Since the ferroptosis was coined in 2012, it has attracted widespread attention. Most organ damage and degenerative diseases are caused by ferroptosis. Drug-resistant tumor cells, especially those in a mesenchymal state prone to metastasis, are highly susceptible to ferroptosis. Therefore, induction and inhibition of ferroptosis through pharmacological regulation have great potential in treating drug-resistant tumors, ischemic organ damage, and degenerative diseases related to extensive lipid peroxidation.
Fig.1 Ferroptosis has played important roles in multiple system diseases (Li, J., et al. 2020).
What is Ferroptosis?
Ferroptosis is a new type of iron-dependent programmed cell death discovered in recent years. It is induced by excessive accumulation of peroxidized lipids. Its morphological characteristics, mode of action, and molecular mechanism are different from other programmed death methods. Ferroptosis-inducing factors can directly or indirectly affect glutathione peroxidase 4 (GPX4) through different pathways, leading to a decrease in cellular antioxidant capacity and accumulation of lipid reactive oxygen species (ROS), ultimately leading to oxidative cell death.
Features of Ferroptosis
Morphological features: Ultrastructural analysis shows that the cell membrane ruptures during iron death, mitochondria shrink, mitochondrial ridges decrease or even disappear, membrane density increases, and the nuclear morphology remains normal but lacks chromatin aggregation. Under electron microscopy, intracellular mitochondria are observed to become smaller and the density of the double-layer membrane increases.
Biological features: Reactive oxygen species (ROS) increase, iron ions aggregate, activate the mitogen-activated protein kinase (MAPK) system, decrease cystine uptake and deplete glutathione, inhibit system Xc- and increase the oxidoreductase of reduced adenylate, releasing mediators such as arachidonic acid.
Immunological features: Damage-associated molecular patterns molecules (DAMPs) release pro-inflammatory mediators (such as high-mobility group protein B1, etc.).
The Mechanism of Ferroptosis
Induction of ferroptosis by inhibition of system Xc: System Xc- is an amino acid anti-transporter widely distributed in the phospholipid bilayer. The activity of the inhibitory system Xc- affects the synthesis of glutathione (GSH) by inhibiting the absorption of cystine, resulting in reduced glutathione peroxidases (GPX) activity, reduced cellular antioxidant capacity, accumulation of lipid ROS, and ultimately oxidative damage and ferroptosis.
Induction of ferroptosis by inhibiting GPX4: Among the many members of the GPX family, GPX4 is crucial in the development of ferroptosis and serves as a pivotal controller of its occurrence mainly by inhibiting the formation of lipid peroxides. GPX4 converts GSH to oxidized glutathione (GSSG) and reduces cytotoxic lipid peroxides (L-OOH) to the corresponding alcohols (L-OH). Inhibiting GPX4 activity leads to the accumulation of lipid peroxides, a marker of ferroptosis.
P53-mediated ferroptosis: P53-mediated cell cycle inhibition, senescence and apoptosis play important roles in the occurrence and development of tumors. Acetylation-deficient P53 mutants were found to promote ferroptosis. Under the action of ROS, the activity of H1299 cells with P53 gene silencing remained unchanged. However, 90% of cells treated with ROS died after P53 activation, suggesting that P53 activation reduces the antioxidant capacity of these cells. Cell death was significantly reduced after treatment with ferroptosis inhibitors. In addition, the P53-SAT1-ALOX15 pathway is also involved in the regulation of ferroptosis. These studies indicate that expression of P53 can also inhibit ferroptosis in certain cells.
The role of iron metabolism in ferroptosis: Iron is an important trace element in the human body. Abnormal iron distribution and content in the body can affect normal physiological processes. Studies have found that heat shock protein β-1 (HSPB1) can reduce intracellular iron concentration by inhibiting the expression of transferrin receptor (TFR1), so overexpression of HSPB1 can significantly inhibit ferroptosis. Ferritin consists of two subunits, namely ferritin light chain (FTL) and ferritin heavy chain 1 (FTH1). The expression of iron-responsive element-binding protein 2 (IREB2), a major transcription factor that inhibits iron metabolism, can significantly increase the expression of FTL and FTH1, thereby inhibiting induced ferroptosis.
References
- Li, J.; et al. Ferroptosis: past, present and future. Cell Death & Disease. 2020, 11(2):88.
- Dixon S.J.; et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell. 2012, 149(5):1060-72.
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