Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2021 Mar 2;10(3):184.
doi: 10.3390/biology10030184.

Lipid Metabolism and Ferroptosis

Ji-Yoon Lee  1 , Won Kon Kim  1   2 , Kwang-Hee Bae  1   2 , Sang Chul Lee  1 , Eun-Woo Lee  1
Affiliations
Review

Lipid Metabolism and Ferroptosis

Ji-Yoon Lee et al. Biology (Basel). .

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.

Keywords: GPX4; ferroptosis; lipid peroxidation; lipoxygenase; polyunsaturated fatty acids.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
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 2
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.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. D’Autréaux B., Toledano M.B. ROS as Signalling Molecules: Mechanisms That Generate Specificity in ROS Homeostasis. Nat. Rev. Mol. Cell Biol. 2007;8:813–824. doi: 10.1038/nrm2256. - DOI - PubMed
    1. Moloney J.N., Cotter T.G. ROS Signalling in the Biology of Cancer. Semin. Cell Dev. Biol. 2018;80:50–64. doi: 10.1016/j.semcdb.2017.05.023. - DOI - PubMed
    1. He L., He T., Farrar S., Ji L., Liu T., Ma X. Antioxidants Maintain Cellular Redox Homeostasis by Elimination of Reactive Oxygen Species. Cell. Physiol. Biochem. 2017;44:532–553. doi: 10.1159/000485089. - DOI - PubMed
    1. Chen Z., Chua C.C., Gao J., Chua K.-W., Ho Y.-S., Hamdy R.C., Chua B.H.L. Prevention of Ischemia/Reperfusion-Induced Cardiac Apoptosis and Injury by Melatonin Is Independent of Glutathione Peroxdiase 1. J. Pineal Res. 2009;46:235–241. doi: 10.1111/j.1600-079X.2008.00654.x. - DOI - PMC - PubMed
    1. Ardanaz N., Yang X.-P., Cifuentes M.E., Haurani M.J., Jackson K.W., Liao T.-D., Carretero O.A., Pagano P.J. Lack of Glutathione Peroxidase 1 Accelerates Cardiac-Specific Hypertrophy and Dysfunction in Angiotensin II Hypertension. Hypertension. 2010;55:116–123. doi: 10.1161/HYPERTENSIONAHA.109.135715. - DOI - PMC - PubMed

LinkOut - more resources