Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease

Abrams, 2016, Five-membered ring peroxide selectively initiates ferroptosis in cancer cells, ACS Chem. Biol., 11, 1305, 10.1021/acschembio.5b00900

Angeli, 2017, Ferroptosis inhibition: mechanisms and opportunities, Trends Pharmacol. Sci., 38, 489, 10.1016/j.tips.2017.02.005

Ayton, 2017, Cerebral quantitative susceptibility mapping predicts β-amyloid-related cognitive decline, Brain, 140, 2112, 10.1093/brain/awx137

Bannai, 1977, Effect of antioxidants on cultured human diploid fibroblasts exposed to cystine-free medium, Biochem. Biophys. Res. Commun., 74, 1582, 10.1016/0006-291X(77)90623-4

Barelli, 2016, Lipid unsaturation and organelle dynamics, Curr. Opin. Cell Biol., 41, 25, 10.1016/j.ceb.2016.03.012

Belaidi, 2016, Iron neurochemistry in Alzheimer’s disease and Parkinson’s disease: targets for therapeutics, J. Neurochem., 139, 179, 10.1111/jnc.13425

Braak, 2015, The preclinical phase of the pathological process underlying sporadic Alzheimer’s disease, Brain, 138, 2814, 10.1093/brain/awv236

Brettschneider, 2015, Spreading of pathology in neurodegenerative diseases: a focus on human studies, Nat. Rev. Neurosci., 16, 109, 10.1038/nrn3887

Buijs, 2017, In vivo assessment of iron content of the cerebral cortex in healthy aging using 7-Tesla T2∗-weighted phase imaging, Neurobiol. Aging, 53, 20, 10.1016/j.neurobiolaging.2016.09.005

Cardoso, 2017, Glutathione peroxidase 4: a new player in neurodegeneration?, Mol. Psychiatry, 22, 328, 10.1038/mp.2016.196

Cenini, 2008, Elevated levels of pro-apoptotic p53 and its oxidative modification by the lipid peroxidation product, HNE, in brain from subjects with amnestic mild cognitive impairment and Alzheimer’s disease, J. Cell. Mol. Med., 12, 987, 10.1111/j.1582-4934.2008.00163.x

Chen, 2015, Ablation of ferroptosis inhibitor glutathione peroxidase 4 in neurons results in rapid motor neuron degeneration and paralysis, J. Biol. Chem., 290, 28097, 10.1074/jbc.M115.680090

Chiang, 2017, Relationships among cortical glutathione levels, brain amyloidosis, and memory in healthy older adults investigated in vivo with (1)H-MRS and Pittsburgh compound-B PET, AJNR Am. J. Neuroradiol., 38, 1130, 10.3174/ajnr.A5143

Conrad, 2016, Regulated necrosis: disease relevance and therapeutic opportunities, Nat. Rev. Drug Discov., 15, 348, 10.1038/nrd.2015.6

Cramer, 2017, Systemic depletion of L-cyst(e)ine with cyst(e)inase increases reactive oxygen species and suppresses tumor growth, Nat. Med., 23, 120, 10.1038/nm.4232

Crapper McLachlan, 1991, Intramuscular desferrioxamine in patients with Alzheimer’s disease, Lancet, 337, 1304, 10.1016/0140-6736(91)92978-B

Devos, 2014, Targeting chelatable iron as a therapeutic modality in Parkinson’s disease, Antioxid. Redox Signal., 21, 195, 10.1089/ars.2013.5593

Di Domenico, 2017, Role of 4-hydroxy-2-nonenal (HNE) in the pathogenesis of alzheimer disease and other selected age-related neurodegenerative disorders, Free Radic. Biol. Med., 111, 253, 10.1016/j.freeradbiomed.2016.10.490

Di Meco, 2017, 12/15-Lipoxygenase inhibition reverses cognitive impairment, brain amyloidosis, and tau pathology by stimulating autophagy in aged triple transgenic mice, Biol. Psychiatry, 81, 92, 10.1016/j.biopsych.2016.05.023

Ding, 2016, Erratum: Pore-forming activity and structural autoinhibition of the gasdermin family, Nature, 540, 150, 10.1038/nature20106

Distéfano, 2017, Heat stress induces ferroptosis-like cell death in plants, J. Cell Biol., 216, 463, 10.1083/jcb.201605110

Dixon, 2014, The role of iron and reactive oxygen species in cell death, Nat. Chem. Biol., 10, 9, 10.1038/nchembio.1416

Dixon, 2012, Ferroptosis: an iron-dependent form of nonapoptotic cell death, Cell, 149, 1060, 10.1016/j.cell.2012.03.042

Dixon, 2014, Pharmacological inhibition of cystine-glutamate exchange induces endoplasmic reticulum stress and ferroptosis, eLife, 3, e02523, 10.7554/eLife.02523

Dixon, 2015, Human haploid cell genetics reveals roles for lipid metabolism genes in nonapoptotic cell death, ACS Chem. Biol., 10, 1604, 10.1021/acschembio.5b00245

Do Van, 2016, Ferroptosis, a newly characterized form of cell death in Parkinson’s disease that is regulated by PKC, Neurobiol. Dis., 94, 169, 10.1016/j.nbd.2016.05.011

Doll, 2017, ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition, Nat. Chem. Biol., 13, 91, 10.1038/nchembio.2239

Dolma, 2003, Identification of genotype-selective antitumor agents using synthetic lethal chemical screening in engineered human tumor cells, Cancer Cell, 3, 285, 10.1016/S1535-6108(03)00050-3

Dysken, 2014, Effect of vitamin E and memantine on functional decline in Alzheimer disease: the TEAM-AD VA cooperative randomized trial, JAMA, 311, 33, 10.1001/jama.2013.282834

Eagle, 1955, Nutrition needs of mammalian cells in tissue culture, Science, 122, 501, 10.1126/science.122.3168.501

Eling, 2015, Identification of artesunate as a specific activator of ferroptosis in pancreatic cancer cells, Oncoscience, 2, 517, 10.18632/oncoscience.160

Enke, 2008, Impact of PUFA on early immune and fetal development, Br. J. Nutr., 100, 1158, 10.1017/S000711450801413X

Fradejas, 2013, Mammalian Trit1 is a tRNA([Ser]Sec)-isopentenyl transferase required for full selenoprotein expression, Biochem. J., 450, 427, 10.1042/BJ20121713

Friedmann Angeli, 2014, Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice, Nat. Cell Biol., 16, 1180, 10.1038/ncb3064

Galluzzi, 2015, Essential versus accessory aspects of cell death: recommendations of the NCCD 2015, Cell Death Differ., 22, 58, 10.1038/cdd.2014.137

Gao, 2015, Glutaminolysis and transferrin regulate ferroptosis, Mol. Cell, 59, 298, 10.1016/j.molcel.2015.06.011

Gao, 2016, Ferroptosis is an autophagic cell death process, Cell Res., 26, 1021, 10.1038/cr.2016.95

Gaschler, 2017, Lipid peroxidation in cell death, Biochem. Biophys. Res. Commun., 482, 419, 10.1016/j.bbrc.2016.10.086

Gascón, 2016, Identification and Successful Negotiation of a Metabolic Checkpoint in Direct Neuronal Reprogramming, Cell Stem Cell, 18, 396, 10.1016/j.stem.2015.12.003

Gong, 2017, ESCRT-III acts downstream of MLKL to regulate necroptotic cell death and its consequences, Cell, 169, 286, 10.1016/j.cell.2017.03.020

Greenamyre, 1985, Alterations in L-glutamate binding in Alzheimer’s and Huntington’s diseases, Science, 227, 1496, 10.1126/science.2858129

Greenshields, 2017, Contribution of reactive oxygen species to ovarian cancer cell growth arrest and killing by the anti-malarial drug artesunate, Mol. Carcinog., 56, 75, 10.1002/mc.22474

Guiney, 2017, Ferroptosis and cell death mechanisms in Parkinson’s disease, Neurochem. Int., 104, 34, 10.1016/j.neuint.2017.01.004

Guo, 2017, Ferroptosis: a novel anti-tumor action for cisplatin, Cancer Res. Treat.

Haas, 2011, Targeted knock-down of a structurally atypical zebrafish 12S-lipoxygenase leads to severe impairment of embryonic development, Proc. Natl. Acad. Sci. USA, 108, 20479, 10.1073/pnas.1117094108

Hambright, 2017, Ablation of ferroptosis regulator glutathione peroxidase 4 in forebrain neurons promotes cognitive impairment and neurodegeneration, Redox Biol., 12, 8, 10.1016/j.redox.2017.01.021

Hayano, 2016, Loss of cysteinyl-tRNA synthetase (CARS) induces the transsulfuration pathway and inhibits ferroptosis induced by cystine deprivation, Cell Death Differ., 23, 270, 10.1038/cdd.2015.93

Heneka, 2015, Effect of pioglitazone medication on the incidence of dementia, Ann. Neurol., 78, 284, 10.1002/ana.24439

Hirayama, 2017, Chemical tools for detecting Fe ions, J. Clin. Biochem. Nutr., 60, 39, 10.3164/jcbn.16-70

Hou, 2016, Autophagy promotes ferroptosis by degradation of ferritin, Autophagy, 12, 1425, 10.1080/15548627.2016.1187366

Jennis, 2016, An African-specific polymorphism in the TP53 gene impairs p53 tumor suppressor function in a mouse model, Genes Dev., 30, 918, 10.1101/gad.275891.115

Jiang, 2015, Ferroptosis as a p53-mediated activity during tumour suppression, Nature, 520, 57, 10.1038/nature14344

Kagan, 2017, Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis, Nat. Chem. Biol., 13, 81, 10.1038/nchembio.2238

Kerins, 2017, The roles of NRF2 in modulating cellular iron homeostasis, Antioxid. Redox Signal., 10.1089/ars.2017.7176

Khanna, 2003, Molecular basis of vitamin E action: tocotrienol modulates 12-lipoxygenase, a key mediator of glutamate-induced neurodegeneration, J. Biol. Chem., 278, 43508, 10.1074/jbc.M307075200

Kim, 2016, Ultrasmall nanoparticles induce ferroptosis in nutrient-deprived cancer cells and suppress tumour growth, Nat. Nanotechnol., 11, 977, 10.1038/nnano.2016.164

Krainz, 2016, A mitochondrial-targeted nitroxide is a potent inhibitor of ferroptosis, ACS Cent. Sci., 2, 653, 10.1021/acscentsci.6b00199

Kuhn, 2015, Mammalian lipoxygenases and their biological relevance, Biochim. Biophys. Acta, 1851, 308, 10.1016/j.bbalip.2014.10.002

Li, 2017, Inhibition of neuronal ferroptosis protects hemorrhagic brain, JCI Insight, 2, e90777, 10.1172/jci.insight.90777

Linkermann, 2013, Two independent pathways of regulated necrosis mediate ischemia-reperfusion injury, Proc. Natl. Acad. Sci. USA, 110, 12024, 10.1073/pnas.1305538110

Linkermann, 2014, Synchronized renal tubular cell death involves ferroptosis, Proc. Natl. Acad. Sci. USA, 111, 16836, 10.1073/pnas.1415518111

Liu, 2017, Inhibiting the system xC(-)/glutathione axis selectively targets cancers with mutant-p53 accumulation, Nat. Commun., 8, 14844, 10.1038/ncomms14844

MacLeod, 2009, Characterization of the cancer chemopreventive NRF2-dependent gene battery in human keratinocytes: demonstration that the KEAP1-NRF2 pathway, and not the BACH1-NRF2 pathway, controls cytoprotection against electrophiles as well as redox-cycling compounds, Carcinogenesis, 30, 1571, 10.1093/carcin/bgp176

Mancias, 2014, Quantitative proteomics identifies NCOA4 as the cargo receptor mediating ferritinophagy, Nature, 509, 105, 10.1038/nature13148

Mandal, 2015, Brain glutathione levels--a novel biomarker for mild cognitive impairment and Alzheimer’s disease, Biol. Psychiatry, 78, 702, 10.1016/j.biopsych.2015.04.005

Massie, 2011, Dopaminergic neurons of system x(c)−-deficient mice are highly protected against 6-hydroxydopamine-induced toxicity, FASEB J., 25, 1359, 10.1096/fj.10-177212

McCullagh, 2014, Behavioral characterization of system xc- mutant mice, Behav. Brain Res., 265, 1, 10.1016/j.bbr.2014.02.010

Milne, 2007, Quantification of F2-isoprostanes as a biomarker of oxidative stress, Nat. Protoc., 2, 221, 10.1038/nprot.2006.375

Murphy, 1989, Glutamate toxicity in a neuronal cell line involves inhibition of cystine transport leading to oxidative stress, Neuron, 2, 1547, 10.1016/0896-6273(89)90043-3

Newton, 2016, RIPK3 deficiency or catalytically inactive RIPK1 provides greater benefit than MLKL deficiency in mouse models of inflammation and tissue injury, Cell Death Differ., 23, 1565, 10.1038/cdd.2016.46

Ou, 2016, Activation of SAT1 engages polyamine metabolism with p53-mediated ferroptotic responses, Proc. Natl. Acad. Sci. USA, 113, E6806, 10.1073/pnas.1607152113

Prasad, 1998, Regional membrane phospholipid alterations in Alzheimer’s disease, Neurochem. Res., 23, 81, 10.1023/A:1022457605436

Raven, 2013, Increased iron levels and decreased tissue integrity in hippocampus of Alzheimer’s disease detected in vivo with magnetic resonance imaging, J. Alzheimers Dis., 37, 127, 10.3233/JAD-130209

Revett, 2013, Glutamate system, amyloid ß peptides and tau protein: functional interrelationships and relevance to Alzheimer disease pathology, J. Psychiatry Neurosci., 38, 6, 10.1503/jpn.110190

Sato, 2005, Redox imbalance in cystine/glutamate transporter-deficient mice, J Biol Chem., 280, 37423, 10.1074/jbc.M506439200

Seiler, 2008, Glutathione peroxidase 4 senses and translates oxidative stress into 12/15-lipoxygenase dependent- and AIF-mediated cell death, Cell Metab., 8, 237, 10.1016/j.cmet.2008.07.005

Shimada, 2016, Cell-line selectivity improves the predictive power of pharmacogenomic analyses and helps identify NADPH as biomarker for ferroptosis sensitivity, Cell Chem. Biol., 23, 225, 10.1016/j.chembiol.2015.11.016

Shimada, 2016, Global survey of cell death mechanisms reveals metabolic regulation of ferroptosis, Nat. Chem. Biol., 12, 497, 10.1038/nchembio.2079

Skouta, 2014, Ferrostatins inhibit oxidative lipid damage and cell death in diverse disease models, J. Am. Chem. Soc., 136, 4551, 10.1021/ja411006a

Song, 2016, FANCD2 protects against bone marrow injury from ferroptosis, Biochem. Biophys. Res. Commun., 480, 443, 10.1016/j.bbrc.2016.10.068

Spangler, 2016, A reactivity-based probe of the intracellular labile ferrous iron pool, Nat. Chem. Biol., 12, 680, 10.1038/nchembio.2116

Sun, 2015, HSPB1 as a novel regulator of ferroptotic cancer cell death, Oncogene, 34, 5617, 10.1038/onc.2015.32

Sun, 2016, Metallothionein-1G facilitates sorafenib resistance through inhibition of ferroptosis, Hepatology, 64, 488, 10.1002/hep.28574

Sun, 2016, Activation of the p62-Keap1-NRF2 pathway protects against ferroptosis in hepatocellular carcinoma cells, Hepatology, 63, 173, 10.1002/hep.28251

Sydenham, 2012, Omega 3 fatty acid for the prevention of cognitive decline and dementia, Cochrane Database Syst. Rev., CD005379

Tonnus, 2017, The in vivo evidence for regulated necrosis, Immunol. Rev., 277, 128, 10.1111/imr.12551

Toyokuni, 2017, Iron and thiol redox signaling in cancer: An exquisite balance to escape ferroptosis, Free Radic. Biol. Med., 108, 610, 10.1016/j.freeradbiomed.2017.04.024

Tuo, 2017, Tau-mediated iron export prevents ferroptotic damage after ischemic stroke, Mol. Psychiatry, 10.1038/mp.2017.171

Ursini, 1982, 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, 10.1016/0005-2760(82)90150-3

van den Brink-van der Laan, 2004, Nonbilayer lipids affect peripheral and integral membrane proteins via changes in the lateral pressure profile, Biochim. Biophys. Acta, 1666, 275, 10.1016/j.bbamem.2004.06.010

Vanden Berghe, 2010, Necroptosis, necrosis and secondary necrosis converge on similar cellular disintegration features, Cell Death Differ., 17, 922, 10.1038/cdd.2009.184

Viswanathan, 2017, Dependency of a therapy-resistant state of cancer cells on a lipid peroxidase pathway, Nature, 547, 453, 10.1038/nature23007

Wan, 2007, Damage of oxidative stress on mitochondria during microspores development in Honglian CMS line of rice, Plant Cell Rep., 26, 373, 10.1007/s00299-006-0234-2

Wang, 2016, Antiferroptotic activity of non-oxidative dopamine, Biochem. Biophys. Res. Commun., 480, 602, 10.1016/j.bbrc.2016.10.099

Wang, 2016, The protective role of mitochondrial ferritin on erastin-induced ferroptosis, Front. Aging Neurosci., 8, 308, 10.3389/fnagi.2016.00308

Wang, 2017, Characterization of ferroptosis in murine models of hemochromatosis, Hepatology, 66, 449, 10.1002/hep.29117

Williams, 2006, Increased levels of 4-hydroxynonenal and acrolein, neurotoxic markers of lipid peroxidation, in the brain in Mild Cognitive Impairment and early Alzheimer’s disease, Neurobiol. Aging, 27, 1094, 10.1016/j.neurobiolaging.2005.06.004

Wolpaw, 2011, Modulatory profiling identifies mechanisms of small molecule-induced cell death, Proc. Natl. Acad. Sci. USA, 108, E771, 10.1073/pnas.1106149108

Xie, 2016, Ferroptosis: process and function, Cell Death Differ., 23, 369, 10.1038/cdd.2015.158

Xie, 2016, Identification of baicalein as a ferroptosis inhibitor by natural product library screening, Biochem. Biophys. Res. Commun., 473, 775, 10.1016/j.bbrc.2016.03.052

Xie, 2017, The tumor suppressor p53 limits ferroptosis by blocking DPP4 activity, Cell Rep., 20, 1692, 10.1016/j.celrep.2017.07.055

Yagoda, 2007, RAS-RAF-MEK-dependent oxidative cell death involving voltage-dependent anion channels, Nature, 447, 864, 10.1038/nature05859

Yang, 2008, Synthetic lethal screening identifies compounds activating iron-dependent, nonapoptotic cell death in oncogenic-RAS-harboring cancer cells, Chem. Biol., 15, 234, 10.1016/j.chembiol.2008.02.010

Yang, 2016, Ferroptosis: death by lipid peroxidation, Trends Cell Biol., 26, 165, 10.1016/j.tcb.2015.10.014

Yang, 2014, Regulation of ferroptotic cancer cell death by GPX4, Cell, 156, 317, 10.1016/j.cell.2013.12.010

Yang, 2016, Peroxidation of polyunsaturated fatty acids by lipoxygenases drives ferroptosis, Proc. Natl. Acad. Sci. USA, 113, E4966, 10.1073/pnas.1603244113

Yoo, 2012, Gpx4 ablation in adult mice results in a lethal phenotype accompanied by neuronal loss in brain, Free Radic. Biol. Med., 52, 1820, 10.1016/j.freeradbiomed.2012.02.043

Yuan, 2016, CISD1 inhibits ferroptosis by protection against mitochondrial lipid peroxidation, Biochem. Biophys. Res. Commun., 478, 838, 10.1016/j.bbrc.2016.08.034

Yuan, 2016, Identification of ACSL4 as a biomarker and contributor of ferroptosis, Biochem. Biophys. Res. Commun., 478, 1338, 10.1016/j.bbrc.2016.08.124

Zilka, 2017, On the mechanism of cytoprotection by ferrostatin-1 and liproxstatin-1 and the role of lipid peroxidation in ferroptotic cell death, ACS Cent. Sci., 3, 232, 10.1021/acscentsci.7b00028

Zille, 2017, Neuronal death after hemorrhagic stroke in vitro and in vivo shares features of ferroptosis and necroptosis, Stroke, 48, 1033, 10.1161/STROKEAHA.116.015609