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Pathway Description
Ferroptosis
Homo sapiens
Signaling Pathway
Created: 2025-03-31
Last Updated: 2025-04-08
Ferroptosis is a form of regulated cell death driven by the accumulation of iron and oxidative stress. The process begins with the release of iron from ferritin in its ferrous (Fe2+) state, which can then participate in the Fenton reaction, where it reacts with hydrogen peroxide to generate highly reactive hydroxyl radicals (OH•). These radicals induce oxidative stress by damaging cellular structures such as lipids, proteins, and DNA. The iron-induced oxidative damage promotes lipid peroxidation, where hydroxyl radicals attack polyunsaturated fatty acids in the cell membrane, forming lipid peroxides that propagate further oxidative damage. This lipid peroxide buildup is a hallmark of ferroptosis and leads to cell death by disrupting the integrity of the cell membrane. The cell’s antioxidant defenses, particularly glutathione, are crucial in protecting against oxidative stress. Glutathione is synthesized from L-glutamine and L-cysteine, with glutamate-cysteine ligase playing a key role. Once produced, glutathione peroxidase 4 (GPX4) uses glutathione to reduce lipid peroxides into non-toxic lipid alcohols, protecting the cell from oxidative damage. However, during ferroptosis, glutathione depletion or inhibition of GPX4, such as by compounds like (1S,3R)-Rsl3, undermines this defense, allowing lipid peroxides to accumulate unchecked. Moreover, inhibitors like L-buthionine-(S,R)-sulfoximine, which block glutamate-cysteine ligase, reduce the cell’s glutathione levels, making it more susceptible to ferroptosis. Iron metabolism also plays a critical role in ferroptosis. The accumulation of Fe3+ on the cell surface activates transferrin receptors, promoting the uptake of iron into the cell. Once inside, Fe2+ can catalyze the Fenton reaction, exacerbating oxidative stress. Additionally, ferritin, which stores iron, can be upregulated in response to iron overload to reduce its availability for catalyzing harmful reactions. However, when the balance between iron storage and release is disrupted, iron overload leads to ferroptosis. Hydroxide radicals (OH) generated during the Fenton reaction can also inhibit the metabolism of arachidonic acid, a precursor to eicosanoids, further exacerbating oxidative stress and lipid peroxidation.
References
Ferroptosis References
Geng L, Liu K and Zhang H (2023) Lipid oxidation in foods and its implications on proteins. Front. Nutr. 10:1192199. doi: 10.3389/fnut.2023.1192199
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Liu, Y., Lu, S., Wu, Ll. et al. The diversified role of mitochondria in ferroptosis in cancer. Cell Death Dis 14, 519 (2023). https://doi.org/10.1038/s41419-023-06045-y
Xie, Y., Hou, W., Song, X. et al. Ferroptosis: process and function. Cell Death Differ 23, 369–379 (2016). https://doi.org/10.1038/cdd.2015.158
Zeng, L., Liu, X., Geng, C., Gao, X., & Liu, L. (2024). Ferroptosis in cancer (Review). Oncology Letters, 28, 304. https://doi.org/10.3892/ol.2024.14437
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