Ferroptosis and Its Potential Role in the Nervous System Diseases

Figures & data

Figure 1 The major induced pathways of ferroptosis. The induced pathways of ferroptosis, including iron metabolism disorder, lipid peroxidation, and failure of antioxidant systems, are summarized. Iron metabolism and lipid metabolism disorders lead to LPO accumulation, the failure of antioxidant systems leads to LPO not being removed in time, and the above process ultimately induces ferroptosis.

Abbreviations: Tf, transferrin; TfR1, transferrin receptor 1; Fe²⁺, ferrous iron; Fe³⁺, ferric iron; LIP, labile iron pool; FPN, ferroportin; FT, ferritin; NCOA4, nuclear receptor coactivator 4; HO•, hydroxyl radicals; ROS, reactive oxygen species; LOXs, lipoxygenases; PL, phospholipid; PL•, phospholipid radical; PLOO•, phospholipid peroxyl radical; PLOOH, phospholipid hydroperoxide; PUFA, polyunsaturated fatty acid; GPX4, glutathione peroxidase 4; GSH, glutathione; GS-SG, oxidized glutathione; GCL, glutamate-cysteine ligase; Glu, glutamic acid; CMA, chaperone-mediated autophagy; FSP1, ferroptosis suppressor protein 1; CoQ10, coenzyme Q10; DHODH, dihydroorotate dehydrogenase; DHO, dihydroorotate; OA, orotate; iFSP1, inhibitor of ferroptosis suppressor protein 1.

Table 1 Potential Regulatory Pathways of Ferroptosis

Regulatory Pathways		Key Mechanisms	Effect on Ferroptosis	References
microRNA	miR-124	Down-regulate the expression of FPN1	Induce	[40]
	miR-214	Down-regulate the expression of TFR1 Inhibit p53 expression and thus upregulate SLC7A11	Inhibit	[66]
	miR-212-5p	Down-regulate the expression of PTGS2	Inhibit	[67]
Histone Modification		BAP1 inhibits SLC7A11 expression via H2Aub deacetylation, which in turn inhibits GSH production	Induce	[69,70]
Nrf2		Promote SLC7A11 expression and increase GSH production Upregulate MRP1 thereby preventing GSH export Upregulate FTH1 expression	Inhibit	[78,79,81]
P53		Inhibit SLC7A11 expression Upregulate SAT1, which in turn increase ALOX15 expression	Induce	[84,85]
		Inhibit DPP4 Upregulate p21 expression to slow GSH depletion	Inhibit	[57,86]
AMPK		Phosphorylate and destroy ACC thereby inhibiting fat synthesis	Inhibit	[90]
		Phosphorylate and activate BECN1 to inhibit the activity of system Xc-	Induce	[92]
Autophagy		NCOA4-mediated ferritinophagy promotes iron accumulation in ferroptosis HSP90-mediated CMA decreases GPX4 content	Induce	[34,96]

Abbreviations: FPN 1, ferroportin 1; TFR1, transferrin receptor 1; PTGS2, prostaglandin-endoperoxide synthase 2; BAP1, BRCA1-associated protein 1; H2Aub, histone 2A ubiquitination; GSH, glutathione; Nrf2, nuclear factor E2-related factor 2; MRP1, multidrug resistance protein 1; FTH1, ferritin heavy chain 1; ALOX15, arachidonate 15-lipoxygenase; DPP4, dipeptidyl-peptidase-4; AMPK, AMP-activated protein kinase; ACC, Acetyl-CoA carboxylase; BECN1, beclin 1; NCOA4, nuclear receptor coactivator 4; HSP90, heat shock protein 90; CMA, chaperone-mediated autophagy; GPX4, glutathione peroxidase 4.

Table 2 Key Mechanisms and Regulators of Ferroptosis in Nervous System Diseases

Diseases		Key Mechanisms	Regulators	References
AD		Iron overload Decrease FPN expression Decrease SLC7A11, GSH, and GPX4 protein levels Increase NCOA4 protein levels	Inhibitor: γ-glutamylcysteine Deferoxamine LA	[119,123,128–131,133]
PD		Iron overload Ferritinophagy and increased DMT1 expression Decrease SLC7A11 and GSH protein levels Decrease CoQ10 protein levels	Inhibitor: Deferiprone Clioquinol	[136,137,139,141–143]
HD		Iron overload Decrease GSH protein level	Inhibitor: Fer-1	[18,148,150]
Epilepsy		Iron overload Increase extracellular glutamate level Decrease GSH and GPX4 protein levels	Inhibitor: Fer-1 EPI-743	[153–155]
Gliomas		Increase intracellular glutamate level Decrease ACSL4 expression Increase GPX4 and FSP1 expression	Inducer: PAB IONPs	[37,158,159,161,162]
Strokes	Ischemic Strokes	Iron overload Decrease SLC7A11, GSH and GPX4 protein levels Decrease CoQ10 protein levels	Inhibitor: Fer-1 Lip-1	[19,168,170,172]
	Hemorrhagic Strokes	Iron overload Increase ROS level	Inhibitor: Fer-1 PIH N-acetylcysteine PGE2	[174,176,178–180]
TBI		Iron and ROS accumulation Decrease GPX4 activity Increase COX2, 15-LOX and ACSL4 protein levels	Inhibitor: Fer-1 Melatonin Polydatin	[20,183–185]

Abbreviations: AD, Alzheimer’s disease; FPN, ferroportin; GSH, glutathione; GPX4, glutathione peroxidase 4; NCOA4, nuclear receptor coactivator 4; LA, alpha-lipoic acid; PD, Parkinson’s disease; CoQ10, coenzyme Q10; HD, Huntington’s disease; Fer-1, ferrostatin-1; EPI-743, vatiquinone; Lip-1, liproxstatin-1; ROS, reactive oxygen species; PIH, pyridoxal isonicotinoyl hydrazine; PGE2, prostaglandin E2; 12/15-LOX, 12/15-lipoxygenase; ACSL4, acyl-CoA synthetase long-chain family member 4; FSP1, ferroptosis suppressor protein 1; PAB, pseudolaric acid B; IONPs, iron oxide nanoparticles; TBI, traumatic brain injury; COX2, cytochrome c oxidase subunit 2.

Bao WD, Zhou XT, Zhou LT, et al. Targeting miR-124/Ferroportin signaling ameliorated neuronal cell death through inhibiting apoptosis and ferroptosis in aged intracerebral hemorrhage murine model. Aging Cell. 2020;19(11):e13235. doi:10.1111/acel.13235

 PubMed Web of Science ®Google Scholar

Lu J, Xu F, Lu H. LncRNA PVT1 regulates ferroptosis through miR-214-mediated TFR1 and p53. Life Sci. 2020;260:118305. doi:10.1016/j.lfs.2020.118305

 PubMed Web of Science ®Google Scholar

Xiao X, Jiang Y, Liang W, et al. miR-212-5p attenuates ferroptotic neuronal death after traumatic brain injury by targeting Ptgs2. Mol Brain. 2019;12(1):78. doi:10.1186/s13041-019-0501-0

 PubMed Web of Science ®Google Scholar

Zhang Y, Shi J, Liu X, et al. BAP1 links metabolic regulation of ferroptosis to tumour suppression. Nat Cell Biol. 2018;20(10):1181–1192. doi:10.1038/s41556-018-0178-0

 PubMed Web of Science ®Google Scholar

Zhang X, Du L, Qiao Y, et al. Ferroptosis is governed by differential regulation of transcription in liver cancer. Redox Biol. 2019;24:101211. doi:10.1016/j.redox.2019.101211

 PubMed Web of Science ®Google Scholar

Carpi-Santos R, Calaza KC. Alterations in system xc(-) expression in the retina of type 1 diabetic rats and the role of Nrf2. Mol Neurobiol. 2018;55(10):7941–7948.

 PubMed Web of Science ®Google Scholar

Cao JY, Poddar A, Magtanong L, et al. A genome-wide haploid genetic screen identifies regulators of glutathione abundance and ferroptosis sensitivity. Cell Rep. 2019;26(6):1544–1556 e8.

 PubMed Web of Science ®Google Scholar

Liu Z, Lv X, Song E, et al. Fostered Nrf2 expression antagonizes iron overload and glutathione depletion to promote resistance of neuron-like cells to ferroptosis. Toxicol Appl Pharmacol. 2020;407:115241.

 PubMed Web of Science ®Google Scholar

Zhao H, Li X, Yang L, et al. Isorhynchophylline relieves ferroptosis-induced nerve damage after intracerebral hemorrhage via miR-122-5p/TP53/SLC7A11 Pathway. Neurochem Res. 2021;46(8):1981–1994.

 PubMed Web of Science ®Google Scholar

Ou Y, Wang SJ, Li D, et al. Activation of SAT1 engages polyamine metabolism with p53-mediated ferroptotic responses. Proc Natl Acad Sci U S A. 2016;113(44):E6806–E6812.

 PubMed Web of Science ®Google Scholar

Xie Y, Zhu S, Song X, et al. The tumor suppressor p53 limits ferroptosis by blocking DPP4 activity. Cell Rep. 2017;20(7):1692–1704. doi:10.1016/j.celrep.2017.07.055

 PubMed Web of Science ®Google Scholar

Tarangelo A, Magtanong L, Bieging-Rolett KT, et al. p53 suppresses metabolic stress-induced ferroptosis in cancer cells. Cell Rep. 2018;22(3):569–575.

 PubMed Web of Science ®Google Scholar

Lee H, Zandkarimi F, Zhang Y, et al. Energy-stress-mediated AMPK activation inhibits ferroptosis. Nat Cell Biol. 2020;22(2):225–234.

 PubMed Web of Science ®Google Scholar

Song X, Zhu S, Chen P, et al. AMPK-mediated BECN1 phosphorylation promotes ferroptosis by directly blocking system Xc(-) activity. Curr Biol. 2018;28(15):2388–2399 e5.

 PubMed Web of Science ®Google Scholar

Zhang Y, Kong Y, Ma Y, et al. Loss of COPZ1 induces NCOA4 mediated autophagy and ferroptosis in glioblastoma cell lines. Oncogene. 2021;40(8):1425–1439. doi:10.1038/s41388-020-01622-3

 PubMed Web of Science ®Google Scholar

Wu Z, Geng Y, Lu X, et al. Chaperone-mediated autophagy is involved in the execution of ferroptosis. Proc Natl Acad Sci U S A. 2019;116(8):2996–3005.

 PubMed Web of Science ®Google Scholar

Smith MA, Harris PL, Sayre LM, et al. Iron accumulation in Alzheimer disease is a source of redox-generated free radicals. Proc Natl Acad Sci U S A. 1997;94(18):9866–9868. doi:10.1073/pnas.94.18.9866

 PubMed Web of Science ®Google Scholar

Bao WD, Pang P, Zhou XT, et al. Loss of ferroportin induces memory impairment by promoting ferroptosis in Alzheimer’s disease. Cell Death Differ. 2021;28(5):1548–1562. doi:10.1038/s41418-020-00685-9

 PubMed Web of Science ®Google Scholar

Zhu ZY, Liu YD, Gong Y, et al. Mitochondrial aldehyde dehydrogenase (ALDH2) rescues cardiac contractile dysfunction in an APP/PS1 murine model of Alzheimer’s disease via inhibition of ACSL4-dependent ferroptosis. Acta Pharmacol Sin. 2022;43(1):39–49.

 PubMed Web of Science ®Google Scholar

Tian Y, Lu J, Hao X, et al. FTH1 inhibits ferroptosis through ferritinophagy in the 6-OHDA model of Parkinson’s disease. Neurotherapeutics. 2020;17(4):1796–1812. doi:10.1007/s13311-020-00929-z

 PubMed Web of Science ®Google Scholar

Bi M, Du X, Jiao Q, et al. Alpha-synuclein regulates iron homeostasis via preventing Parkin-mediated DMT1 ubiquitylation in Parkinson’s disease models. ACS Chem Neurosci. 2020;11(11):1682–1691. doi:10.1021/acschemneuro.0c00196

 PubMed Web of Science ®Google Scholar

Devos D, Moreau C, Devedjian JC, et al. Targeting chelatable iron as a therapeutic modality in Parkinson’s disease. Antioxid Redox Signal. 2014;21(2):195–210. doi:10.1089/ars.2013.5593

 PubMed Web of Science ®Google Scholar

Dominguez JF, Ng AC, Poudel G, et al. Iron accumulation in the basal ganglia in Huntington’s disease: cross-sectional data from the IMAGE-HD study. J Neurol Neurosurg Psychiatry. 2016;87(5):545–549. doi:10.1136/jnnp-2014-310183

 PubMed Web of Science ®Google Scholar

Kumar P, Kalonia H, Kumar A. Nitric oxide mechanism in the protective effect of antidepressants against 3-nitropropionic acid-induced cognitive deficit, glutathione and mitochondrial alterations in animal model of Huntington’s disease. Behav Pharmacol. 2010;21(3):217–230. doi:10.1097/FBP.0b013e32833a5bf4

 PubMed Web of Science ®Google Scholar

Skouta R, Dixon SJ, Wang J, et al. Ferrostatins inhibit oxidative lipid damage and cell death in diverse disease models. J Am Chem Soc. 2014;136(12):4551–4556. doi:10.1021/ja411006a

 PubMed Web of Science ®Google Scholar

Wang Z, Ding Y, Wang X, et al. Pseudolaric acid B triggers ferroptosis in glioma cells via activation of Nox4 and inhibition of xCT. Cancer Lett. 2018;428:21–33. doi:10.1016/j.canlet.2018.04.021

 PubMed Web of Science ®Google Scholar

Obara-Michlewska M, Szeliga M. Targeting glutamine addiction in gliomas. Cancers (Basel). 2020;12(2):310. doi:10.3390/cancers12020310

 PubMed Web of Science ®Google Scholar

Cheng J, Fan YQ, Liu BH, et al. ACSL4 suppresses glioma cells proliferation via activating ferroptosis. Oncol Rep. 2020;43(1):147–158. doi:10.3892/or.2019.7419

 PubMed Web of Science ®Google Scholar

Huang R, Dong R, Wang N, et al. Adaptive changes allow targeting of ferroptosis for glioma treatment. Cell Mol Neurobiol. 2021. doi:10.1007/s10571-021-01092-5

 Web of Science ®Google Scholar

Zhang Y, Fu X, Jia J, et al. Glioblastoma therapy using codelivery of cisplatin and glutathione peroxidase targeting siRNA from iron oxide nanoparticles. ACS Appl Mater Interfaces. 2020;12(39):43408–43421. doi:10.1021/acsami.0c12042

 PubMed Web of Science ®Google Scholar

Tuo QZ, Zhang ST, Lei P. Mechanisms of neuronal cell death in ischemic stroke and their therapeutic implications. Med Res Rev. 2022;42(1):259–305.

 PubMed Web of Science ®Google Scholar

Tuo QZ, Lei P, Jackman KA, et al. Tau-mediated iron export prevents ferroptotic damage after ischemic stroke. Mol Psychiatry. 2017;22(11):1520–1530. doi:10.1038/mp.2017.171

 PubMed Web of Science ®Google Scholar

Liu Y, Min JW, Feng S, et al. Therapeutic role of a cysteine precursor, OTC, in ischemic stroke is mediated by improved proteostasis in mice. Transl Stroke Res. 2020;11(1):147–160. doi:10.1007/s12975-019-00707-w

 PubMed Web of Science ®Google Scholar

Nasoohi S, Simani L, Khodagholi F, et al. Coenzyme Q10 supplementation improves acute outcomes of stroke in rats pretreated with atorvastatin. Nutr Neurosci. 2019;22(4):264–272. doi:10.1080/1028415X.2017.1376928

 PubMed Web of Science ®Google Scholar

Fang Y, Gao S, Wang X, et al. Programmed cell deaths and potential crosstalk with blood-brain barrier dysfunction after hemorrhagic stroke. Front Cell Neurosci. 2020;14:68. doi:10.3389/fncel.2020.00068

 PubMed Web of Science ®Google Scholar

Li Q, Han X, Lan X, et al. Inhibition of neuronal ferroptosis protects hemorrhagic brain. JCI Insight. 2017;2(7):e90777. doi:10.1172/jci.insight.90777

 PubMed Web of Science ®Google Scholar

Xie BS, Wang YQ, Lin Y, et al. Inhibition of ferroptosis attenuates tissue damage and improves long-term outcomes after traumatic brain injury in mice. CNS Neurosci Ther. 2019;25(4):465–475. doi:10.1111/cns.13069

 PubMed Web of Science ®Google Scholar