists. Semin. Cell Dev. Biol. 39, 132–138 (2015).

    Article  CAS  PubMed  Google Scholar 

  173. Kobayashi, S. et al. Cystathionine is a novel substrate of cystine/glutamate transporter: implications for immune function. J. Biol. Chem. 290, 8778–8788 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Bannai, S. & Kitamura, E. Transport interaction of l-cystine and l-glutamate in human diploid fibroblasts in culture. J. Biol. Chem. 255, 2372–2376 (1980).

    CAS  PubMed  Google Scholar 

  175. Gout, P. W., Buckley, A. R., Simms, C. R. & Bruchovsky, N. Sulfasalazine, a potent suppressor of lymphoma growth by inhibition of the Xc− cystine transporter: a new action for an old drug. Leukemia 15, 1633–1640 (2001).

    Article  CAS  PubMed  Google Scholar 

  176. Patel, S. A., Warren, B. A., Rhoderick, J. F. & Bridges, R. J. Differentiation of substrate and non-substrate inhibitors of transport system Xc−: an obligate exchanger of l -glutamate and l-cystine. Neuropharmacology 46, 273–284 (2004).

    Article  CAS  PubMed  Google Scholar 

  177. Fatokun, A. A., Dawson, V. L. & Dawson, T. M. Parthanatos: mitochondrial-linked mechanisms and therapeutic opportunities. Br. J. Pharmacol. 171, 2000–2016 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Shall, S. Proceedings: experimental manipulation of the specific activity of poly(ADP-ribose) polymerase. J. Biochem 77, 2p (1975).

    Article  CAS  PubMed  Google Scholar 

  179. Fatokun, A. A., Liu, J. O., Dawson, V. L. & Dawson, T. M. Identification through high-throughput screening of 4′-methoxyflavone and 3′,4′-dimethoxyflavone as novel neuroprotective inhibitors of parthanatos. Br. J. Pharmacol. 169, 1263–1278 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Greco, R. et al. Neuroprotection by the PARP inhibitor PJ34 modulates cerebral and circulating RAGE levels in rats exposed to focal brain ischemia. Eur. J. Pharmacol. 744, 91–97 (2014).

    Article  CAS  PubMed  Google Scholar 

  181. Wang, J. et al. Inhibition of poly (ADP-ribose) polymerase and inducible nitric oxide synthase protects against ischemic myocardial damage by reduction of apoptosis. Mol. Med. Rep. 11, 1768–1776 (2015).

    Article  CAS  PubMed  Google Scholar 

  182. Ha, H. C. & Snyder, S. H. Poly(ADP-ribose) polymerase is a mediator of necrotic cell death by ATP depletion. Proc. Natl Acad. Sci. USA 96, 13978–13982 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Meier, H. L., Ballough, G. P., Forster, J. S. & Filbert, M. G. Benzamide, a poly(ADP-ribose) polymerase inhibitor, is neuroprotective against soman-induced seizure-related brain damage. Ann. NY Acad. Sci. 890, 330–335 (1999).

    Article  CAS  PubMed  Google Scholar 

  184. Purnell, M. R. & Whish, W. J. Novel inhibitors of poly(ADP-ribose) synthetase. Biochem. J. 185, 775–777 (1980).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Szabo, G. et al. INO-1001 a novel poly(ADP-ribose) polymerase (PARP) inhibitor improves cardiac and pulmonary function after crystalloid cardioplegia and extracorporal circulation. Shock 21, 426–432 (2004).

    Article  CAS  PubMed  Google Scholar 

  186. d'Avila, J. C. et al. Microglial activation induced by brain trauma is suppressed by post-injury treatment with a PARP inhibitor. J. Neuroinflamm. 9, 31 (2012).

    CAS  Google Scholar 

  187. US National Library of Medicine. ClinicalTrials.gov [online], (2006).

  188. US National Library of Medicine. ClinicalTrials.gov [online], (2005).

  189. van Leyen, K. et al. Novel lipoxygenase inhibitors as neuroprotective reagents. J. Neurosci. Res. 86, 904–909 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Niki, E. & Traber, M. G. A history of vitamin E. Ann. Nutr. Metab. 61, 207–212 (2012).

    Article  CAS  PubMed  Google Scholar 

  191. Griffith, O. W. Mechanism of action, metabolism, and toxicity of buthionine sulfoximine and its higher homologs, potent inhibitors of glutathione synthesis. J. Biol. Chem. 257, 13704–13712 (1982).

    CAS  PubMed  Google Scholar 

  192. Harris, I. S. et al. Glutathione and thioredoxin antioxidant pathways synergize to drive cancer initiation and progression. Cancer Cell 27, 211–222 (2015).

    Article  CAS  PubMed  Google Scholar 

  193. Kim, S. Y. et al. Inhibition of cyclophilin D by cyclosporin A promotes retinal ganglion cell survival by preventing mitochondrial alteration in ischemic injury. Cell Death Dis. 5, e1105 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Teixeira, G. et al. Synergistic protective effect of cyclosporin A and rotenone against hypoxia–reoxygenation in cardiomyocytes. J. Mol. Cell Cardiol. 56, 55–62 (2013).

    Article  CAS  PubMed  Google Scholar 

  195. Wang, X. et al. Developmental shift of cyclophilin D contribution to hypoxic-ischemic brain injury. J. Neurosci. 29, 2588–2596 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Hausenloy, D., Wynne, A., Duchen, M. & Yellon, D. Transient mitochondrial permeability transition pore opening mediates preconditioning-induced protection. Circulation 109, 1714–1717 (2004).

    Article  CAS  PubMed  Google Scholar 

  197. Strom, E. et al. Small-molecule inhibitor of p53 binding to mitochondria protects mice from gamma radiation. Nat. Chem. Biol. 2, 474–479 (2006).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors are grateful to B. Proneth (Helmholtz Zentrum München) for help in the preparation of figures and to M. Lamkanfi (Flanders Institute for Biotechnology, Ghent University) for critically reading and comments on the inflammasome section of this manuscript. M.C. is partially supported by the Deutsche Forschungsgemeinschaft (DFG) research grant CO 291/2-3 and DFG Priority Programme 1710 (CO 291/5-1), the Human Frontier Science Program (HFSP) RGP0013/14, and the m4 Award (Bavarian Ministry of Economic Affairs). B.R.S. is an Early Career Scientist of the Howard Hughes Medical Institute and is supported by New York State Stem Cell Science (NYSTEM) contract No. C026715, and the US National Institutes of Health (NIH) (grants 5R01CA097061, 1R21CA177591 and R01CA161061). The authors thank J. Decatur and the Columbia Chemistry NMR core facility (US National Science Foundation grant CHE 0840451 and NIH grant 1S10RR025431-01A1). Research in the P.V. unit is supported by Belgian grants (Interuniversity Attraction Poles, IAP 7/32), Flemish grants (Research Foundation Flanders, FWO G.0875.11, FWO G.0973.11N, FWO G.0A45.12 N, FWO G.0172.12, FWO G.0787.13N, G0C3114N, FWO KAN 31528711, and Foundation against Cancer 2012–188), Ghent University grants (MRP, GROUP-ID consortium) and grants from the Flanders Institute for Biotechnology. P.V. holds a Methusalem grant (BOF09/01M00709) from the Flemish Government.

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Author notes

  1. Marcus Conrad and José Pedro Friedmann Angeli: These authors contributed equally to this work.

Authors and Affiliations

  1. Helmholtz Zentrum München, Institute of Developmental Genetics, 85764, Neuherberg, Germany

    Marcus Conrad & José Pedro Friedmann Angeli

  2. Molecular Signaling and Cell Death Unit, Inflammation Research Center, Flanders Institute for Biotechnology, 9052, Ghent, Belgium

    Peter Vandenabeele

  3. Department of Biomedical Molecular Biology, Molecular Signaling and Cell Death Unit, Ghent University, 9000, Ghent, Belgium

    Peter Vandenabeele

  4. Methusalem Program, Ghent University, 9000, Ghent, Belgium

    Peter Vandenabeele

  5. 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, 10027, New York, USA

    Brent R. Stockwell

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Correspondence to Marcus Conrad, Peter Vandenabeele or Brent R. Stockwell.

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Competing interests

M.C. and B.R.S. have filed patent applications for some of the molecules described in the article.

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Glossary

Pseudokinase

A protein that contains a catalytically inactive kinase domain. The loss of activity is attributed to the lack of at least one of three motifs (namely, VAIK, HRD or DFG) that are normally required for catalysis.

Fluorescence polarization assay

An assay used to analyse macromolecular interactions: one of the studied molecules is labelled with a fluorophore, which allows the measurement of the ratio of bound to unbound molecule, thus directly providing an estimation of molecular affinity.

Type II kinase inhibitor

An inhibitor that binds competitively with ATP, using the Asp-Phe-Gly (DFG)-out conformation.

DFG-out conformation

A state in which the kinase adopts a catalytically inactive conformation whereby the Asp-Phe-Gly (DFG) motif at the amino terminus of the activation loop faces outwards.

Gaucher disease

A genetic disorder characterized by deficiency of the enzyme glucocerebrosidase, leading to the accumulation of sphingolipids in certain organs. The disease is also characterized by enlargement of the liver and the spleen, low blood cell count and anaemia.

Glutaminolysis

A series of metabolic reactions based on the use of glutamine to produce energy and substrates to replenish the tricarboxylic acid cycle.

Pentose phosphate pathway

(PPP). A series of metabolic reactions converting glucose into precursors for nucleotide biosynthesis and reducing equivalents in the form of NADPH/H+.

Network perturbation analysis

A hybrid computational and experimental approach for mode-of-action analysis. Compound-induced dysregulations in the expression of genes in a regulatory network are scored, allowing compounds with a similar mode of action to be clustered.

Peroxide tone

The steady-state level of peroxides or lipid peroxides in a given cell.

Harlequin neuronal cells

Neuronal cells derived from the Harlequin mouse. These animals contain a proviral insertion in the apoptosis inducing factor (Aif) gene, leading to approximately 70% reduction of AIF expression.

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Conrad, M., Angeli, J., Vandenabeele, P. et al. Regulated necrosis: disease relevance and therapeutic opportunities. Nat Rev Drug Discov 15, 348–366 (2016). https://doi.org/10.1038/nrd.2015.6

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