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Ferroptosis: From regulation of lipid peroxidation to the treatment of diseases

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Abstract

Ferroptosis is a regulated cell death mainly manifested by iron-dependent lipid peroxide accumulation. The leading cause of ferroptosis is the imbalance of intracellular oxidative systems (e.g., LOXs, POR, ROS) and antioxidant systems (e.g., GSH/GPx4, CoQ10/FSP1, BH4/GCH1), which is regulated by a complex network. In the past decade, this metabolic network has been continuously refined, and the links with various pathophysiological processes have been gradually established. Apoptosis has been regarded as the only form of regulated cell death for a long time, and the application of chemotherapeutic drugs to induce apoptosis of cancer cells is the mainstream method. However, studies have reported that cancer cells’ key features are resistance to apoptosis and chemotherapeutics. For high proliferation, cancer cells often have very active lipid metabolism and iron metabolism, which pave the way for ferroptosis. Interestingly, researchers found that drug-resistant or highly aggressive cancer cells are more prone to ferroptosis. Therefore, ferroptosis may be a potential strategy to eliminate cancer cells. In addition, links between ferroptosis and other diseases, such as neurological disorders and ischemia–reperfusion injury, have also been found. Understanding these diseases from the perspective of ferroptosis may provide new insights into clinical treatment. Herein, the metabolic processes in ferroptosis are reviewed, and the potential mechanisms and targets of ferroptosis in different diseases are summarized.

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Abbreviations

GPx4:

Glutathione peroxidase 4

ACSL4:

Acyl-CoA synthetase long chain family member 4

LPCAT3:

Lysophosphatidylcholine acyltransferase 3

LOXs:

Lipoxygenases

GSH:

Glutathione

PUFA:

Polyunsaturated fatty acid

MUFA:

Monounsaturated fatty acid

PUFA-PLs:

Polyunsaturated phospholipids

AA:

Arachidonic acid

AdA:

Adrenoyl acid

NADPH:

Nicotinamide adenine dinucleotide phosphate

HMGB1:

High mobility group box 1

VDAC2/3:

Voltage dependent anion channel-3/2

NOX:

Nitrogen oxides

TFR1:

Transferrin receptor 1

LIP:

Labile iron pool

CARS:

Cysteinyl tRNA synthetase

SLC7A11:

Solute carrier family 7 member 11

HSPB1:

Heat shock protein family B (small) member 1

Nrf2:

Nuclear factor erythroid 2-related factor 2

ROS:

Reactive oxygen species

NCOA4:

Nuclear receptor coactivator 4

DMT1:

Divalent metal transporter 1

FPN1:

Ferroportin 1

OA:

Oleic acid

PA:

Palmitic acid

LA:

Linoleic acid

ALOXs:

Arachidonic acid lipoxygenases

G6PDH:

Glucose 6-phosphate dehydrogenase

GDH:

Glutamate dehydrogenase

PGDH:

6-Phosphogluconate dehydrogenase

SCP2:

Sterol carrier protein 2

DHA:

Docosahexaenoic acid

POR:

Cytochrome P450 reductase

CoQ10:

Coenzyme Q10

AMPK:

AMP-activated protein kinase

ACC:

Acetyl-CoA carboxylase

LKB1:

Serine/threonine-protein kinase 1

GLS:

Glutaminase

α-KG:

α-Ketoglutaric acid

OTUB1:

Ubiquitin aldehyde binding 1

GSSG:

Oxidized glutathione

AIFM2/FSP1:

Apoptosis inducing factor mitochondria associated 2

ESCRT-III:

Endosomal sorting complex

BH4 :

Tetrahydrobiopterin

GCH1:

GTP-cyclohydrolase 1

EMT:

Epithelial-mesenchymal transition

DAMPs:

Damage-associated molecular pattern

IRI:

Ischemia-reperfusion injury

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Funding

This work was supported by the National Natural Science Foundation of China (82001887 to JW and 81900105 to ZW), in part by a horizontal project of Sun Yat-sen University (K21-75110–007), Shenzhen Science and Technology Program (JCYJ20210324115003009), and the Guangdong Basic and Applied Basic Research Foundation (2019A1515110326).

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  1. School of Pharmaceutical Sciences, Shenzhen Campus of Sun Yat-Sen University, Shenzhen, 518107, China

    Yonghui Lv, Meiying Wu & Junqing Wang

  2. Department of Pathology, The Eighth Affiliated Hospital, Sun Yat-Sen University, Shenzhen, 518033, China

    Zhe Wang

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Y.L. and J.W. wrote the main manuscript text, Z.W. prepared figures, and M.W. prepared tables. All authors reviewed the manuscript.

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Correspondence to Meiying Wu, Zhe Wang or Junqing Wang.

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Lv, Y., Wu, M., Wang, Z. et al. Ferroptosis: From regulation of lipid peroxidation to the treatment of diseases. Cell Biol Toxicol 39, 827–851 (2023). https://doi.org/10.1007/s10565-022-09778-2

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