铁死亡与重大慢性疾病

doi:10.3785/j.issn.1008-9292.2020.02.24

浙江大学学报（医学版）

2020, Vol. 49

Issue (1): 44-57 DOI: 10.3785/j.issn.1008-9292.2020.02.24

专题报道

铁死亡与重大慢性疾病

陈峻逸(

),杨翔,方学贤,王福俤,闵军霞*(

)

浙江大学医学院, 浙江杭州 310058

The role of ferroptosis in chronic diseases

CHEN Junyi(

),YANG Xiang,FANG Xuexian,WANG Fudi,MIN Junxia*(

)

School of Medicine, Zhejiang University, Hangzhou 310058, China

全文: PDF(2588 KB)

HTML( 39 )

摘要：

铁死亡是近年发现的一种铁依赖的新型细胞死亡方式，其特征是脂质过氧化物和活性氧簇的过量蓄积。大量研究表明，铁死亡不仅在重大慢性疾病的发生发展过程中发挥重要作用，而且在不同的疾病背景下扮演不同角色。目前认为，铁死亡可抑制肿瘤生长并增加多种肿瘤对化疗药物和免疫治疗的敏感性，因此诱导铁死亡的发生拓展了肿瘤治疗思路。然而，在心脑血管疾病和神经退行性疾病中，铁死亡的发生通过引发正常组织器官损伤和功能丧失直接参与疾病的发生、发展及转归，因此针对心脑血管疾病和神经退行性疾病，抑制铁死亡的发生能够有效预防并延缓这些疾病的发生和发展。本文综述了铁死亡在恶性肿瘤、神经退行性疾病和心脑血管疾病三类不同重大慢性疾病中的最新研究进展及其潜在的作用机制，系统讨论了靶向铁死亡在防治重大慢性疾病中的临床应用前景，为重大慢性疾病的防治提供新的依据。

关键词： 铁代谢障碍; 铁死亡; 肿瘤; 神经退行性疾病; 血管疾病; 综述

Abstract:

Recently, ferroptosis, an iron-dependent novel type of cell death, has been characterized as an excessive accumulation of lipid peroxides and reactive oxygen species. Emerging studies demonstrate that ferroptosis not only plays an important role in the pathogenesis and progression of chronic diseases, but also functions differently in the different disease context. Notably, it is shown that activation of ferroptosis could potently inhibit tumor growth and increase sensitivity to chemotherapy and immunotherapy in various cancer settings. As a result, the development of more efficacious ferroptosis agonists remains the mainstay of ferroptosis-targeting strategy for cancer therapeutics. By contrast, in non-cancerous chronic diseases, including cardiovascular & cerebrovascular diseases and neurodegenerative diseases, ferroptosis functions as a risk factor to promote these diseases progression through triggering or accelerating tissue injury. As a matter of fact, blocking ferroptosis has been demonstrated to effectively prevent ischemia-reperfusion heart disease in preclinical animal models. Therefore, it is a promising field to develope potent ferroptosis inhibitors for preventing and treating cardiovascular & cerebrovascular diseases and neurodegenerative diseases. In this article, we summarize the most recent progress on ferroptosis in chronic diseases, and draw attention to the possible clinical impact of this recently emerged ferroptosis modalities.

Key words: Iron metabolism disorder Ferroptosis Neoplasms Neurodegeneration Vascular diseases Review

收稿日期: 2019-11-18 出版日期: 2020-06-08

CLC:

R364

基金资助: 国家重点研发计划(2018YFC2000400)

通讯作者: 闵军霞 E-mail: junyichen@zju.edu.cn;junxiamin@zju.edu.cn

作者简介: 陈峻逸(1998-), 男, 硕士研究生, 主要从事靶向铁死亡的小分子筛选及作用机制研究; E-mail:junyichen@zju.edu.cn; https://orcid.org/0000-0002-8130-9426

	服务
	把本文推荐给朋友
	加入引用管理器
	E-mail Alert
	RSS
	作者相关文章
	陈峻逸
	杨翔
	方学贤
	王福俤
	闵军霞

引用本文:

陈峻逸,杨翔,方学贤,王福俤,闵军霞. 铁死亡与重大慢性疾病[J]. 浙江大学学报（医学版）, 2020, 49(1): 44-57.

CHEN Junyi,YANG Xiang,FANG Xuexian,WANG Fudi,MIN Junxia. The role of ferroptosis in chronic diseases. J Zhejiang Univ (Med Sci), 2020, 49(1): 44-57.

链接本文:

http://www.zjujournals.com/med/CN/10.3785/j.issn.1008-9292.2020.02.24 或 http://www.zjujournals.com/med/CN/Y2020/V49/I1/44

图 1 铁死亡分子机制

表 1 铁死亡与肿瘤相关研究进展

表 2 铁死亡与神经退行性疾病相关研究进展

表 3 铁死亡与心脑血管疾病相关研究进展

1	World Health Organization. World health statistics 2018: monitoring health for the SDGs[R]. Geneva: World Health Organization, 2018.
2	中华人民共和国国家卫生健康委员会 . 2018中国卫生统计年鉴[M]. 北京: 中国协和医科大学出版社, 2018. National Health Commission of the People's Republic of China . 2018 China health statistics yearbook[M]. Beijing: China Union Medical University Press, 2018.
3	DIXON S J , LEMBERG K M , LAMPRECHT M R et al. Ferroptosis:an iron-dependent form of nonapoptotic cell death[J]. Cell, 2012, 149 (5): 1060- 1072 doi: 10.1016/j.cell.2012.03.042
4	CAO J Y , DIXON S J . Mechanisms of ferroptosis[J]. Cell Mol Life Sci, 2016, 73 (11-12): 2195- 2209 doi: 10.1007/s00018-016-2194-1
5	DIXON S J , STOCKWELL B R . The role of iron and reactive oxygen species in cell death[J]. Nat Chem Biol, 2014, 10 (1): 9- 17 doi: 10.1038/nchembio.1416
6	MANCIAS J D , WANG X , GYGI S P et al. Quantitative proteomics identifies NCOA4 as the cargo receptor mediating ferritinophagy[J]. Nature, 2014, 509 (7498): 105- 109 doi: 10.1038/nature13148
7	HOU W , XIE Y , SONG X et al. Autophagy promotes ferroptosis by degradation of ferritin[J]. Autophagy, 2016, 12 (8): 1425- 1428 doi: 10.1080/15548627.2016.1187366
8	YANG W S , STOCKWELL B R . Synthetic lethal screening identifies compounds activating iron-dependent, nonapoptotic cell death in oncogenic-RAS-harboring cancer cells[J]. Chem Biol, 2008, 15 (3): 234- 245 doi: 10.1016/j.chembiol.2008.02.010
9	WENZEL S E , TYURINA Y Y , ZHAO J et al. PEBP1 wardens ferroptosis by enabling lipoxygenase generation of lipid death signals[J]. Cell, 2017, 171 (3): 628- 641 doi: 10.1016/j.cell.2017.09.044
10	DOLL S , PRONETH B , TYURINA Y Y et al. ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition[J]. Nat Chem Biol, 2017, 13 (1): 91- 98 doi: 10.1038/nchembio.2239
11	HANGAUER M J , VISWANATHAN V S , RYAN M J et al. Drug-tolerant persister cancer cells are vulnerable to GPX4 inhibition[J]. Nature, 2017, 551 (7679): 247- 250 doi: 10.1038/nature24297
12	DIXON S J , WINTER G E , MUSAVI L S et al. Human haploid cell genetics reveals roles for lipid metabolism genes in nonapoptotic cell death[J]. ACS Chem Biol, 2015, 10 (7): 1604- 1609 doi: 10.1021/acschembio.5b00245
13	XIE Y , HOU W , SONG X et al. Ferroptosis:process and function[J]. Cell Death Differ, 2016, 23 (3): 369- 379 doi: 10.1038/cdd.2015.158
14	FRIEDMANN ANGELI J P , CONRAD M . Selenium and GPX4, a vital symbiosis[J]. Free Radic Biol Med, 2018, 127:153- 159 doi: 10.1016/j.freeradbiomed.2018.03.001
15	MAIORINO M , CONRAD M , URSINI F . GPx4, lipid peroxidation, and cell death:discoveries, rediscoveries, and open issues[J]. Antioxid Redox Signal, 2018, 29 (1): 61- 74 doi: 10.1089/ars.2017.7115
16	LU L , HOPE B T , SHAHAM Y . The cystine-glutamate transporter in the accumbens:a novel role in cocaine relapse[J]. Trends Neurosci, 2004, 27 (2): 74- 76 doi: 10.1016/j.tins.2003.11.007
17	WANG H , AN P , XIE E et al. Characterization of ferroptosis in murine models of hemochromatosis[J]. Hepatology, 2017, 66 (2): 449- 465 doi: 10.1002/hep.29117
18	BERSUKER K , HENDRICKS J M , LI Z et al. The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis[J]. Nature, 2019, 575 (7784): 688- 692 doi: 10.1038/s41586-019-1705-2
19	DOLL S , FREITAS F P , SHAH R et al. FSP1 is a glutathione-independent ferroptosis suppressor[J]. Nature, 2019, 575 (7784): 693- 698 doi: 10.1038/s41586-019-1707-0
20	STOCKWELL B R , FRIEDMANN ANGELI J P , BAYIR H et al. Ferroptosis:a regulated cell death nexus linking metabolism, redox biology, and disease[J]. Cell, 2017, 171 (2): 273- 285 doi: 10.1016/j.cell.2017.09.021
21	LOUANDRE C , EZZOUKHRY Z , GODIN C et al. Iron-dependent cell death of hepatocellular carcinoma cells exposed to sorafenib[J]. Int J Cancer, 2013, 133 (7): 1732- 1742 doi: 10.1002/ijc.28159
22	LOUANDRE C , MARCQ I , BOUHLAL H et al. The retinoblastoma (Rb) protein regulates ferroptosis induced by sorafenib in human hepatocellular carcinoma cells[J]. Cancer Lett, 2015, 356 (2 Pt B): 971- 977 doi: 10.1016/j.canlet.2014.11.014
23	SUN X , OU Z , CHEN R et al. Activation of the p62-Keap1-NRF2 pathway protects against ferroptosis in hepatocellular carcinoma cells[J]. Hepatology, 2016, 63 (1): 173- 184 doi: 10.1002/hep.28251
24	SUZUKI T , MOTOHASHI H , YAMAMOTO M . Toward clinical application of the Keap1-Nrf2 pathway[J]. Trends Pharmacol Sci, 2013, 34 (6): 340- 346 doi: 10.1016/j.tips.2013.04.005
25	HARRISON P M , AROSIO P . The ferritins:molecular properties, iron storage function and cellular regulation[J]. Biochim Biophys Acta, 1996, 1275 (3): 161- 203 doi: 10.1016/0005-2728(96)00022-9
26	ARLT A , SEBENS S , KREBS S et al. Inhibition of the Nrf2 transcription factor by the alkaloid trigonelline renders pancreatic cancer cells more susceptible to apoptosis through decreased proteasomal gene expression and proteasome activity[J]. Oncogene, 2013, 32 (40): 4825- 4835 doi: 10.1038/onc.2012.493
27	KINOSHITA H , OKABE H , BEPPU T et al. Cystine/glutamic acid transporter is a novel marker for predicting poor survival in patients with hepatocellular carcinoma[J]. Oncol Rep, 2013, 29 (2): 685- 689 doi: 10.3892/or.2012.2162
28	SUN X , NIU X , CHEN R et al. Metallothionein-1G facilitates sorafenib resistance through inhibition of ferroptosis[J]. Hepatology, 2016, 64 (2): 488- 500 doi: 10.1002/hep.28574
29	EFFERTH T , DUNSTAN H , SAUERBREY A et al. The anti-malarial artesunate is also active against cancer[J]. Int J Oncol, 2001, 18 (4): 767- 773 doi: 10.3892/ijo.18.4.767
30	ELING N , REUTER L , HAZIN J et al. Identification of artesunate as a specific activator of ferroptosis in pancreatic cancer cells[J]. Oncoscience, 2015, 2 (5): 517- 532 doi: 10.18632/oncoscience.160
31	YAMAGUCHI Y , KASUKABE T , KUMAKURA S . Piperlongumine rapidly induces the death of human pancreatic cancer cells mainly through the induction of ferroptosis[J]. Int J Oncol, 2018, 52 (3): 1011- 1022 doi: 10.3892/ijo.2018.4259
32	YANG W S , SRIRAMARATNAM R , WELSCH M E et al. Regulation of ferroptotic cancer cell death by GPX4[J]. Cell, 2014, 156 (1-2): 317- 331 doi: 10.1016/j.cell.2013.12.010
33	ZOU Y , PALTE M J , DEIK A A et al. HIF-2α drives an intrinsic vulnerability to ferroptosis in clear cell renal cell carcinoma[J]. BioRxiv, 2018, doi: 10.1101/388041
34	WU J , MINIKES A M , GAO M et al. Intercellular interaction dictates cancer cell ferroptosis via NF2-YAP signalling[J]. Nature, 2019, 572 (7769): 402- 406 doi: 10.1038/s41586-019-1426-6
35	YANG W H , DING C C , SUN T et al. The hippo pathway effector TAZ regulates ferroptosis in renal cell carcinoma[J]. Cell Rep, 2019, 28 (10): 2501- 2508 doi: 10.1016/j.celrep.2019.07.107
36	MA S , HENSON E S , CHEN Y et al. Ferroptosis is induced following siramesine and lapatinib treatment of breast cancer cells[J]. Cell Death Dis, 2016, 7:e2307 doi: 10.1038/cddis.2016.208
37	HASEGAWA M , TAKAHASHI H , RAJABI H et al. Functional interactions of the cystine/glutamate antiporter, CD44v and MUC1-C oncoprotein in triple-negative breast cancer cells[J]. Oncotarget, 2016, 7 (11): 11756- 11769 doi: 10.18632/oncotarget.7598
38	TIMMERMAN L A , HOLTON T , YUNEVA M et al. Glutamine sensitivity analysis identifies the xCT antiporter as a common triple-negative breast tumor therapeutic target[J]. Cancer Cell, 2013, 24 (4): 450- 465 doi: 10.1016/j.ccr.2013.08.020
39	LANZARDO S , CONTI L , ROOKE R et al. Immunotargeting of antigen xCT attenuates stem-like cell behavior and metastatic progression in breast cancer[J]. Cancer Res, 2016, 76 (1): 62- 72 doi: 10.1158/0008-5472.CAN-15-1208
40	HABASHY H O , POWE D G , STAKA C M et al. Transferrin receptor (CD71) is a marker of poor prognosis in breast cancer and can predict response to tamoxifen[J]. Breast Cancer Res Treat, 2010, 119 (2): 283- 293 doi: 10.1007/s10549-009-0345-x
41	TONIK S E , SHINDELMAN J E , SUSSMAN H H . Transferrin receptor is inversely correlated with estrogen receptor in breast cancer[J]. Breast Cancer Res Treat, 1986, 7 (2): 71- 76 doi: 10.1007/bf01806791
42	YUAN H , LI X , ZHANG X et al. CISD1 inhibits ferroptosis by protection against mitochondrial lipid peroxidation[J]. Biochem Biophys Res Commun, 2016, 478 (2): 838- 844 doi: 10.1016/j.bbrc.2016.08.034
43	CHEN W C , WANG C Y , HUNG Y H et al. Systematic analysis of gene expression alterations and clinical outcomes for long-chain acyl-coenzyme a synthetase family in cancer[J]. PLoS One, 2016, 11 (5): e0155660 doi: 10.1371/journal.pone.0155660
44	HABIB E , LINHER-MELVILLE K , LIN H X et al. Expression of xCT and activity of system xc(-) are regulated by NRF2 in human breast cancer cells in response to oxidative stress[J]. Redox Biol, 2015, 5:33- 42 doi: 10.1016/j.redox.2015.03.003
45	LI T , KON N , JIANG L et al. Tumor suppression in the absence of p53-mediated cell-cycle arrest, apoptosis, and senescence[J]. Cell, 2012, 149 (6): 1269- 1283 doi: 10.1016/j.cell.2012.04.026
46	JIANG L , KON N , LI T et al. Ferroptosis as a p53-mediated activity during tumour suppression[J]. Nature, 2015, 520 (7545): 57- 62 doi: 10.1038/nature14344
47	WANG S J , LI D , OU Y et al. Acetylation is crucial for p53-mediated ferroptosis and tumor suppression[J]. Cell Rep, 2016, 17 (2): 366- 373 doi: 10.1016/j.celrep.2016.09.022
48	JENNIS M , KUNG C P , BASU S et al. An African-specific polymorphism in the TP53 gene impairs p53 tumor suppressor function in a mouse model[J]. Genes Dev, 2016, 30 (8): 918- 930 doi: 10.1101/gad.275891.115
49	XIE Y , ZHU S , SONG X et al. The tumor suppressor p53 limits ferroptosis by blocking DPP4 activity[J]. Cell Rep, 2017, 20 (7): 1692- 1704 doi: 10.1016/j.celrep.2017.07.055
50	MA Q . Role of nrf2 in oxidative stress and toxicity[J]. Annu Rev Pharmacol Toxicol, 2013, 53:401- 426 doi: 10.1146/annurev-pharmtox-011112-140320
51	WANG X J , SUN Z , VILLENEUVE N F et al. Nrf2 enhances resistance of cancer cells to chemotherapeutic drugs, the dark side of Nrf2[J]. Carcinogenesis, 2008, 29 (6): 1235- 1243 doi: 10.1093/carcin/bgn095
52	YUAN H , LI X , ZHANG X et al. Identification of ACSL4 as a biomarker and contributor of ferroptosis[J]. Biochem Biophys Res Commun, 2016, 478 (3): 1338- 1343 doi: 10.1016/j.bbrc.2016.08.124
53	RADLOWSKI E C , JOHNSON R W . Perinatal iron deficiency and neurocognitive development[J]. Front Hum Neurosci, 2013, 7:585 doi: 10.3389/fnhum.2013.00585
54	BELAIDI A A , BUSH A I . Iron neurochemistry in Alzheimer's disease and Parkinson's disease:targets for therapeutics[J]. J Neurochem, 2016, 139 (Suppl 1): 179- 197 doi: 10.1111/jnc.13425
55	WEILAND A , WANG Y , WU W et al. Ferroptosis and its role in diverse brain diseases[J]. Mol Neurobiol, 2019, 56 (7): 4880- 4893 doi: 10.1007/s12035-018-1403-3
56	AYTON S , FAUX N G , BUSH A I et al. Ferritin levels in the cerebrospinal fluid predict Alzheimer's disease outcomes and are regulated by APOE[J]. Nat Commun, 2015, 6:6760 doi: 10.1038/ncomms7760
57	HAMBRIGHT W S , FONSECA R S , CHEN L et al. Ablation of ferroptosis regulator glutathione peroxidase 4 in forebrain neurons promotes cognitive impairment and neurodegeneration[J]. Redox Biol, 2017, 12:8- 17 doi: 10.1016/j.redox.2017.01.021
58	ZHANG Y H , WANG D W , XU S F et al. α-Lipoic acid improves abnormal behavior by mitigation of oxidative stress, inflammation, ferroptosis, and tauopathy in P301S Tau transgenic mice[J]. Redox Biol, 2018, 14:535- 548 doi: 10.1016/j.redox.2017.11.001
59	DO VAN B , GOUEL F , JONNEAUX A et al. Ferroptosis, a newly characterized form of cell death in Parkinson's disease that is regulated by PKC[J]. Neurobiol Dis, 2016, 94:169- 178 doi: 10.1016/j.nbd.2016.05.011
60	GOUEL F , DO VAN B , CHOU M L et al. The protective effect of human platelet lysate in models of neurodegenerative disease:involvement of the Akt and MEK pathways[J]. J Tissue Eng Regen Med, 2017, 11 (11): 3236- 3240 doi: 10.1002/term.2222
61	CUI Z , ZHONG Z , YANG Y et al. Ferrous iron induces Nrf2 expression in mouse brain astrocytes to prevent neurotoxicity[J]. J Biochem Mol Toxicol, 2016, 30 (8): 396- 403 doi: 10.1002/jbt.21803
62	ISHII T , WARABI E , MANN G E . Circadian control of BDNF-mediated Nrf2 activation in astrocytes protects dopaminergic neurons from ferroptosis[J]. Free Radic Biol Med, 2019, 133:169- 178 doi: 10.1016/j.freeradbiomed.2018.09.002
63	CODAZZI F , PELIZZONI I , ZACCHETTI D et al. Iron entry in neurons and astrocytes:a link with synaptic activity[J]. Front Mol Neurosci, 2015, 8:18 doi: 10.3389/fnmol.2015.00018
64	BUSH A I , CURTAIN C C . Twenty years of metallo-neurobiology:where to now?[J]. Eur Biophys J, 2008, 37 (3): 241- 245 doi: 10.1007/s00249-007-0228-1
65	CONNOR J R , SNYDER B S , BEARD J L et al. Regional distribution of iron and iron-regulatory proteins in the brain in aging and Alzheimer's disease[J]. J Neurosci Res, 1992, 31 (2): 327- 335 doi: 10.1002/jnr.490310214
66	LOVELL M A , ROBERTSON J D , TEESDALE W J et al. Copper, iron and zinc in Alzheimer's disease senile plaques[J]. J Neurol Sci, 1998, 158 (1): 47- 52 doi: 10.1016/s0022-510x(98)00092-6
67	BILGIC B , PFEFFERBAUM A , ROHLFING T et al. MRI estimates of brain iron concentration in normal aging using quantitative susceptibility mapping[J]. Neuroimage, 2012, 59 (3): 2625- 2635 doi: 10.1016/j.neuroimage.2011.08.077
68	HAMBRIGHT W S , FONSECA R S , CHEN L et al. Ablation of ferroptosis regulator glutathione peroxidase 4 in forebrain neurons promotes cognitive impairment and neurodegeneration[J]. Redox Biol, 2017, 12:8- 17 doi: 10.1016/j.redox.2017.01.021
69	KHANDELWAL P J , HERMAN A M , MOUSSA C E . Inflammation in the early stages of neurodegenerative pathology[J]. J Neuroimmunol, 2011, 238 (1-2): 1- 11 doi: 10.1016/j.jneuroim.2011.07.002
70	RAINA A K , HOCHMAN A , ZHU X et al. Abortive apoptosis in Alzheimer's disease[J]. Acta Neuropathol, 2001, 101 (4): 305- 310 doi: 10.1007/s004010100378
71	RAEFSKY S M , FURMAN R , MILNE G et al. Deuterated polyunsaturated fatty acids reduce brain lipid peroxidation and hippocampal amyloid beta-peptide levels, without discernable behavioral effects in an APP/PS1 mutant transgenic mouse model of Alzheimer's disease[J]. Neurobiol Aging, 2018, 66:165- 176 doi: 10.1016/j.neurobiolaging.2018.02.024
72	YANG W S , KIM K J , GASCHLER M M et al. Peroxidation of polyunsaturated fatty acids by lipoxygenases drives ferroptosis[J]. Proc Natl Acad Sci U S A, 2016, 113 (34): E4966- E4975 doi: 10.1073/pnas.1603244113
73	DEXTER D T , WELLS F R , AGID F et al. Increased nigral iron content in postmortem parkinsonian brain[J]. Lancet, 1987, 2 (8569): 1219- 1220 doi: 10.1016/s0140-6736(87)91361-4
74	DEXTER D T , WELLS F R , LEES A J et al. Increased nigral iron content and alterations in other metal ions occurring in brain in Parkinson's disease[J]. J Neurochem, 1989, 52 (6): 1830- 1836 doi: 10.1111/j.1471-4159.1989.tb07264.x
75	AYTON S , LEI P , DUCE J A et al. Ceruloplasmin dysfunction and therapeutic potential for Parkinson disease[J]. Ann Neurol, 2013, 73 (4): 554- 559 doi: 10.1002/ana.23817
76	BOLL M C , SOTELO J , OTERO E et al. Reduced ferroxidase activity in the cerebrospinal fluid from patients with Parkinson's disease[J]. Neurosci Lett, 1999, 265 (3): 155- 158 doi: 10.1016/s0304-3940(99)00221-9
77	OLIVIERI S , CONTI A , IANNACCONE S et al. Ceruloplasmin oxidation, a feature of Parkinson's disease CSF, inhibits ferroxidase activity and promotes cellular iron retention[J]. J Neurosci, 2011, 31 (50): 18568- 18577 doi: 10.1523/JNEUROSCI.3768-11.2011
78	SALAZAR J , MENA N , HUNOT S et al. Divalent metal transporter 1(DMT1) contributes to neurodegeneration in animal models of Parkinson's disease[J]. Proc Natl Acad Sci U S A, 2008, 105 (47): 18578- 18583 doi: 10.1073/pnas.0804373105
79	FAUCHEUX B A , MARTIN M E , BEAUMONT C et al. Lack of up-regulation of ferritin is associated with sustained iron regulatory protein-1 binding activity in the substantia nigra of patients with Parkinson's disease[J]. J Neurochem, 2002, 83 (2): 320- 330 doi: 10.1046/j.1471-4159.2002.01118.x
80	LEI P , AYTON S , APPUKUTTAN A T et al. Clioquinol rescues Parkinsonism and dementia phenotypes of the tau knockout mouse[J]. Neurobiol Dis, 2015, 81:168- 175 doi: 10.1016/j.nbd.2015.03.015
81	LEI P , AYTON S , FINKELSTEIN D I et al. Tau protein:relevance to Parkinson's disease[J]. Int J Biochem Cell Biol, 2010, 42 (11): 1775- 1778 doi: 10.1016/j.biocel.2010.07.016
82	LEI P , AYTON S , MOON S et al. Motor and cognitive deficits in aged tau knockout mice in two background strains[J]. Mol Neurodegener, 2014, 9:29 doi: 10.1186/1750-1326-9-29
83	SIAN J , DEXTER D T , LEES A J et al. Alterations in glutathione levels in Parkinson's disease and other neurodegenerative disorders affecting basal ganglia[J]. Ann Neurol, 1994, 36 (3): 348- 355 doi: 10.1002/ana.410360305
84	LEI P , AYTON S , FINKELSTEIN D I et al. Tau deficiency induces parkinsonism with dementia by impairing APP-mediated iron export[J]. Nat Med, 2012, 18 (2): 291- 295 doi: 10.1038/nm.2613
85	DEVOS D , MOREAU C , DEVEDJIAN J C et al. Targeting chelatable iron as a therapeutic modality in parkinson's disease[J]. Antioxid Redox Signal, 2014, 21 (2): 195- 210 doi: 10.1089/ars.2013.5593
86	COLES L D , TUITE P J , ?Z G et al. Repeated-dose oral n-acetylcysteine in Parkinson's disease:pharmacokinetics and effect on brain glutathione and oxidative stress[J]. J Clin Pharmacol, 2018, 58 (2): 158- 167 doi: 10.1002/jcph.1008
87	PARK S W , KIM S H , PARK K H et al. Preventive effect of antioxidants in MPTP-induced mouse model of Parkinson's disease[J]. Neurosci Lett, 2004, 363 (3): 243- 246 doi: 10.1016/j.neulet.2004.03.072
88	PERRY T L , YONG V W , CLAVIER R M et al. Partial protection from the dopaminergic neurotoxin N-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine by four different antioxidants in the mouse[J]. Neurosci Lett, 1985, 60 (2): 109- 114 doi: 10.1016/0304-3940(85)90229-0
89	MONTI D A , ZABRECKY G , KREMENS D et al. N-acetyl cysteine may support dopamine neurons in Parkinson's disease:preliminary clinical and cell line data[J]. PLoS One, 2016, 11 (6): e0157602 doi: 10.1371/journal.pone.0157602
90	GAJOWIAK A , STYS' A , STARZYN'SKI R R et al. Misregulation of iron homeostasis in amyotrophic lateral sclerosis[J]. Postepy Hig Med Dosw (Online), 2016, 70 (0): 709- 721 doi: 10.5604/17322693.1208036
91	MOREAU C , DANEL V , DEVEDJIAN J C et al. Could conservative iron chelation lead to neuroprotection in amyotrophic lateral sclerosis?[J]. Antioxid Redox Signal, 2018, 29 (8): 742- 748 doi: 10.1089/ars.2017.7493
92	VEYRAT-DUREBEX C , CORCIA P , MUCHA A et al. Iron metabolism disturbance in a French cohort of ALS patients[J]. Biomed Res Int, 2014, 2014:485723 doi: 10.1155/2014/485723
93	CHOI I Y , LEE P , STATLAND J et al. Reduction in cerebral antioxidant, glutathione (GSH), in patients with ALS:A preliminary study (P6.105)[J]. Neurology, 2015, 84 (14 Supplement):
94	SIMPSON E P , HENRY Y K , HENKEL J S et al. Increased lipid peroxidation in sera of ALS patients:a potential biomarker of disease burden[J]. Neurology, 2004, 62 (10): 1758- 1765 doi: 10.1212/wnl.62.10.1758
95	GAO M , MONIAN P , QUADRI N et al. Glutaminolysis and transferrin regulate ferroptosis[J]. Mol Cell, 2015, 59 (2): 298- 308 doi: 10.1016/j.molcel.2015.06.011
96	FANG X , WANG H , HAN D et al. Ferroptosis as a target for protection against cardiomyopathy[J]. Proc Natl Acad Sci U S A, 2019, 116 (7): 2672- 2680 doi: 10.1073/pnas.1821022116
97	LI W , FENG G , GAUTHIER J M et al. Ferroptotic cell death and TLR4/Trif signaling initiate neutrophil recruitment after heart transplantation[J]. J Clin Invest, 2019, 129 (6): 2293- 2304 doi: 10.1172/JCI126428
98	SPEER R E , KARUPPAGOUNDER S S , BASSO M et al. Hypoxia-inducible factor prolyl hydroxylases as targets for neuroprotection by "antioxidant" metal chelators:From ferroptosis to stroke[J]. Free Radic Biol Med, 2013, 62:26- 36 doi: 10.1016/j.freeradbiomed.2013.01.026
99	TUO Q Z , LEI P , JACKMAN K A et al. Tau-mediated iron export prevents ferroptotic damage after ischemic stroke[J]. Mol Psychiatry, 2017, 22 (11): 1520- 1530 doi: 10.1038/mp.2017.171
100	CHANG C F , CHO S , WANG J . (-)-Epicatechin protects hemorrhagic brain via synergistic Nrf2 pathways[J]. Ann Clin Transl Neurol, 2014, 1 (4): 258- 271 doi: 10.1002/acn3.54
101	LI Q , HAN X , LAN X et al. Inhibition of neuronal ferroptosis protects hemorrhagic brain[J]. JCI Insight, 2017, 2 (7): e90777 doi: 10.1172/jci.insight.90777
102	ZILLE M , KARUPPAGOUNDER S S , CHEN Y et al. Neuronal death after hemorrhagic stroke in vitro and in vivo shares features of ferroptosis and necroptosis[J]. Stroke, 2017, 48 (4): 1033- 1043 doi: 10.1161/STROKEAHA.116.015609
103	ZHANG Z , WU Y , YUAN S et al. Glutathione peroxidase 4 participates in secondary brain injury through mediating ferroptosis in a rat model of intracerebral hemorrhage[J]. Brain Res, 2018, 1701:112- 125 doi: 10.1016/j.brainres.2018.09.012
104	CADENAS S . ROS and redox signaling in myocardial ischemia-reperfusion injury and cardioprotection[J]. Free Radic Biol Med, 2018, 117:76- 89 doi: 10.1016/j.freeradbiomed.2018.01.024
105	DAS D K , ENGELMAN R M , LIU X et al. Oxygen-derived free radicals and hemolysis during open heart surgery[J]. Mol Cell Biochem, 1992, 111 (1-2): 77- 86 doi: 10.1007/bf00229577
106	MEERSON F Z , KAGAN V E , YUP K et al. The role of lipid peroxidation in pathogenesis of ischemic damage and the antioxidant protection of the heart[J]. Basic Res Cardiol, 1982, 77 (5): 465- 485 doi: 10.1007/bf01907940
107	LINKERMANN A , SKOUTA R , HIMMERKUS N et al. Synchronized renal tubular cell death involves ferroptosis[J]. Proc Natl Acad Sci U S A, 2014, 111 (47): 16836- 16841 doi: 10.1073/pnas.1415518111
108	FRIEDMANN ANGELI J P , SCHNEIDER M , PRONETH B et al. Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice[J]. Nat Cell Biol, 2014, 16 (12): 1180- 1191 doi: 10.1038/ncb3064
109	LU L , WU W , YAN J et al. Adriamycin-induced autophagic cardiomyocyte death plays a pathogenic role in a rat model of heart failure[J]. Int J Cardiol, 2009, 134 (1): 82- 90 doi: 10.1016/j.ijcard.2008.01.043
110	TAKEMURA G , KANOH M , MINATOGUCHI S et al. Cardiomyocyte apoptosis in the failing heart——a critical review from definition and classification of cell death[J]. Int J Cardiol, 2013, 167 (6): 2373- 2386 doi: 10.1016/j.ijcard.2013.01.163
111	ZHANG T , ZHANG Y , CUI M et al. CaMKII is a RIP3 substrate mediating ischemia- and oxidative stress-induced myocardial necroptosis[J]. Nat Med, 2016, 22 (2): 175- 182 doi: 10.1038/nm.4017
112	DIETRICH R B , BRADLEY WG J R . Iron accumulation in the basal ganglia following severe ischemic-anoxic insults in children[J]. Radiology, 1988, 168 (1): 203- 206 doi: 10.1148/radiology.168.1.3380958
113	LIPSCOMB D C , GORMAN L G , TRAYSTMAN R J et al. Low molecular weight iron in cerebral ischemic acidosis in vivo[J]. Stroke, 1998, 29 (2): 487- 492 doi: 10.1161/01.str.29.2.487
114	DING H , YAN C Z , SHI H et al. Hepcidin is involved in iron regulation in the ischemic brain[J]. PLoS One, 2011, 6 (9): e25324 doi: 10.1371/journal.pone.0025324
115	PARK U J , LEE Y A , WON S M et al. Blood-derived iron mediates free radical production and neuronal death in the hippocampal CA1 area following transient forebrain ischemia in rat[J]. Acta Neuropathol, 2011, 121 (4): 459- 473 doi: 10.1007/s00401-010-0785-8
116	PATT A , HORESH I R , BERGER E M et al. Iron depletion or chelation reduces ischemia/reperfusion-induced edema in gerbil brains[J]. J Pediatr Surg, 1990, 25 (2): 224- 227 doi: 10.1016/0022-3468(90)90407-z
117	DAVIS S , HELFAER M A , TRAYSTMAN R J et al. Parallel antioxidant and antiexcitotoxic therapy improves outcome after incomplete global cerebral ischemia in dogs[J]. Stroke, 1997, 28 (1): 198- 204 doi: 10.1161/01.str.28.1.198
118	PRASS K , RUSCHER K , KARSCH M et al. Desferrioxamine induces delayed tolerance against cerebral ischemia in vivo and in vitro[J]. J Cereb Blood Flow Metab, 2002, 22 (5): 520- 525 doi: 10.1097/00004647-200205000-00003
119	HANSON L R , ROEYTENBERG A , MARTINEZ P M et al. Intranasal deferoxamine provides increased brain exposure and significant protection in rat ischemic stroke[J]. J Pharmacol Exp Ther, 2009, 330 (3): 679- 686 doi: 10.1124/jpet.108.149807
120	HANDA P , THOMAS S , MORGAN-STEVENSON V et al. Iron alters macrophage polarization status and leads to steatohepatitis and fibrogenesis[J]. J Leukoc Biol, 2019, 105 (5): 1015- 1026 doi: 10.1002/JLB.3A0318-108R
121	WOODHOO A , IRUARRIZAGA-LEJARRETA M , BERAZA N et al. Human antigen R contributes to hepatic stellate cell activation and liver fibrosis[J]. Hepatology, 2012, 56 (5): 1870- 1882 doi: 10.1002/hep.25828
122	ZHANG Z , YAO Z , WANG L et al. Activation of ferritinophagy is required for the RNA-binding protein ELAVL1/HuR to regulate ferroptosis in hepatic stellate cells[J]. Autophagy, 2018, 14 (12): 2083- 2103 doi: 10.1080/15548627.2018.1503146
123	ATARASHI M , IZAWA T , KUWAMURA M et al. The role of iron overload in the progression of nonalcoholic steatohepatitis (NASH)[J]. Nihon Yakurigaku Zasshi, 2019, 154 (2): 61- 65 doi: 10.1254/fpj.154.61
124	TSURUSAKI S , TSUCHIYA Y , KOUMURA T et al. Hepatic ferroptosis plays an important role as the trigger for initiating inflammation in nonalcoholic steatohepatitis[J]. Cell Death Dis, 2019, 10 (6): 449 doi: 10.1038/s41419-019-1678-y
125	WANG W , GREEN M , CHOI J E et al. CD8+ T cells regulate tumour ferroptosis during cancer immunotherapy[J]. Nature, 2019, 569 (7755): 270- 274 doi: 10.1038/s41586-019-1170-y
126	方学贤, 蔡昭贤, 王浩 et al. 铁过载及铁死亡在心脏疾病中的研究进展[J]. 科学通报, 2019, 64 (28-29): 2974- 2987 FANG Xuexian , CAI Zhaoxian , WANG Hao et al. Role of iron overload and ferroptosis in heart disease[J]. Chinese Science Bulletin, 2019, 64 (28-29): 2974- 2987 doi: 10.1360/TB-2019-0242
127	ZHENG D W , LEI Q , ZHU J Y et al. Switching apoptosis to ferroptosis:metal-organic network for high-efficiency anticancer therapy[J]. Nano Lett, 2017, 17 (1): 284- 291 doi: 10.1021/acs.nanolett.6b04060

[1]	杨泽然,张欣,马杰,金丽,何徐军. 大肠癌患者肿瘤相关血管中胰岛素受体表达及其与肿瘤组织病理学特征的关系[J]. 浙江大学学报（医学版）, 2020, 49(6): 725-731.
[2]	朱慧琦,应可净. 组织因子与肿瘤患者静脉血栓栓塞[J]. 浙江大学学报（医学版）, 2020, 49(6): 772-778.
[3]	林翠翠,陈正云,王春艳,席咏梅. 基于脂质组学的子宫内膜异位症生物标志物研究进展[J]. 浙江大学学报（医学版）, 2020, 49(6): 779-784.
[4]	李梦瑶,刘盼,柯越海,张雪. 放射性肺损伤中巨噬细胞作用机制的研究进展[J]. 浙江大学学报（医学版）, 2020, 49(5): 623-628.
[5]	韩雪,蒋国军,石巧娟. 降血糖药对内皮祖细胞作用的研究进展[J]. 浙江大学学报（医学版）, 2020, 49(5): 629-636.
[6]	段润平,许叶圣,郑利斌,姚玉峰. 病毒感染性眼病病原学诊断的研究进展[J]. 浙江大学学报（医学版）, 2020, 49(5): 644-650.
[7]	吴唯,徐键. 正五聚蛋白3在多囊卵巢综合征中的作用研究进展[J]. 浙江大学学报（医学版）, 2020, 49(5): 637-643.
[8]	徐清霖,楼国东,王甜甜,张力三. 发作性睡病的药物治疗进展[J]. 浙江大学学报（医学版）, 2020, 49(4): 419-424.
[9]	蒋沛然,王志萍. 模式生物神经轴突再生的研究进展[J]. 浙江大学学报（医学版）, 2020, 49(4): 500-507.
[10]	刘露,黄国俊,白宏震,汤谷平. 叶酸修饰壳聚糖纳米载药胶束的制备及其体外抗肿瘤效果研究[J]. 浙江大学学报（医学版）, 2020, 49(3): 364-374.
[11]	俞卿, 熊秀芳, 孙毅. 靶向Cullin-RING E3泛素连接酶的抗肿瘤策略及相关药物研发进展[J]. 浙江大学学报（医学版）, 2020, 49(1): 1-19.
[12]	段玲艳,尹香菊,孟红恩,方学贤,闵军霞,王福俤. 铁稳态代谢表观遗传调控机制的研究进展[J]. 浙江大学学报（医学版）, 2020, 49(1): 58-70.
[13]	李艾,张添源,高建青. 间充质干细胞的肿瘤归巢特性及其肿瘤靶向治疗应用研究进展[J]. 浙江大学学报（医学版）, 2020, 49(1): 20-34.
[14]	黄耀凭,杨凤,周天华,谢珊珊. Hippo信号通路及其在消化系统肿瘤中的作用研究进展[J]. 浙江大学学报（医学版）, 2020, 49(1): 35-43.
[15]	钟文,楼燕,邱宸阳,李栋林,张鸿坤. 髂静脉支架植入术后药物治疗策略研究进展[J]. 浙江大学学报（医学版）, 2020, 49(1): 131-136.

Viewed

Full text

Abstract

Cited

Shared

Discussed