CoChat
Sign Up
Cited by 375Ferroptosis and cancer prognosisIron Metabolism and DisordersCancer, Lipids, and Metabolism

The DOI matches its Crossref record; 104 of the 113 references it cites were found in a registry or an index.

Lipid Metabolism and Ferroptosis

Open access
Lee, Ji-Yoon, Kim, Won Kon, Bae, Kwang-Hee, Lee, Sang Chul, Lee, Eun-Woo·2021·Biology
DOI 10.3390/biology10030184PMC PMC8000263
Open this paper in CoChat — free accountOpen PDF

Abstract

Ferroptosis is a type of iron-dependent regulated necrosis induced by lipid peroxidation that occurs in cellular membranes. Among the various lipids, polyunsaturated fatty acids (PUFAs) associated with several phospholipids, such as phosphatidylethanolamine (PE) and phosphatidylcholine (PC), are responsible for ferroptosis-inducing lipid peroxidation. Since the de novo synthesis of PUFAs is strongly restricted in mammals, cells take up essential fatty acids from the blood and lymph to produce a variety of PUFAs via PUFA biosynthesis pathways. Free PUFAs can be incorporated into the cellular membrane by several enzymes, such as ACLS4 and LPCAT3, and undergo lipid peroxidation through enzymatic and non-enzymatic mechanisms. These pathways are tightly regulated by various metabolic and signaling pathways. In this review, we summarize our current knowledge of how various lipid metabolic pathways are associated with lipid peroxidation and ferroptosis. Our review will provide insight into treatment strategies for ferroptosis-related diseases.

Overview

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.3390/biology10030184

Cites

104 of 104 references verified0 citation errors · 0 not checkable

Statistics

Figures

Figure 1 The ferroptosis signaling pathway. Polyunsaturated fatty acids (PUFAs) in membrane phospholipids undergo lipid peroxidation, which directly destroys the cellular membrane, thereby causing necrotic cell death via ferroptosis. Glutathione Peroxidase 4 (GPX4) reduces lipid peroxide to lipid alcohol by oxidizing glutathione (GSH), thereby protecting cells from ferroptosis under normal conditions. Inactivation of GPX4 or depletion of GSH therefore leads to massive lipid peroxidation and induces ferroptosis. Ferroptosis-inducing compounds (FINs) are categorized into two main groups: those that inhibit system xc−, thereby depleting GSH levels (class I FINs), and those that directly inhibit GPX4 (class II FINs). Among various membrane phospholipids, arachidonic acid (AA)- and adrenic acid (AdA)-containing phosphatidylethanolamine (PE) and phosphatidylcholine (PC) are the primary targets for lipid peroxidation. Acyl-CoA synthetase long-chain family member 4 (ACSL4) links free PUFAs to CoA, generating fatty acyl-CoA esters, which are eventually incorporated into PC/PE by lysophosphatidylcholine acyltransferase 3 (LPCAT3). PE-AA and PE-AdA can be oxidized by lipoxygenases (LOXs). LOX might require phosphatidylethanolamine-binding protein 1 (PEBP1) to induce lipid peroxidation on the membrane. In addition, other oxygenases, such as NADPH oxidases (NOXs) and cytochrome P450 oxidoreductase (POR), are known to contribute to lipid peroxidation. Lipid peroxidation is also mediated by nonenzymatic autoxidation, which is suggested to be the ultimate driver of ferroptotic cell death. In contrast, NO• reacts with lipid peroxyradicals, thereby attenuating lipid peroxidation and ferroptosis.
Figure 1 The ferroptosis signaling pathway. Polyunsaturated fatty acids (PUFAs) in membrane phospholipids undergo lipid peroxidation, which directly destroys the cellular membrane, thereby causing necrotic cell death via ferroptosis. Glutathione Peroxidase 4 (GPX4) reduces lipid peroxide to lipid alcohol by oxidizing glutathione (GSH), thereby protecting cells from ferroptosis under normal conditions. Inactivation of GPX4 or depletion of GSH therefore leads to massive lipid peroxidation and induces ferroptosis. Ferroptosis-inducing compounds (FINs) are categorized into two main groups: those that inhibit system xc−, thereby depleting GSH levels (class I FINs), and those that directly inhibit GPX4 (class II FINs). Among various membrane phospholipids, arachidonic acid (AA)- and adrenic acid (AdA)-containing phosphatidylethanolamine (PE) and phosphatidylcholine (PC) are the primary targets for lipid peroxidation. Acyl-CoA synthetase long-chain family member 4 (ACSL4) links free PUFAs to CoA, generating fatty acyl-CoA esters, which are eventually incorporated into PC/PE by lysophosphatidylcholine acyltransferase 3 (LPCAT3). PE-AA and PE-AdA can be oxidized by lipoxygenases (LOXs). LOX might require phosphatidylethanolamine-binding protein 1 (PEBP1) to induce lipid peroxidation on the membrane. In addition, other oxygenases, such as NADPH oxidases (NOXs) and cytochrome P450 oxidoreductase (POR), are known to contribute to lipid peroxidation. Lipid peroxidation is also mediated by nonenzymatic autoxidation, which is suggested to be the ultimate driver of ferroptotic cell death. In contrast, NO• reacts with lipid peroxyradicals, thereby attenuating lipid peroxidation and ferroptosis.CC BY · PubMed Central
Figure 2 Lipid metabolic pathways that regulate ferroptosis. (a) In cells, PUFAs can accumulate through the ω-6 de novo PUFA biosynthesis pathway and fatty acid transport pathways via fatty acid translocase (FAT/CD36), fatty acid transport protein (FATP) and fatty acid binding protein (FABP). Imported linoleic acid (LA) is metabolized by elongation of very long-chain fatty acid protein (ELOVL) and fatty acid desaturases (FADS) to synthesize AA and AdA, which are utilized to produce membrane phospholipids. (b) Additionally, AA can be directly imported and transported by FAT/CD36, FATP and FABP proteins. In particular, CD36 activates cytoplasmic phospholipase A2 (cPLA2), releasing AA from phospholipids. The intracellular pools of AA might be the critical checkpoint in ferroptosis and AA-mediated cellular signaling. (c) In contrast, monounsaturated fatty acid (MUFA), which is catalyzed from palmitate, a saturated fatty acid (SFA) by stearyl-CoA desaturase-1 (SCD1), is incorporated into phospholipids in an ACSL3-dependent manner, thereby interfering with the formation of PUFA-phospholipids and protecting cells from ferroptosis. Under glucose deprivation conditions, the depletion of ATPs activate the AMP-activated protein kinase (AMPK) pathway, which suppresses de novo lipogenesis by phosphorylating and inhibiting acetyl-CoA carboxylase (ACC). As a result, the levels of not only palmitate but also dihomo-γ-linolenic acid (DGLA) and AA are reduced upon glucose starvation, preventing ferroptosis. (d) The mevalonate pathway also provides several critical regulatory axes. Isopentenyl pyrophosphate (IPP) is required for the isopentenylation of selenocysteine-tRNA, leading to the synthesis of selenoproteins, including GPX4. Inhibition of HMG-CoA reductase (HMGCR) by statins might induce ferroptosis by inactivating GPX4. FIN56, a class III FIN, degrades GPX4 and activates squalene synthase (SQS). Activation of SQS results in the squalene depletion of coenzyme Q10 (CoQ10), contributing to ferroptosis. In contrast, inhibition of SQS leads to squalene depletion and facilitates ferroptosis in lymphoma, as squalene also possesses antiferroptotic activity.
Figure 2 Lipid metabolic pathways that regulate ferroptosis. (a) In cells, PUFAs can accumulate through the ω-6 de novo PUFA biosynthesis pathway and fatty acid transport pathways via fatty acid translocase (FAT/CD36), fatty acid transport protein (FATP) and fatty acid binding protein (FABP). Imported linoleic acid (LA) is metabolized by elongation of very long-chain fatty acid protein (ELOVL) and fatty acid desaturases (FADS) to synthesize AA and AdA, which are utilized to produce membrane phospholipids. (b) Additionally, AA can be directly imported and transported by FAT/CD36, FATP and FABP proteins. In particular, CD36 activates cytoplasmic phospholipase A2 (cPLA2), releasing AA from phospholipids. The intracellular pools of AA might be the critical checkpoint in ferroptosis and AA-mediated cellular signaling. (c) In contrast, monounsaturated fatty acid (MUFA), which is catalyzed from palmitate, a saturated fatty acid (SFA) by stearyl-CoA desaturase-1 (SCD1), is incorporated into phospholipids in an ACSL3-dependent manner, thereby interfering with the formation of PUFA-phospholipids and protecting cells from ferroptosis. Under glucose deprivation conditions, the depletion of ATPs activate the AMP-activated protein kinase (AMPK) pathway, which suppresses de novo lipogenesis by phosphorylating and inhibiting acetyl-CoA carboxylase (ACC). As a result, the levels of not only palmitate but also dihomo-γ-linolenic acid (DGLA) and AA are reduced upon glucose starvation, preventing ferroptosis. (d) The mevalonate pathway also provides several critical regulatory axes. Isopentenyl pyrophosphate (IPP) is required for the isopentenylation of selenocysteine-tRNA, leading to the synthesis of selenoproteins, including GPX4. Inhibition of HMG-CoA reductase (HMGCR) by statins might induce ferroptosis by inactivating GPX4. FIN56, a class III FIN, degrades GPX4 and activates squalene synthase (SQS). Activation of SQS results in the squalene depletion of coenzyme Q10 (CoQ10), contributing to ferroptosis. In contrast, inhibition of SQS leads to squalene depletion and facilitates ferroptosis in lymphoma, as squalene also possesses antiferroptotic activity.CC BY · PubMed Central

Verification

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Citations

Cites

Show all 113 references

Research works printed but not linked: 1

  1. Xu, S., Chaudhary, O., Rodríguez-Morales, P., Sun, X., Zappasodi, R., Xu, Z., Pinto, A.F.M., Williams, A., Chen, D., and Low, J.S. (2020). Oxidized Lipids and CD36-Mediated Lipid Peroxidation in CD8 T Cells Suppress Anti-Tumor Immune Responses. bioRxiv. · DOI

Cited by

Sorted by citations

Related

See all

Metadata

Authors
Lee, J.-Y., Kim, W. K., Bae, K.-H., Lee, S. C., & Lee, E.-W.
Affiliations
Korea Research Institute of Bioscience and Biotechnology (KR)
Corresponding author
  • Lee, Sang Chul
  • Lee, Eun-Woo
ORCID
Venue
Biology
Publisher
MDPI AG
Published
2021-03-02
Volume
10
Issue
3
Pages
184
ISSN
2079-7737 (ISSN-L)
DOI
10.3390/biology10030184
PMC
PMC8000263
OpenAlex
W3134191433
Cited by
374
References
113
Citations by year
2026: 58 · 2025: 103 · 2024: 96 · 2023: 69 · 2022: 38 · 2021: 10
FWCI
8.60
Type
journal article
Language
en
Open access
Licence
Locations
  • Biology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Korea Research Institute of Bioscience and Biotechnology (Research Initiative Progam)
  • National Research Foundation of Korea (NRF-2017M3A9G5083321, NRF-2019R1C1C1002831, NRF-2020R1A2C1006841)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Ferroptosis and cancer prognosis
  • Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
Keywords
ferroptosis, lipid metabolism, lipid peroxidation, polyunsaturated fatty acids, phosphatidylethanolamine, phosphatidylcholine, LPCAT3

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review