Deeper insight into ferroptosis: association with Alzheimer’s, Parkinson’s disease, and brain tumors and their possible treatment by nanomaterials induced ferroptosis

Figures & data

Table 1. Major milestones in ferroptosis research in last two deacdes.

Year	Milestones		References
	Molecules	Roles
2003	Erastin	Mutant RAS selective compound	[22]
2007	Vitamin-E	Antioxidant	[22]
	VDAC2/3	Mitochondrial porins	[22]
	Mutated RAS	Oncogene	[22]
2008	TFRC	Iron transporter	[22]
	RSL3 RSL5	Mutant RAS selective compounds	[22]
	DFO	Iron chelator	[22]
2010	ML162 ML210	Mutant RAS selective compounds	[23–25]
2012	SLC7A11	Cystine/glutamate transporter. Coined the term ferroptosis	[22]
	Ferrostatin-1	Ferroptosis inhibitor	[22]
	Sulfasalazine	SLC7A11 inhibitor	[22]
2014	GPX4	Phospholipidhydroperoxidase	[22]
	Sorafenib	SLC7A11 inhibitor	[22]
	Liporoxststin-1	Ferroptosis inhibitor	[26]
	Zileuton	ALOX inhibitor	[27]
2015	SLC38A1	Glutamine transporter	[28–30]
	HSPB1	Heat shock protein	[31]
	TP53 (mutated tumor suppressor gene)	Transcription factor	[32]
	Artesunate	Antimalarial agent	[33]
	IKE	SLC7A11 inhibitor	[22]
2016	ACSL4	Lipid biosynthesis	[34]
	FIN56	GPX4 and coenzyme Q10 (CoQ10) inhibitor	[22]
	NEF2L2	Transcription factor	[35]
	NCOA4	Ferritinophagy	[28–30]
	ALOXs	Lipoxygenases	[22]
	FINO2	Inactivation of GPX4 & oxidation of Fe	[36]
	Statins	HMG-CoA reductase	[22]
2017	BH3-interacting domain death agonist (BID)	BCL2 family	[37]
	ZEB1	EMT-activator	[38]
	ITGA6-ITGB4	Cell adhesion	[39]
	Hemoglobin Hemin	Iron-containing protein	[40]
	Rosiglitazone	ACSL4 inhibitor	[41]
2018	BAP1	Epigenetic regulation	[42]
	NECTIN4	Cell clustering	[43]
	CTSB	Lysosomal cell death	[31]
	Withaferin A	Increase iron	[44]
	LOX-Block-1	ALOX inhibitor	[45]
2019	YAP1 NF2 WWTR1	Cell contact	[46]
	Apoptosis-inducing factor mitochondria-associated 2 (AIFM2)	CoQ10 production	[47]
	Cyst(e)inase	Cysteine depletion	[48]
	Ferroptocide	Thioredoxin inhibitor	[49]
	iFSP	AIFM2 inhibitor	[50]
2020	PEX10 PEX3	Peroxisome	[51]
	GCH1	BH4 production	[52]
	CHMP5 CHMP6	ESCRT-III membrane repair	[31]
	POR (p450 reductase)	Phospholipid peroxidation	[53]
	Zalcitabine	Antiretroviral agent	[31]
	Quercetin	Antioxidant agent	[54]
2023	Piezo1 & TRP channels	Cooperatively promote ferroptosis by facilitating cation flux	[55]

Figure 1. Mechanism pathways of ferroptosis adapted from [16].

Figure 2. Cystine/glutamic acid-mediated ferroptosis pathway.

Figure 3. Ferroptosis mechanism pathways adapted from [14].

Table 2. Inhibitors and inducers of ferroptosis.

Role	Mode of action	Small molecules	Nanoparticles	References
Inducer	Fe homeostasis	FAC	Fe-based NMs like IONPs, Fe-organic NPs, FePt	[116]
	NRF2 inhibition	Trigonelline, brusatol	–	[117]
	LiPr	FINO2	WS2, Fe-organic NP, FePt & MoS2	[36]
	Inhibition system xc −	Sulfasalazine; glutamate, erastin, PE, sorafenib, IKE erastin analogs	–	[118]
	GSH depletion	Cystine/cysteine deprivation, acetaminophen, cisplatin, BSO, DPI2, cysteinase	Zinc oxide NPs	[119]
	Suppression GPX4	(1S,3R)-RSL3; ML162, FIN56; DPI family members	Fe-free NMs, (WS2, MoS2 & Copper NPs)	[120]
	CoQ10 biosynthesis inhibition	Statins	–	[121]
Inhibitor	System xc− activation	β-mercaptoethanol, Cycloheximide	–	[122]
	Fe chelators	DFX, CPX, DFO, DFP	–	[116]
	Selenoprotein increment	Se	–	[116]
	Reduction of LiPr	Vit-E, BHT, BHA, Fer-1, AA-861, zileuton; vildagliptin, alogliptin, trolox, tocotrienols, Lip-1; CoQ10, idebenone; XJB-5-131; deferoxamine, cyclipirox, deferiprone; CDC, baicalein, PD-146176 and linagliptin	CPS	[123]
	GPX4 upgradation	Dopamine	–	[124]

Figure 4. Hallmarks features of ferroptosis.

Figure 5. Various markers of ferroptosis.

Figure 6. Mechanisms of NPs-induced ferroptosis. (a) Membrane impairment induced by NPs involving LiPr and inactivation of system xc-; (b) lysosome dysfunction induced by NPs including disruption of lysosomal membrane, alteration of acidic environment, modification of STEAP3 and DMT1 activities; and (c) mitochondrial damage induced by NPs including destruction of mitochondrial morphology and dysregulation of the mitochondrial antioxidant defense as well as iron dyshomeostasis.

Figure 7. Putative pathway for ferroptosis participates in neuroinflammation to NDDs reprinted from [16].

Figure 8. Signalling pathways of ferroptosis and associated NDDs.

Stockwell BR, Friedmann Angeli JP, Bayir H, et al. Ferroptosis: a regulated cell death nexus linking metabolism, redox biology, and disease. Cell. 2017;171:273–285. doi:10.1016/j.cell.2017.09.021

 PubMed Web of Science ®Google Scholar

Fan BY, Pang YL, Li WX, et al. Liproxstatin-1 is an effective inhibitor of oligodendrocyte ferroptosis induced by inhibition of glutathione peroxidase 4. Neural Regen Res. 2021;16:561–566. doi:10.4103/1673-5374.293157

 PubMed Web of Science ®Google Scholar

Hu W-M, Liu S-Q, Zhu K-F, et al. The ALOX5 inhibitor Zileuton regulates tumor-associated macrophage M2 polarization by JAK/STAT and inhibits pancreatic cancer invasion and metastasis. Int Immunopharmacol. 2023;121:110505. doi:10.1016/j.intimp.2023.110505

 PubMed Web of Science ®Google Scholar

Tang D, Kroemer G. Ferroptosis. Curr Biol. 2020;30:R1292–R1297. doi:10.1016/j.cub.2020.09.068

 PubMed Web of Science ®Google Scholar

Liu Y, Gu W. P53 in ferroptosis regulation: the new weapon for the old guardian. Cell Death Differ. 2022;29:895–910. doi:10.1038/s41418-022-00943-y

 PubMed Web of Science ®Google Scholar

Song Q, Peng S, Che F, et al. Artesunate induces ferroptosis via modulation of p38 and ERK signaling pathway in glioblastoma cells. J Pharmacol Sci. 2022;148:300–306. doi:10.1016/j.jphs.2022.01.007

 PubMed Web of Science ®Google Scholar

Doll S, Proneth B, Tyurina YY, et al. ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition. Nat Chem Biol. 2017;13:91–98. doi:10.1038/nchembio.2239

 PubMed Web of Science ®Google Scholar

Song X, Long D. Nrf2 and ferroptosis: a new research direction for neurodegenerative diseases. Front Neurosci. 2020;14. doi:10.3389/fnins.2020.00267

 Web of Science ®Google Scholar

Gaschler MM, Andia AA, Liu H, et al. FINO2 initiates ferroptosis through GPX4 inactivation and iron oxidation. Nat Chem Biol. 2018;14:507–515. doi:10.1038/s41589-018-0031-6

 PubMed Web of Science ®Google Scholar

Li W, Xiang Z, Xing Y, et al. Mitochondria bridge HIF signaling and ferroptosis blockage in acute kidney injury. Cell Death Dis. 2022;13:308. doi:10.1038/s41419-022-04770-4

 PubMed Web of Science ®Google Scholar

Lee J, You JH, Kim M-S, et al. Epigenetic reprogramming of epithelial-mesenchymal transition promotes ferroptosis of head and neck cancer. Redox Biol. 2020;37:101697. doi:10.1016/j.redox.2020.101697

 PubMed Web of Science ®Google Scholar

Zhou B, Liu J, Kang R, et al. Ferroptosis is a type of autophagy-dependent cell death. Semin Cancer Biol. 2020;66:89–100. doi:10.1016/j.semcancer.2019.03.002

 PubMed Web of Science ®Google Scholar

Zille M, Oses-Prieto JA, Savage SR, et al. Hemin-induced death models hemorrhagic stroke and is a variant of classical neuronal ferroptosis. J Neurosci. 2022;42:2065–2079. doi:10.1523/JNEUROSCI.0923-20.2021

 PubMed Web of Science ®Google Scholar

Yang X-D, Yang Y-Y. Ferroptosis as a novel therapeutic target for diabetes and its complications. Front Endocrinol. 2022;13:853822.

 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;20:1181–1192. doi:10.1038/s41556-018-0178-0

 PubMed Web of Science ®Google Scholar

Brown CW, Amante JJ, Mercurio AM. Cell clustering mediated by the adhesion protein PVRL4 is necessary for α6β4 integrin-promoted ferroptosis resistance in matrix-detached cells. J Biol Chem. 2018;293:12741–12748. doi:10.1074/jbc.RA118.003017

 PubMed Web of Science ®Google Scholar

Vanden BT, Linkermann A, Jouan-Lanhouet S, et al. Regulated necrosis: the expanding network of non-apoptotic cell death pathways. Nat Rev Mol Cell Biol. 2014;15:135–147. doi:10.1038/nrm3737

 PubMed Web of Science ®Google Scholar

Schnapp G, Neubauer H, Büttner FH, et al. A small-molecule inhibitor of lectin-like oxidized LDL receptor-1 acts by stabilizing an inactive receptor tetramer state. Commun Chem. 2020;3:75. doi:10.1038/s42004-020-0321-2

 PubMed Web of Science ®Google Scholar

Wu J, Minikes AM, Gao M, et al. Intercellular interaction dictates cancer cell ferroptosis via NF2–YAP signalling. Nature. 2019;572:402–406. doi:10.1038/s41586-019-1426-6

 PubMed Web of Science ®Google Scholar

Dai E, Zhang W, Cong D, et al. AIFM2 blocks ferroptosis independent of ubiquinol metabolism. Biochem Biophys Res Commun. 2020;523:966–971. doi:10.1016/j.bbrc.2020.01.066

 PubMed Web of Science ®Google Scholar

Poltorack CD, Dixon SJ. Understanding the role of cysteine in ferroptosis: progress & paradoxes. FEBS J. 2022;289:374–385. doi:10.1111/febs.15842

 PubMed Web of Science ®Google Scholar

Tang D, Chen X, Kang R, et al. Ferroptosis: molecular mechanisms and health implications. Cell Res. 2021;31:107–125. doi:10.1038/s41422-020-00441-1

 PubMed Web of Science ®Google Scholar

Xavier da Silva TN, Schulte C, Alves AN, et al. Molecular characterization of AIFM2/FSP1 inhibition by iFSP1-like molecules. Cell Death Dis. 2023;14:281. doi:10.1038/s41419-023-05787-z

 PubMed Web of Science ®Google Scholar

Tang D, Kroemer G. Peroxisome: the new player in ferroptosis. Signal Transduct Target Ther. 2020;5:273. doi:10.1038/s41392-020-00404-3

 PubMed Web of Science ®Google Scholar

Kraft VAN, Bezjian CT, Pfeiffer S, et al. GTP cyclohydrolase 1/tetrahydrobiopterin counteract ferroptosis through lipid remodeling. ACS Cent Sci. 2020;6:41–53. doi:10.1021/acscentsci.9b01063

 PubMed Web of Science ®Google Scholar

Koppula P, Zhuang L, Gan B. Cytochrome P450 reductase (POR) as a ferroptosis fuel. Protein Cell. 2021;12:675–679. doi:10.1007/s13238-021-00823-0

 PubMed Web of Science ®Google Scholar

Chen X, Xu S, Zhao C, et al. Role of TLR4/NADPH oxidase 4 pathway in promoting cell death through autophagy and ferroptosis during heart failure. Biochem Biophys Res Commun. 2019;516:37–43. doi:10.1016/j.bbrc.2019.06.015

 PubMed Web of Science ®Google Scholar

Hirata Y, Cai R, Volchuk A, et al. Lipid peroxidation increases membrane tension, piezo1 gating, and cation permeability to execute ferroptosis. Curr Biol. 2023;33:1282–1294.e5. doi:10.1016/j.cub.2023.02.060

 PubMed Web of Science ®Google Scholar

Cheng Y, Song Y, Chen H, et al. Ferroptosis mediated by lipid reactive oxygen species: a possible causal link of neuroinflammation to neurological disorders. Oxid Med Cell Longev. 2021;2021. doi:10.1155/2021/5005136

 Google Scholar

Reichert CO, de Freitas FA, Sampaio-Silva J, et al. Ferroptosis mechanisms involved in neurodegenerative diseases. Int J Mol Sci. 2020;21:1–27. doi:10.3390/ijms21228765

 Web of Science ®Google Scholar

Du Y, Guo Z. Recent progress in ferroptosis: inducers and inhibitors. Cell Death Discov. 2022;8. doi:10.1038/s41420-022-01297-7

 Web of Science ®Google Scholar

Zhang L, Zhang J, Jin Y, et al. Nrf2 Is a potential modulator for orchestrating iron homeostasis and redox balance in cancer cells. Front Cell Dev Biol. 2021;9:728172.

 PubMed Web of Science ®Google Scholar

Li F-J, Long H-Z, Zhou Z-W, et al. System Xc−/GSH/GPX4 axis: An important antioxidant system for the ferroptosis in drug-resistant solid tumor therapy. Front Pharmacol. 2022;13:910292.

 PubMed Web of Science ®Google Scholar

Li Y, Wang X, Huang Z, et al. CISD3 inhibition drives cystine-deprivation induced ferroptosis. Cell Death Dis. 2021;12. doi:10.1038/s41419-021-04128-2

 Web of Science ®Google Scholar

Sun Y, Berleth N, Wu W, et al. Fin56-induced ferroptosis is supported by autophagy-mediated GPX4 degradation and functions synergistically with mTOR inhibition to kill bladder cancer cells. Cell Death Dis. 2021;12. doi:10.1038/s41419-021-04306-2

 Web of Science ®Google Scholar

Wang D, Tang L, Zhang Y, et al. Regulatory pathways and drugs associated with ferroptosis in tumors. Cell Death Dis. 2022;13. doi:10.1038/s41419-022-04927-1

 Web of Science ®Google Scholar

Liu M, Zhu W, Pei D. System Xc−: a key regulatory target of ferroptosis in cancer. Invest New Drugs. 2021;39:1123–1131. doi:10.1007/s10637-021-01070-0

 PubMed Web of Science ®Google Scholar

Jin Y, Zhuang Y, Liu M, et al. Inhibiting ferroptosis: a novel approach for stroke therapeutics. Drug Discov Today. 2021;26:916–930. doi:10.1016/j.drudis.2020.12.020

 PubMed Web of Science ®Google Scholar

Sekhar KR, Hanna DN, Cyr S, et al. Glutathione peroxidase 4 inhibition induces ferroptosis and mTOR pathway suppression in thyroid cancer. Sci Rep. 2022;12. doi:10.1038/s41598-022-23906-2

 Web of Science ®Google Scholar

Data availability statement

All the data are present within the manuscript.