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Review
. 2020 Mar 17:11:239.
doi: 10.3389/fphar.2020.00239. eCollection 2020.

Ferroptosis and Its Potential Role in Human Diseases

Chu Han  1   2 , Yuanyuan Liu  1   2 , Rongji Dai  3 , Nafissa Ismail  4   5 , Weijun Su  6 , Bo Li  1   2   3
Affiliations
Review

Ferroptosis and Its Potential Role in Human Diseases

Chu Han et al. Front Pharmacol. .

Abstract

Ferroptosis is a novel regulated cell death pattern discovered when studying the mechanism of erastin-killing RAS mutant tumor cells in 2012. It is an iron-dependent programmed cell death pathway mainly caused by an increased redox imbalance but with distinct biological and morphology characteristics when compared to other known cell death patterns. Ferroptosis is associated with various diseases including acute kidney injury, cancer, and cardiovascular, neurodegenerative, and hepatic diseases. Moreover, activation or inhibition of ferroptosis using a variety of ferroptosis initiators and inhibitors can modulate disease progression in animal models. In this review, we provide a comprehensive analysis of the characteristics of ferroptosis, its initiators and inhibitors, and the potential role of its main metabolic pathways in the treatment and prevention of various diseased states. We end the review with the current knowledge gaps in this area to provide direction for future research on ferroptosis.

Keywords: degenerative diseases; ferroptosis; pharmacology design; reactive oxygen species; signaling pathways.

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Figures

Figure 1
Figure 1
The free radical chain mechanism of lipid peroxidation.
Figure 2
Figure 2
Metabolic pathways affecting ferroptosis. The brown box contains three currently known pathways: Lipid Oxidation Metabolism、Glutathione Metabolic Pathway、Iron Metabolic Pathway and some related mechanisms of action. Several pharmacological inducer have been shown to induce ferroptosis (eg erastin、RSL3). A variety of ferroptosis inhibitors inhibit iron death from various pathways (eg Fer-1、lip-1、BP、DFO). AA, Arachidonic acid; ACSL4, Acyl-CoA synthetase long-chain family member 4; AKR1C1-3, Aldo-keto reductase family 1 member C1-3; Atg5, autophagy-related 5; Atg7, autophagy-related 7; CISD1, CDGSH iron domain 1; Cys, cysteine; Cys2, cystine; DFO, Deferoxamine; DMT1, Divalent metal transporter 1; Fer-1, Ferrostatin-1; Glu, Glutamate; Gly, glycine; GPX4, Glutathione peroxidase 4; G6PD, Glucose-6-phosphate dehydrogenase; GSH, Glutathione; GSSH, Glutathione disulfide; IREB2, Iron-responsive element-binding protein 2; Lip-1, Liproxstatin-1; LOX, Lipoxygenase; LPCAT3, Lysophosphatidylcholine acyltransferase 3; NADPH, Nicotinamide adenine dinucleotide phosphate; NRF2, Nuclear factor erythroid 2-related factor 2; PE, Phosphatidylethanolamine; PGD, 6-Phosphogluconate dehydrogenase; PKC, Protein kinase C; RSL3, Ras-selective lethal small molecules 3; SLC7A11, Solute carrier family 7 member 11.
Figure 3
Figure 3
Fenton reaction.
Figure 4
Figure 4
Structures of Ac-MtFluNox, Lyso-RhoNox, and ER-SiRhoNox.
See this image and copyright information in PMC

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