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Review
. 2023 Dec;33(12):1077-1087.
doi: 10.1016/j.tcb.2023.05.003. Epub 2023 Jul 3.

Regulation of ferroptosis by lipid metabolism

Lauren E Pope  1 , Scott J Dixon  2
Affiliations
Review

Regulation of ferroptosis by lipid metabolism

Lauren E Pope et al. Trends Cell Biol. 2023 Dec.

Abstract

Ferroptosis is an iron-dependent lethal mechanism that can be activated in disease and is a proposed target for cancer therapy. Ferroptosis is defined by the overwhelming accumulation of membrane lipid peroxides. Ferroptotic lipid peroxidation is initiated on internal membranes and then appears at the plasma membrane, triggering lethal ion imbalances and membrane permeabilization. Sensitivity to ferroptosis is governed by the levels of peroxidizable polyunsaturated lipids and associated lipid metabolic enzymes. A different network of enzymes and endogenous metabolites restrains lipid peroxidation by interfering with the initiation or propagation of this process. This emerging understanding is informing new approaches to treat disease by modulating lipid metabolism to enhance or inhibit ferroptosis.

Keywords: MUFA; PUFA; cell death; ferroptosis; lipid; metabolism.

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Conflict of interest statement

Declaration of interests S.J.D. is a cofounder of Prothegen and a member of the scientific advisory board for Hillstream Biopharma. S.J.D. holds patents related to ferroptosis. L.E.P. has no interests to declare.

Figures

Figure 1.
Figure 1.. Endogenous mechanisms limiting lipid peroxide accumulation.
Cells possess several mechanisms to limit lipid peroxidation and thereby prevent the onset of ferroptosis. Glutathione peroxidase 4 (GPX4) uses reduced glutathione (GSH) to convert potentially toxic lipid peroxides to non-toxic lipid alcohols. Alpha-tocopherol is a natural lipophilic radical trapping antioxidant (RTA). Ferroptosis suppressor protein 1 (FSP1), which can be anchored at the plasma membrane via a myristoyl group, uses NAD(P)H to generate reduced version of both ubiquinone (CoQ10) and vitamin K, which can then act as RTAs at the plasma membrane. GTP-cyclohydrolase 1 (GCH1) helps defend against lipid peroxidation via the synthesis of the metabolite tetrahydrobiopterin (BH2), which can be reduced to the (BH4) by dihydrofolate reductase. Mitochondrial dihydroorotate dehydrogenase (DHODH) may also help prevent the spread of lipid peroxides from the mitochondria to the plasma membrane, although this remains controversial. StAR related lipid transfer domain containing 7 (STARD7) helps transport CoQ10 from the mitochondria to the plasma membrane. Exogenous monounsaturated fatty acids (MUFAs) are used by cells to create MUFA-containing phospholipids (MUFA-PLs) which are less susceptible to peroxidation than PUFA-containing PLs.
Figure 2.
Figure 2.. Lipid metabolism in ferroptosis.
Free fatty acids can be taken up into cells by diffusion or via transporters such as CD36 and fatty acid transport proteins (FATP). Some lipids, such as monounsaturated fatty acids (MUFAs), can be synthesized de novo within cells, first through the incorporation of malonyl-CoA and acetyl-CoA to palmitate, then through elongation and subsequent desaturation by stearoyl-CoA desaturase-1 (SCD1). MUFAs are preferentially activated by acyl-CoA synthetase long chain family member 3 (ACSL3), which then allows for insertion of the MUFA into phospholipids which can go on to inhibit lipid peroxidation. Meanwhile, PUFAs taken up from the extracellular environment are activated by ACSL4. Phospholipids can be remodeled by enzymes that remove or add PUFAs from/to membrane phospholipids, such as phospholipase A2 group VI (PLA2G6, iPLA2β), lysophosphatidylcholine acyltransferase 3 (LPCAT3) and 1-acylglycerol-3-phosphate O-acyltransferase 3 (AGPAT3), which in turn alters the oxidizability of phospholipids in the membrane. Tumor protein D52 (TPD52) is a lipid droplet synthesis enzyme that promotes resistance to ferroptosis; one hypothesis is that it promotes sequestration of PUFAs into lipid droplets and away from membrane phospholipids.
Figure 3.
Figure 3.. Cell biology of lipid peroxide accumulation.
Lipid peroxides accumulate at many sites within the cell, including the endoplasmic reticulum, the lysosome, and the mitochondria. The accumulation of lipid peroxides at the endoplasmic reticulum (ER) may be especially important for the initiation of ferroptosis, although it remains to be established if spreading of signals from the ER to the plasma membrane is necessary for ferroptosis, or whether lipid peroxides merely accumulate on the ER first.
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