Ferroptosis: Role of lipid peroxidation, iron and ferritinophagy
Open accessAbstract
Ferroptosis is a form of regulated cell death that is dependent on iron and reactive oxygen species (ROS) and is characterized by lipid peroxidation. It is morphologically and biochemically distinct and disparate from other processes of cell death. As ferroptosis is induced by inhibition of cysteine uptake or inactivation of the lipid repair enzyme glutathione peroxidase 4 (GPX4), the process is favored by chemical or mutational inhibition of the cystine/glutamate antiporter and culminates in the accumulation of reactive oxygen species (ROS) in the form of lipid hydroperoxides. Excessive lipid peroxidation leads to death by ferroptosis and the phenotype is accentuated respectively by the repletion and depletion of iron and glutathione in cells. Furthermore, oxidized phosphatidylethanolamines (PE) harbouring arachidonoyl (AA) and adrenoyl moieties (AdA) have been shown as proximate executioners of ferroptosis. Induction of ferroptosis due to cysteine depletion leads to the degradation of ferritin (i.e. ferritinophagy), which releases iron via the NCOA4-mediated autophagy pathway. Evidence of the manifestation of ferroptosis in vivo in iron overload mice mutants is emerging. Thus, a concerted synchronization of iron availability, ROS generation, glutamate excess and cysteine deficit leads to ferroptosis. A number of questions on the molecular mechanisms of some features of ferroptosis are highlighted as subjects for future investigations.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
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?
The toxicity of high extracellular glutamate may depend at least in part on activation of ferroptosis through cysteine imbalance.
“the toxicity of high extracellular glutamate may depend (at least in part) on the activation of ferroptosis through cysteine imbalance [534, 538, 552].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [552]
If at the cellular level ROS production exceeds the cell's scavenging ability, lipid peroxidation and DNA damage can lead to cell death via ferroptosis.
“Furthermore, if at the cellular level ROS production exceeds the cell's scavenging ability, lipid peroxidation and DNA damage can lead to cell death, via a process known as ferroptosis [116].”
From Iron oxide nanoparticles: Diagnostic, therapeutic and theranostic applications (2019) · cites this paper as [116]
Cites
Ferroptosis: An Iron-Dependent Form of Nonapoptotic Cell Death
Dixon, S. J., Lemberg, K. M., Lamprecht, M. R., Skouta, R., Zaitsev, E. M., Gleason, C. E., Patel, D. N., Bauer, A. J., Cantley, A. M., Yang, W. S., et al. (2012) · Cell · doi:10.1016/j.cell.2012.03.042 · Cited by 18,691 · see citing works
Regulation of Ferroptotic Cancer Cell Death by GPX4
Yang, W. S., SriRamaratnam, R., Welsch, M. E., Shimada, K., Skouta, R., Viswanathan, V. S., Cheah, J. H., Clemons, P. A., Shamji, A. F., Clish, C. B., et al. (2014) · Cell · doi:10.1016/j.cell.2013.12.010 · Cited by 7,713 · see citing works
ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition
Doll, S., Proneth, B., Tyurina, Y. Y., Panzilius, E., Kobayashi, S., Ingold, I., Irmler, M., Beckers, J., Aichler, M., Walch, A., et al. (2017) · Nature Chemical Biology · doi:10.1038/nchembio.2239 · Cited by 4,293 · see citing works
Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice
Friedmann Angeli, J. P., Schneider, M., Proneth, B., Tyurina, Y. Y., Tyurin, V. A., Hammond, V. J., Herbach, N., Aichler, M., Walch, A., Eggenhofer, E., et al. (2014) · Nature Cell Biology · doi:10.1038/ncb3064 · Cited by 3,732 · see citing works
Ferroptosis: process and function
Xie, Y., Hou, W., Song, X., Yu, Y., Huang, J., Sun, X., Kang, R., & Tang, D. (2016) · Cell Death & Differentiation · doi:10.1038/cdd.2015.158 · Cited by 3,727 · see citing works
Autophagy and the Integrated Stress Response
Kroemer, G., Mariño, G., & Levine, B. (2010) · Molecular Cell · doi:10.1016/j.molcel.2010.09.023 · Cited by 3,506 · see citing works
Ferroptosis as a p53-mediated activity during tumour suppression
Jiang, L., Kon, N., Li, T., Wang, S.-J., Su, T., Hibshoosh, H., Baer, R., & Gu, W. (2015) · Nature · doi:10.1038/nature14344 · Cited by 3,398 · see citing works
Ferroptosis: Death by Lipid Peroxidation
Yang, W. S., & Stockwell, B. R. (2016) · Trends in Cell Biology · doi:10.1016/j.tcb.2015.10.014 · Cited by 3,088 · see citing works
Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis
Kagan, V. E., Mao, G., Qu, F., Angeli, J. P. F., Doll, S., Croix, C. S., Dar, H. H., Liu, B., Tyurin, V. A., Ritov, V. B., et al. (2017) · Nature Chemical Biology · doi:10.1038/nchembio.2238 · Cited by 3,029 · see citing works
The role of iron and reactive oxygen species in cell death
Dixon, S. J., & Stockwell, B. R. (2014) · Nature Chemical Biology · doi:10.1038/nchembio.1416 · Cited by 2,381 · see citing works
Autophagy promotes ferroptosis by degradation of ferritin
Hou, W., Xie, Y., Song, X., Sun, X., Lotze, M. T., Zeh, H. J., Kang, R., & Tang, D. (2016) · Autophagy · doi:10.1080/15548627.2016.1187366 · Cited by 2,332 · see citing works
Peroxidation of polyunsaturated fatty acids by lipoxygenases drives ferroptosis
Yang, W. S., Kim, K. J., Gaschler, M. M., Patel, M., Shchepinov, M. S., & Stockwell, B. R. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1603244113 · Cited by 2,329 · see citing works
Quantitative proteomics identifies NCOA4 as the cargo receptor mediating ferritinophagy
Mancias, J. D., Wang, X., Gygi, S. P., Harper, J. W., & Kimmelman, A. C. (2014) · Nature · doi:10.1038/nature13148 · Cited by 2,084 · see citing works
Glutaminolysis and transferrin regulate ferroptosis
Gao, M., Monian, P., Quadri, N., Ramasamy, R., & Jiang, X. (2015) · Molecular Cell · doi:10.1016/j.molcel.2015.06.011 · Cited by 2,069 · see citing works
Sun, X., Ou, Z., Chen, R., Niu, X., Chen, D., Kang, R., & Tang, D. (2016) · Hepatology · doi:10.1002/hep.28251 · Cited by 2,012 · see citing works
Ferroptosis is an autophagic cell death process
Gao, M., Monian, P., Pan, Q., Zhang, W., Xiang, J., & Jiang, X. (2016) · Cell Research · doi:10.1038/cr.2016.95 · Cited by 1,899 · see citing works
Seiler, A., Schneider, M., Förster, H., Roth, S., Wirth, E. K., Culmsee, C., Plesnila, N., Kremmer, E., Rådmark, O., Wurst, W., et al. (2008) · Cell Metabolism · doi:10.1016/j.cmet.2008.07.005 · Cited by 1,470 · see citing works
Dolma, S., Lessnick, S. L., Hahn, W. C., & Stockwell, B. R. (2003) · Cancer Cell · doi:10.1016/s1535-6108(03)00050-3 · Cited by 1,446 · see citing works
Murphy, T. H., Miyamoto, M., Sastre, A., Schnaar, R. L., & COYLE, J. T. (1989) · Neuron · doi:10.1016/0896-6273(89)90043-3 · Cited by 1,033 · see citing works
Activation of SAT1 engages polyamine metabolism with p53-mediated ferroptotic responses
Ou, Y., Wang, S.-J., Li, D., Chu, B., & Gu, W. J. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1607152113 · Cited by 775 · see citing works
Dowdle, W. E., Nyfeler, B., Nagel, J., Elling, R. A., Liu, S., Triantafellow, E., Menon, S., Wang, Z., Honda, A., Pardee, G., et al. (2014) · Nature Cell Biology · doi:10.1038/ncb3053 · Cited by 759 · see citing works
Ferroptosis, a new form of cell death, and its relationships with tumourous diseases
Yu, H., Guo, P., Xie, X., Wang, Y., & Chen, G. (2016) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.13008 · Cited by 712 · see citing works
HSPB1 as a novel regulator of ferroptotic cancer cell death
Sun, X., Ou, Z., Xie, M., Kang, R., Fan, Y., Niu, X., Wang, H., Cao, L., & Tang, D. (2015) · Oncogene · doi:10.1038/onc.2015.32 · Cited by 666 · see citing works
Characterization of ferroptosis in murine models of hemochromatosis
Wang, H., An, P., Xie, E., Wu, Q., Fang, X., Gao, H., Zhang, Z., Li, Y., Wang, X., Zhang, J., et al. (2017) · Hepatology · doi:10.1002/hep.29117 · Cited by 656 · see citing works
LaVaute, T., Smith, S., Cooperman, S., Iwai, K., Land, W., Meyron-Holtz, E., Drake, S. K., Miller, G., Abu-Asab, M., Tsokos, M., et al. (2001) · Nature Genetics · doi:10.1038/84859 · Cited by 509 · see citing works
Chen, L., Hambright, W. S., Na, R., & Ran, Q. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.680090 · Cited by 498 · see citing works
Iron and ferroptosis: A still ill‐defined liaison
Doll, S. G., & Conrad, M. (2017) · IUBMB Life · doi:10.1002/iub.1616 · Cited by 472 · see citing works
Redox imbalance in cystine/glutamate transporter-deficient mice
Sato, H., Shiiya, A., Kimata, M., Maebara, K., Tamba, M., Sakakura, Y., Makino, N., Sugiyama, F., Yagami, K.-I., Moriguchi, T., et al. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m506439200 · Cited by 422 · see citing works
Jennis, M., Kung, C.-P., Basu, S., Budina-Kolomets, A., Leu, J. I.-J., Khaku, S., Scott, J. P., Cai, K. Q., Campbell, M. R., Porter, D. K., et al. (2016) · Genes & Development · doi:10.1101/gad.275891.115 · Cited by 355 · see citing works
Zaman, K., Ryu, H., Hall, D. H., O’Donovan, K., Lin, K., Miller, M. P., Marquis, J. C., Baraban, J. M., Semenza, G. L., & Ratan, R. R. (1999) · Journal of Neuroscience · doi:10.1523/jneurosci.19-22-09821.1999 · Cited by 319 · see citing works
Glutathione peroxidase 4 and vitamin E cooperatively prevent hepatocellular degeneration
Carlson, B. A., Tobe, R., Yefremova, E., Tsuji, P. A., Hoffmann, V. J., Schweizer, U., Gladyshev, V. N., Hatfield, D. L., & Conrad, M. (2016) · Redox Biology · doi:10.1016/j.redox.2016.05.003 · Cited by 316 · see citing works
Frey, P. A., & Reed, G. H. (2012) · ACS Chemical Biology · doi:10.1021/cb300323q · Cited by 299 · see citing works
Arrigo, A., Virot, S., Chaufour, S., et al. (2005) · Antioxidants and Redox Signaling · doi:10.1089/ars.2005.7.414 · Cited by 248 · see citing works
Wirth, E. K., Conrad, M., Winterer, J., Wozny, C., Carlson, B. A., Roth, S., Schmitz, D., Bornkamm, G. W., Coppola, V., Tessarollo, L., et al. (2010) · The FASEB Journal · doi:10.1096/fj.09-143974 · Cited by 237 · see citing works
Dynamic roles of p53-mediated metabolic activities in ROS-induced stress responses
Jiang, L., Hickman, J. H., Wang, S.-J., & Gu, W. J. (2015) · Cell Cycle · doi:10.1080/15384101.2015.1068479 · Cited by 232 · see citing works
Intralysosomal iron: a major determinant of oxidant-induced cell death
Yu, Z., Persson, H. L., Eaton, J. W., & Brunk, U. T. (2003) · Free Radical Biology and Medicine · doi:10.1016/s0891-5849(03)00109-6 · Cited by 226 · see citing works
Shen, J., Sheng, X., Chang, Z., Wu, Q., Wang, S., Xuan, Z., Li, D., Wu, Y., Shang, Y., Kong, X., et al. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.02.042 · Cited by 215 · see citing works
Petrat, F., Rauen, U., & de GROOT, H. (1999) · Hepatology · doi:10.1002/hep.510290435 · Cited by 202 · see citing works
Prevention of oxidant-induced cell death by lysosomotropic iron chelators
Persson, H. L., Yu, Z., Tirosh, O., Eaton, J. W., & Brunk, U. T. (2003) · Free Radical Biology and Medicine · doi:10.1016/s0891-5849(03)00106-0 · Cited by 185 · see citing works
Wortmann, M., Schneider, M., Pircher, J., Hellfritsch, J., Aichler, M., Naidu, V. M., Kölle, P., Kuhlencordt, P. J., Walch, A. K., Pohl, U., et al. (2013) · Circulation Research · doi:10.1161/circresaha.113.279984 · Cited by 160 · see citing works
Speer, R. E., Karuppagounder, S. S., Basso, M., Sleiman, S. F., Kumar, A., Brand, D., Smirnova, N., Gazaryan, I. G., Khim, S. J., & Ratan, R. R. (2013) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2013.01.026 · Cited by 155 · see citing works
D'Herde, K. G. M. A., & Krysko, D. V. (2016) · Nature Chemical Biology · doi:10.1038/nchembio.2261 · Cited by 142 · see citing works
Siddiq, A., Aminova, L. R., Troy, C. M., Suh, K., Messer, Z. R., Semenza, G. L., & Ratan, R. R. (2009) · Journal of Neuroscience · doi:10.1523/jneurosci.1779-09.2009 · Cited by 127 · see citing works
Heat shock protein 27 downregulates the transferrin receptor 1-mediated iron uptake
Chen, H., Zheng, C., Zhang, Y., Chang, Y., Qian, Z., & Shen, X. (2006) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2006.02.006 · Cited by 88 · see citing works
Necroptosis: A new way of dying?
Hanson, B. (2016) · Cancer Biology & Therapy · doi:10.1080/15384047.2016.1210732 · Cited by 87 · see citing works
Maichele, A. J., Burwinkel, B., Maire, I., Sövik, O., & Kilimann, M. W. (1996) · Nature Genetics · doi:10.1038/ng1196-337 · Cited by 82 · see citing works
Iron-mediated oxidative stress plays an essential role in ferritin-induced cell death
Bresgen, N., Jaksch, H., Lacher, H., Ohlenschläger, I., Uchida, K., & Eckl, P. (2010) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2010.02.019 · Cited by 62 · see citing works
Discovery of a Genetic Metabolic Cause for Mauriac Syndrome in Type 1 Diabetes
MacDonald, M. J., Hasan, N. M., Ansari, I. H., Longacre, M. J., Kendrick, M. A., & Stoker, S. W. (2016) · Diabetes · doi:10.2337/db16-0099 · Cited by 60 · see citing works
The mechanism of catalase action. II. Electric analog computer studies
Chance, B., Greenstein, D. S., Higgins, J. J., et al. (1952) · Archives of Biochemistry and Biophysics · doi:10.1016/0003-9861(52)90195-1 · Cited by 41 · see citing works
In vitro studies on the lymphoma growth-inhibitory activity of sulfasalazine
Gout, P. W., Simms, C. R., & Robertson, M. C. (2003) · Anti-Cancer Drugs · doi:10.1097/00001813-200301000-00004 · Cited by 39 · see citing works
Salvatore, M. F., Fisher, B., Surgener, S. P., Gerhardt, G. A., & Rouault, T. A. (2005) · Molecular Brain Research · doi:10.1016/j.molbrainres.2005.06.002 · Cited by 38 · see citing works
On the mechanism of iron sensing by IRP2: new players, new paradigms
Takahashi‐Makise, N., Ward, D. M., & Kaplan, J. (2009) · Nature Chemical Biology · doi:10.1038/nchembio.261 · Cited by 20 · see citing works
Iron, friend or foe? “Freedom” makes the difference
Pietrangelo, A. (2000) · Journal of Hepatology · doi:10.1016/s0168-8278(00)80258-5 · Cited by 17 · see citing works
Increased iron-59 absorption in patients with hepatic cirrhosis.
Friedman, B. I., Schaefer, J. W., & Schiff, L. (1966) · PubMed · Cited by 15 · see citing works
Bresgen, N., Jaksch, H., Bauer, H.-C., et al. (2006) · Journal of Neuroscience Research · doi:10.1002/jnr.21069 · Cited by 12 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Galluzzi, L., Vitale, I., Aaronson, S. A., Abrams, J. M., Adam, D., Agostinis, P., Alnemri, E. S., Altucci, L., Amelio, I., Andrews, D. W., et al. (2018) · Cell Death & Differentiation · doi:10.1038/s41418-017-0012-4 · Cited by 6,680 · see citing works
Biological Functions of Autophagy Genes: A Disease Perspective
Levine, B., & Kroemer, G. (2019) · Cell · doi:10.1016/j.cell.2018.09.048 · Cited by 2,832 · see citing works
Reactive Oxygen Species-Induced Lipid Peroxidation in Apoptosis, Autophagy, and Ferroptosis
Su, L.-J., Zhang, J.-H., Gomez, H., Murugan, R., Hong, X., Xu, D., Jiang, F., & Peng, Z.-Y. (2019) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2019/5080843 · Cited by 2,166 · see citing works
NLRP3 inflammasome activation and cell death
Huang, Y., Xu, W., & Zhou, R. (2021) · Cellular & Molecular Immunology · doi:10.1038/s41423-021-00740-6 · Cited by 1,527 · see citing works
Ferroptosis: Mechanisms and links with diseases
Yan, H.-F., Zou, T., Tuo, Q.-Z., Xu, S., Li, H., Belaidi, A. A., & Lei, P. (2021) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-020-00428-9 · Cited by 1,471 · see citing works
Iron oxide nanoparticles: Diagnostic, therapeutic and theranostic applications
Dadfar, S. M., Roemhild, K., Drude, N. I., von Stillfried, S., Knüchel, R., Kiessling, F., & Lammers, T. (2019) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2019.01.005 · Cited by 1,181 · see citing works
Miao, R., Fang, X., Zhang, Y., Wei, J., Zhang, Y., & Tian, J. (2023) · Cell Death & Disease · doi:10.1038/s41419-023-05708-0 · Cited by 192 · see citing works
Ferroptosis at the crossroads of infection, aging and cancer
Toyokuni, S., Yanatori, I., Kong, Y., Zheng, H., Motooka, Y., & Jiang, L. (2020) · Cancer Science · doi:10.1111/cas.14496 · Cited by 142 · see citing works
Wu, Y., Torabi, S.-F., Lake, R. J., Hong, S., Yu, Z., Wu, P., Yang, Z., Nelson, K., Guo, W., Pawel, G. T., et al. (2023) · Science Advances · doi:10.1126/sciadv.ade7622 · Cited by 91 · see citing works
Mobilization of iron from ferritin: New steps and details
La, A., Nguyen, T., Tran, K., Sauble, E., Tu, D., Gonzalez, A., Kidane, T. Z., Soriano, C., Morgan, J., Doan, M., et al. (2018) · Metallomics · doi:10.1039/c7mt00284j · Cited by 56 · see citing works
Wu, H., Li, N., Peng, S., Fu, H., Hu, Z., & Su, L. (2024) · International Immunopharmacology · doi:10.1016/j.intimp.2024.111792 · Cited by 32 · see citing works
Anti-cancer effects of fenbendazole on 5-fluorouracil-resistant colorectal cancer cells
Park, D., Lee, J.-H., & Yoon, S.-P. (2022) · The Korean Journal of Physiology & Pharmacology · doi:10.4196/kjpp.2022.26.5.377 · Cited by 23 · see citing works
- Authors
- Latunde-Dada, G. O.
- Affiliations
- King's College London (GB)
- Corresponding author
- Latunde-Dada, Gladys O.
- Venue
- Biochimica et Biophysica Acta (BBA) - General Subjects
- Publisher
- Elsevier BV
- Published
- 2017-08
- Volume
- 1861
- Issue
- 8
- Pages
- 1893-1900
- ISSN
- 0304-4165 (ISSN-L)
- OpenAlex
- W2619512829
- Cited by
- 892
- References
- 55
- Citations by year
- 2026: 77 · 2025: 129 · 2024: 137 · 2023: 139 · 2022: 153 · 2021: 112 · 2020: 60 · 2019: 53 · 2018: 24 · 2017: 7
- FWCI
- 7.18
- Type
- journal article
- Language
- en
- Open access
- green
- kclpure.kcl.ac.uk
- Licence
- cc-by-nc-nd
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- Locations
- Biochimica et Biophysica Acta (BBA) - General Subjects (publishedVersion)
- PubMed (publishedVersion)
- Research Portal (King's College London) (submittedVersion, cc-by-nc-nd)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Ferroptosis and cancer prognosis
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- ferroptosis, lipid peroxidation, iron, ferritinophagy, GPX4, SLC7A11, cysteine depletion, reactive oxygen species, lipid hydroperoxides, NCOA4, autophagy, iron overload, glutamate
- MeSH terms
- Animals, Autophagy, Cysteine, Ferritins, Glutathione, Humans, Iron, Lipid Peroxidation, Cell Death, Reactive Oxygen Species
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
