Synthetic lethal screening identifies compounds activating iron-dependent, nonapoptotic cell death in oncogenic-RAS-harboring cancer cells.
Open accessAbstract
We screened small molecules to identify two compounds, which we named RSL3 and RSL5, that have increased lethality in the presence of oncogenic RAS. Counter screening with biologically active compounds defined aspects of the mechanism of action for RSL3 and RSL5, such as a nonapoptotic, MEK-dependent, and iron-dependent oxidative cell death. Erastin, a previously reported compound with RAS-selective lethality, showed similar properties. RNA interference experiments targeting voltage-dependent anion channel 3 (VDAC3), a target of erastin, demonstrated that RSL5 is a scaffold that acts through VDACs to activate the observed pathway. RSL3 activated a similar death mechanism but in a VDAC-independent manner. We found that cells transformed with oncogenic RAS have increased iron content relative to their normal cell counterparts through upregulation of transferrin receptor 1 and downregulation of ferritin heavy chain 1 and ferritin light chain.
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Depletion of intracellular glutathione reduces GPX functionality.
“Under normal circumstances, glutathione peroxidase (GPX) neutralizes lipid peroxide to lipid alcohols, but the depletion of intracellular glutathione (GSH, GPX substrate) reduces GPX functionality (Yang and Stockwell, 2008; Friedmann Angeli et al., 2014).”
From Toxic Concentrations of Glutamate Induce Ferroptosis without Affecting Mitochondrial Respiration in Rodent Brain Slice Cultures (2026) · cites this paper as Yang and Stockwell, 2008
In the Mechanism of Action Study section (page unavailable), reduced glutathione (GSH) appears only in a list of compounds considered for cell-death experiments. Searches for GPX, glutathione peroxidase, and glutathione depletion found no passage linking intracellular GSH depletion to reduced GPX functionality. (LLM, conf=0.76)
Experimental — accuracy not yet measuredIron depletion by chelators or PHKG2 knockdown inhibits ferroptosis.
“the ferroptosis-inhibiting effect of iron depletion by either chelators [539, 543, 548] or phosphorylase kinase catalytic subunit gamma 2 (PHKG2) knockdown [566]”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [543]
Erastin- and RSL3-induced death is non-apoptotic, occurring without apoptotic hallmarks and even when core apoptosis machinery is suppressed.
“The mode of cell death induced by these compounds was surprisingly found to be non-apoptotic, as cells treated with erastin and RSL3 died in the absence of apoptotic hallmarks [11, 12, 13], and in cells where the core apoptosis machinery – caspases, BAX, and BAK was suppressed [14].”
From Ferroptosis: Death by Lipid Peroxidation (2016) · cites this paper as [12]
Erastin and RSL3 were the first compounds found to induce ferroptosis, identified through high-throughput small-molecule screening.
“The first ferroptosis-inducing compounds, erastin [11] and RSL3 [12], were discovered using high-throughout screening of small molecule libraries [11, 12].”
From Ferroptosis: Death by Lipid Peroxidation (2016) · cites this paper as [12]
RSL3-induced death shares iron, MEK, and ROS dependencies with erastin-mediated ferroptosis.
“Cell death induced by RSL3 shares common features with erastin-mediated ferroptosis, such as iron, MEK, and ROS dependencies [12].”
From Ferroptosis: Death by Lipid Peroxidation (2016) · cites this paper as [12]
Iron chelators block RSL3-induced death, showing that cellular iron is required.
“Moreover, iron chelators were identified as inhibitors of cell death induction, after RSL3 treatment, revealing the requirement of cellular iron [12].”
From Ferroptosis: Death by Lipid Peroxidation (2016) · cites this paper as [12]
Cells are desensitized to ferroptosis through genetic silencing of iron uptake (TfR1), metabolism (IRP2 and ISCU) and storage (ferritin) genes, or through depletion of transferrin in the extracellular environment.
“Cells are also desensitized to ferroptosis through genetic silencing of iron uptake (TfR1), metabolism (IRP2 and ISCU) and storage (ferritin) genes [62], [66], [82], or through depletion of transferrin in the extracellular environment [83].”
From Iron accumulation in senescent cells is coupled with impaired ferritinophagy and inhibition of ferroptosis (2018) · cites this paper as [66]
Cell death elicited by ferroptosis-inducing compounds (e.g., erastin and RSL3) can be mitigated through various iron chelators.
“Cell death elicited by ferroptosis-inducing compounds (FINs) (e.g. erastin and RSL3) can also be mitigated through various iron chelators (Dfo, 2,2-bipyridile or compound 311) [62], [66], [81].”
From Iron accumulation in senescent cells is coupled with impaired ferritinophagy and inhibition of ferroptosis (2018) · cites this paper as [66]
Ferroptosis is a unique cell death pathway distinct from apoptosis, reliant on availability of iron liberated through ferritinophagy.
“Ferroptosis, a unique cell death pathway distinct from apoptosis [62], [66], [80], is reliant on the availability of iron [62], [66], [81] liberated through ferritinophagy [63].”
From Iron accumulation in senescent cells is coupled with impaired ferritinophagy and inhibition of ferroptosis (2018) · cites this paper as [66]
Erastin and RSL3 are two structurally different inducers of ferroptosis that affect distinct pathways.
“two structurally different inducers of ferroptosis that affect distinct pathways [66].”
From Iron accumulation in senescent cells is coupled with impaired ferritinophagy and inhibition of ferroptosis (2018) · cites this paper as [66]
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Cites
Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase
Bryant, H. E., Schultz, N., Thomas, H. D., Parker, K. M., Flower, D., Lopez, E., Kyle, S., Meuth, M., Curtin, N. J., & Helleday, T. (2005) · Nature · doi:10.1038/nature03443 · Cited by 5,198 · see citing works
The ferritins: molecular properties, iron storage function and cellular regulation
Harrison, P. M., & Arosio, P. (1996) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/0005-2728(96)00022-9 · Cited by 2,667 · see citing works
Creation of human tumour cells with defined genetic elements
Hahn, W. C., Counter, C. M., Lundberg, A. S., Beijersbergen, R. L., Brooks, M. W., & Weinberg, R. A. (1999) · Nature · doi:10.1038/22780 · Cited by 2,345 · see citing works
Systematic Genetic Analysis with Ordered Arrays of Yeast Deletion Mutants
Tong, A. H. Y., Evangelista, M., Parsons, A. B., Xu, H., Bader, G. D., Pagé, N., Robinson, M., Raghibizadeh, S., Hogue, C. W. V., Bussey, H., et al. (2001) · Science · doi:10.1126/science.1065810 · Cited by 2,138 · see citing works
Discovery and development of sorafenib: a multikinase inhibitor for treating cancer
Wilhelm, S. M., Carter, C., Lynch, M. J., Lowinger, T. B., Dumas, J., Smith, R. A., Schwartz, B. E., Simantov, R., & Kelley, S. L. (2006) · Nature Reviews Drug Discovery · doi:10.1038/nrd2130 · Cited by 1,826 · see citing works
A Lentiviral RNAi Library for Human and Mouse Genes Applied to an Arrayed Viral High-Content Screen
Moffat, J., Grueneberg, D. A., Yang, X., Kim, S. Y., Kloepfer, A. M., Hinkle, G., Piqani, B., Eisenhaure, T., Luo, B., Grenier, J. K., et al. (2006) · Cell · doi:10.1016/j.cell.2006.01.040 · Cited by 1,803 · see citing works
Self-citationRAS–RAF–MEK-dependent oxidative cell death involving voltage-dependent anion channels
Yagoda, N., von Rechenberg, M., Zaganjor, E., Bauer, A. J., Yang, W. S., Fridman, D. J., Wolpaw, A. J., Smukste, I., Peltier, J. M., Boniface, J. J., et al. (2007) · Nature · doi:10.1038/nature05859 · Cited by 1,631 · see citing works
Self-citationDolma, 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
Self-citationEnhanced sensitivity of PTEN-deficient tumors to inhibition of FRAP/mTOR
Neshat, M., Mellinghoff, I., Tran, C., Stiles, B. L., Thomas, G., Petersen, R., Frost, P., Gibbons, J., Wu, H., & Sawyers, C. (2001) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.171076798 · Cited by 1,033 · see citing works
Paull, K. D., Shoemaker, R. H., Hodes, L., Monks, A. P., Scudiero, D. A., Rubinstein, L., Plowman, J., & Boyd, M. R. (1989) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/81.14.1088 · Cited by 970 · see citing works
Integrating Genetic Approaches into the Discovery of Anticancer Drugs
Hartwell, L. H., Szankasi, P., Roberts, C. J., Murray, A. W., & Friend, S. H. (1997) · Science · doi:10.1126/science.278.5340.1064 · Cited by 777 · see citing works
The Evolution of Iron Chelators for the Treatment of Iron Overload Disease and Cancer
Kalinowski, D. S., & Richardson, D. R. (2005) · Pharmacological Reviews · doi:10.1124/pr.57.4.2 · Cited by 721 · see citing works
Requirement for c-ras proteins during viral oncogene transformation
Smith, M. R., DeGudicibus, S. J., & Stacey, D. W. (1986) · Nature · doi:10.1038/320540a0 · Cited by 653 · see citing works
Enumeration of the Simian Virus 40 Early Region Elements Necessary for Human Cell Transformation
Hahn, W. C., Dessain, S. K., Brooks, M. W., King, J. E., Elenbaas, B., Sabatini, D. M., DeCaprio, J. A., & Weinberg, R. A. (2002) · Molecular and Cellular Biology · doi:10.1128/mcb.22.7.2111-2123.2002 · Cited by 603 · see citing works
Body Iron Stores and the Risk of Cancer
Stevens, R. G., Jones, D. Y., Micozzi, M. S., & Taylor, P. R. (1988) · New England Journal of Medicine · doi:10.1056/nejm198810203191603 · Cited by 576 · see citing works
Structure of the human transferrin receptor-transferrin complex
Cheng, Y., Zak, O., Aisen, P., Harrison, S. C., & Walz, T. (2004) · Cell · doi:10.1016/s0092-8674(04)00130-8 · Cited by 571 · see citing works
Voltage-dependent anion channel (VDAC) as mitochondrial governator—Thinking outside the box
Lemasters, J. J., & Holmuhamedov, E. (2005) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2005.10.006 · Cited by 437 · see citing works
Chemical genetics: ligand-based discovery of gene function
Stockwell, B. R. (2000) · Nature Reviews Genetics · doi:10.1038/35038557 · Cited by 418 · see citing works
Self-citationA novel one-step, highly sensitive fluorometric assay to evaluate cell-mediated cytotoxicity
Nociari, M., Shalev, A., Benias, P. C., & Russo, C. (1998) · Journal of Immunological Methods · doi:10.1016/s0022-1759(98)00028-3 · Cited by 351 · see citing works
Coordinated Regulation of Iron-Controlling Genes, H-Ferritin and IRP2 , by c-MYC
Wu, K., Polack, A., & Dalla‐Favera, R. (1999) · Science · doi:10.1126/science.283.5402.676 · Cited by 328 · see citing works
Rodenhuis, S. (1992) · PubMed · Cited by 220 · see citing works
Bleomycin pharmacology: mechanism of action and resistance, and clinical pharmacokinetics.
Dorr, R. T. (1992) · PubMed · Cited by 146 · see citing works
Determination of the Chelatable Iron Pool of Single Intact Cells by Laser Scanning Microscopy
Petrat, F., de GROOT, H., & Rauen, U. (2000) · Archives of Biochemistry and Biophysics · doi:10.1006/abbi.2000.1711 · Cited by 112 · see citing works
Green, D. A., Antholine, W. E., Wong, S. J., Richardson, D. R., & Chitambar, C. R. (2001) · PubMed · Cited by 90 · see citing works
Role of E2F-1 in chemosensitivity.
Banerjee, D., Schnieders, B., Fu, J. Z., Adhikari, D., Zhao, S., & Bertino, J. R. (1998) · PubMed · Cited by 84 · see citing works
Shterman, N., Kupfer, B., & Moroz, C. (2008) · Pathobiology · doi:10.1159/000163611 · Cited by 81 · see citing works
Chemotherapy for Advanced Germ Cell Tumors
Kondagunta, G. V., & Motzer, R. J. (2006) · Journal of Clinical Oncology · doi:10.1200/jco.2006.08.7882 · Cited by 72 · see citing works
FER-1, an Enhancer of the Ferritin H Gene and a Target of E1A-Mediated Transcriptional Repression
Tsuji, Y., Akebi, N., Lam, T. K., Nakabeppu, Y., Torti, S. V., & Torti, F. M. (1995) · Molecular and Cellular Biology · doi:10.1128/mcb.15.9.5152 · Cited by 54 · see citing works
Selective inhibitors of death in mutant huntingtin cells
Varma, H., Voisine, C., DeMarco, C. T., Cattaneo, E. F., Lo, D. C., Hart, A. C., & Stockwell, B. R. (2006) · Nature Chemical Biology · doi:10.1038/nchembio852 · Cited by 42 · see citing works
Self-citationOuyang, Q., Bommakanti, M., & Miskimins, W. K. (1993) · Molecular and Cellular Biology · doi:10.1128/mcb.13.3.1796-1804.1993 · Cited by 37 · see citing works
The Promoter Region of the Human Transferrin Receptor Gene
Casey, J. L., Jeso, B. D., Rao, K., Rouault, T. A., Klausner, R. D., & Harford, J. B. (1988) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.1988.tb55492.x · Cited by 15 · see citing works
Ras Superfamily and Interacting Proteins Database
Bernards, A. (2006) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/s0076-6879(05)07001-1 · Cited by 13 · see citing works
Clinical trials referral resource. Current clinical trials investigating 3-AP.
Low, J. A., & Schoenfeldt, M. (2004) · PubMed · Cited by 1 · see citing works
Flagged first, then by citations
2 of the 35 references couldn’t be matched to a known paper.
Cited by
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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
Self-citationFerroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease
Stockwell, B. R., Friedmann Angeli, J. P., Bayir, H., Bush, A. I., Conrad, M., Dixon, S. J., Fulda, S., Gascón, S., Hatzios, S. K., Kagan, V. E., et al. (2017) · Cell · doi:10.1016/j.cell.2017.09.021 · Cited by 7,695 · see citing works
Self-citationRegulation 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
Self-citationGalluzzi, 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
Self-citationACSL4 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
Ferroptosis: past, present and future
Li, J., Cao, F., Yin, H.-L., Huang, Z.-J., Lin, Z.-T., Mao, N., Sun, B., & Wang, G. (2020) · Cell Death & Disease · doi:10.1038/s41419-020-2298-2 · Cited by 4,171 · 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
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
Self-citationFerroptosis turns 10: Emerging mechanisms, physiological functions, and therapeutic applications
Stockwell, B. R. (2022) · Cell · doi:10.1016/j.cell.2022.06.003 · Cited by 3,132 · see citing works
Self-citationOxidized 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
Self-citationBroadening horizons: the role of ferroptosis in cancer
Chen, X., Kang, R., Kroemer, G., & Tang, D. (2021) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-020-00462-0 · Cited by 2,942 · see citing works
Hayes, J. D., Dinkova-Kostova, A. T., & Tew, K. D. (2020) · Cancer Cell · doi:10.1016/j.ccell.2020.06.001 · Cited by 2,654 · see citing works
The molecular machinery of regulated cell death
Tang, D., Kang, R., Berghe, T. V., Vandenabeele, P., & Kroemer, G. (2019) · Cell Research · doi:10.1038/s41422-019-0164-5 · Cited by 2,595 · see citing works
Targeting Ferroptosis to Iron Out Cancer
Hassannia, B., Vandenabeele, P., & Berghe, T. V. (2019) · Cancer Cell · doi:10.1016/j.ccell.2019.04.002 · Cited by 2,483 · 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
Self-citationAutophagy 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
Self-citationNRF2 plays a critical role in mitigating lipid peroxidation and ferroptosis
Dodson, M., Castro-Portuguez, R., & Zhang, D. D. (2019) · Redox Biology · doi:10.1016/j.redox.2019.101107 · Cited by 2,435 · see citing works
Antioxidants Maintain Cellular Redox Homeostasis by Elimination of Reactive Oxygen Species
He, L., He, T., Farrar, S., Ji, L., Liu, T., & Ma, X. (2017) · Cellular Physiology and Biochemistry · doi:10.1159/000485089 · Cited by 2,142 · 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: machinery and regulation
Chen, X., Li, J., Kang, R., Klionsky, D. J., & Tang, D. (2021) · Autophagy · doi:10.1080/15548627.2020.1810918 · Cited by 2,099 · see citing works
Ferroptosis, a new form of cell death: opportunities and challenges in cancer
Mou, Y., Wang, J., Wu, J., He, D., Zhang, C., Duan, C., & Li, B. (2019) · Journal of Hematology & Oncology · doi:10.1186/s13045-019-0720-y · Cited by 1,943 · see citing works
Recent Progress in Ferroptosis Inducers for Cancer Therapy
Liang, C., Zhang, X., Yang, M., & Dong, X. (2019) · Advanced Materials · doi:10.1002/adma.201904197 · Cited by 1,569 · see citing works
The Cell Biology of Ferroptosis
Dixon, S. J., & Olzmann, J. A. (2024) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-024-00703-5 · Cited by 1,596 · see citing works
Cao, J. Y., & Dixon, S. J. (2016) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-016-2194-1 · Cited by 1,515 · 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
Ferroptosis in cancer therapy: a novel approach to reversing drug resistance
Zhang, C., Liu, X., Jin, S., Chen, Y., & Guo, R. (2022) · Molecular Cancer · doi:10.1186/s12943-022-01530-y · Cited by 1,363 · see citing works
The Metabolic Underpinnings of Ferroptosis
Zheng, J., & Conrad, M. (2020) · Cell Metabolism · doi:10.1016/j.cmet.2020.10.011 · Cited by 1,338 · see citing works
Ferrostatins Inhibit Oxidative Lipid Damage and Cell Death in Diverse Disease Models
Skouta, R., Dixon, S. J., Wang, J., Dunn, D. E., Orman, M., Shimada, K., Rosenberg, P. A., Lo, D. C., Weinberg, J. M., Linkermann, A., et al. (2014) · Journal of the American Chemical Society · doi:10.1021/ja411006a · Cited by 1,146 · see citing works
Self-citationFricker, M., Tolkovsky, A. M., Borutaitė, V., Coleman, M. P., & Brown, G. C. (2018) · Physiological Reviews · doi:10.1152/physrev.00011.2017 · Cited by 1,122 · see citing works
Emerging Mechanisms and Disease Relevance of Ferroptosis
Stockwell, B. R., Jiang, X., & Gu, W. J. (2020) · Trends in Cell Biology · doi:10.1016/j.tcb.2020.02.009 · Cited by 1,107 · see citing works
Self-citationThe molecular and metabolic landscape of iron and ferroptosis in cardiovascular disease
Fang, X., Ardehali, H., Min, J., & Wang, F. (2022) · Nature Reviews Cardiology · doi:10.1038/s41569-022-00735-4 · Cited by 1,094 · see citing works
Ferroptosis is a type of autophagy-dependent cell death
Zhou, B., Liu, J., Kang, R., Klionsky, D. J., Kroemer, G., & Tang, D. (2019) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2019.03.002 · Cited by 1,071 · see citing works
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Forcina, G. C., & Dixon, S. J. (2019) · PROTEOMICS · doi:10.1002/pmic.201800311 · Cited by 1,080 · see citing works
Autophagy, ferroptosis, pyroptosis, and necroptosis in tumor immunotherapy
Gao, W., Wang, Y., Zhou, Y., Wang, X., & Yu, Y. (2022) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-022-01046-3 · Cited by 1,069 · see citing works
Global survey of cell death mechanisms reveals metabolic regulation of ferroptosis
Shimada, K., Skouta, R., Kaplan, A., Yang, W. S., Hayano, M., Dixon, S. J., Brown, L. M., Valenzuela, C. A., Wolpaw, A. J., & Stockwell, B. R. (2016) · Nature Chemical Biology · doi:10.1038/nchembio.2079 · Cited by 1,017 · see citing works
Self-citationIron Metabolism in Ferroptosis
Chen, X., Yu, C., Kang, R., & Tang, D. (2020) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.590226 · Cited by 980 · see citing works
Tsoi, J., Robert, L., Paraiso, K., Galvan, C., Sheu, K. M., Lay, J., Wong, D. J. L., Atefi, M., Shirazi, R., Wang, X., et al. (2018) · Cancer Cell · doi:10.1016/j.ccell.2018.03.017 · Cited by 938 · see citing works
The development of the concept of ferroptosis
Hirschhorn, T., & Stockwell, B. R. (2019) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2018.09.043 · Cited by 1,052 · see citing works
Self-citationA guide to cell death pathways
Yuan, J., & Ofengeim, D. (2023) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-023-00689-6 · Cited by 972 · see citing works
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Zhou, Q., Meng, Y., Li, D., Yao, L., Le, J., Liu, Y., Sun, Y., Zeng, F., Chen, X., & Deng, G. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-01769-5 · Cited by 980 · see citing works
Iron homeostasis and oxidative stress: An intimate relationship
Galaris, D., Barbouti, A., & Pantopoulos, K. (2019) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2019.118535 · Cited by 922 · see citing works
Reactive oxygen species and cancer paradox: To promote or to suppress?
Galadari, S., Rahman, A. U., Pallichankandy, S., & Thayyullathil, F. (2017) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2017.01.004 · Cited by 895 · see citing works
Transferrin Receptor Is a Specific Ferroptosis Marker
Feng, H., Schorpp, K., Jin, J., Yozwiak, C. E., Hoffstrom, B. G., Decker, A., Rajbhandari, P., Stokes, M. E., Bender, H. G., Csuka, J. M., et al. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.02.049 · Cited by 891 · see citing works
Self-citationLipid metabolism reprogramming and its potential targets in cancer
Cheng, C., Geng, F., Cheng, X., & Guo, D. (2018) · 癌症：英文版 · doi:10.1186/s40880-018-0301-4 · Cited by 862 · see citing works
Regulated cell death (RCD) in cancer: key pathways and targeted therapies
Peng, F., Liao, M., Qin, R., Zhu, S., Peng, C. Y., Fu, L., Chen, Y., & Han, B. (2022) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-022-01110-y · Cited by 850 · see citing works
Autophagy-Dependent Ferroptosis: Machinery and Regulation
Liu, J., Kuang, F.-M., Kroemer, G., Klionsky, D., Kang, R., & Tang, D. (2020) · Cell Chemical Biology · doi:10.1016/j.chembiol.2020.02.005 · Cited by 763 · see citing works
Signaling pathways and defense mechanisms of ferroptosis
Liu, J., Kang, R., & Tang, D. (2021) · FEBS Journal · doi:10.1111/febs.16059 · Cited by 809 · see citing works
Resolving the Role of Lipoxygenases in the Initiation and Execution of Ferroptosis
Shah, R., Shchepinov, M. S., & Pratt, D. A. (2018) · ACS Central Science · doi:10.1021/acscentsci.7b00589 · Cited by 782 · see citing works
Ferroptosis: A Novel Anti-tumor Action for Cisplatin
Guo, J., Xu, B.-F., Han, Q., Zhou, H., Xia, Y. F., Gong, C., Dai, X., Li, Z., & Wu, G. (2017) · Cancer Research and Treatment · doi:10.4143/crt.2016.572 · Cited by 787 · see citing works
Loss of Cardiac Ferritin H Facilitates Cardiomyopathy via Slc7a11-Mediated Ferroptosis
Fang, X., Cai, Z., Wang, H., Han, D., Cheng, Q., Zhang, P., Gao, F., Yu, Y., Song, Z., Wu, Q., et al. (2020) · Circulation Research · doi:10.1161/circresaha.120.316509 · Cited by 770 · see citing works
Emerging Strategies of Cancer Therapy Based on Ferroptosis
Shen, Z., Song, J., Yung, B. C., Zhou, Z., Wu, A., & Chen, X. S. (2018) · Advanced Materials · doi:10.1002/adma.201704007 · Cited by 740 · see citing works
Mechanisms of neuronal cell death in ischemic stroke and their therapeutic implications
Tuo, Q., Zhang, S., & Lei, P. (2021) · Medicinal Research Reviews · doi:10.1002/med.21817 · Cited by 747 · 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
GPx4, Lipid Peroxidation, and Cell Death: Discoveries, Rediscoveries, and Open Issues
Maiorino, M., Conrad, M., & Ursini, F. (2017) · Antioxidants and Redox Signaling · doi:10.1089/ars.2017.7115 · Cited by 709 · see citing works
The interaction between ferroptosis and lipid metabolism in cancer
Li, D., & Li, Y. (2020) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-020-00216-5 · Cited by 713 · see citing works
The tumor suppressor protein p53 and the ferroptosis network
Kang, R., Kroemer, G., & Tang, D. (2018) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2018.05.074 · Cited by 701 · see citing works
Nrf2-Keap1 pathway promotes cell proliferation and diminishes ferroptosis
Fan, Z., Wirth, A.-K., Chen, D., Wruck, C. J., Rauh, M., Buchfelder, M., & Savaskan, N. E. (2017) · Oncogenesis · doi:10.1038/oncsis.2017.65 · Cited by 695 · see citing works
Oxidative Stress and Antioxidants in Neurodegenerative Disorders
Olufunmilayo, E. O., Gerke-Duncan, M. B., & Holsinger, R. M. D. (2023) · Antioxidants · doi:10.3390/antiox12020517 · Cited by 722 · 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
The multifaceted role of ferroptosis in liver disease
Chen, J., Li, X., Ge, C., Min, J., & Wang, F. (2022) · Cell Death and Differentiation · doi:10.1038/s41418-022-00941-0 · Cited by 679 · see citing works
Ferroptosis in cancer and cancer immunotherapy
Zhao, L., Zhou, X., Xie, F., Zhang, L., Yan, H., Huang, J., Zhang, C., Zhou, F., Chen, J., & Zhang, L. (2022) · Cancer Communications · doi:10.1002/cac2.12250 · Cited by 684 · see citing works
Molecular mechanisms of ferroptosis and its role in cancer therapy
Xu, T., Ding, W., Ji, X., Ao, X., Liu, Y., Yu, W., & Wang, J. (2019) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.14511 · Cited by 639 · see citing works
Regulated necrosis: disease relevance and therapeutic opportunities
Conrad, M., Angeli, J. P. F., Vandenabeele, P., & Stockwell, B. R. (2016) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2015.6 · Cited by 630 · see citing works
Self-citationHeme oxygenase-1 accelerates erastin-induced ferroptotic cell death
Kwon, M.-Y., Park, E., Lee, S.-J., & Chung, S. W. (2015) · Oncotarget · doi:10.18632/oncotarget.5162 · Cited by 612 · see citing works
Ferroptosis is induced following siramesine and lapatinib treatment of breast cancer cells
Ma, S., Henson, E. S., Chen, Y., & Gibson, S. B. (2016) · Cell Death and Disease · doi:10.1038/cddis.2016.208 · Cited by 627 · see citing works
Lipid Peroxidation-Dependent Cell Death Regulated by GPx4 and Ferroptosis
Imai, H., Matsuoka, M., Kumagai, T., Sakamoto, T., & Koumura, T. (2016) · Current topics in microbiology and immunology · doi:10.1007/82_2016_508 · Cited by 629 · see citing works
Targeting ferroptosis opens new avenues for the development of novel therapeutics
Sun, S., Shen, J., Jiang, J., Wang, F., & Min, J. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01606-1 · Cited by 632 · see citing works
Dixon, S. J., & Stockwell, B. R. (2018) · Annual Review of Cancer Biology · doi:10.1146/annurev-cancerbio-030518-055844 · Cited by 589 · see citing works
Self-citationCell line-based platforms to evaluate the therapeutic efficacy of candidate anticancer agents
Sharma, S. V., Haber, D. A., & Settleman, J. (2010) · Nature reviews. Cancer · doi:10.1038/nrc2820 · Cited by 585 · see citing works
Prominin2 Drives Ferroptosis Resistance by Stimulating Iron Export
Brown, C. W., Amante, J. J., Chhoy, P., Elaimy, A. L., Liu, H., Zhu, L. J., Baer, C. E., Dixon, S. J., & Mercurio, A. M. (2019) · Developmental Cell · doi:10.1016/j.devcel.2019.10.007 · Cited by 582 · see citing works
Ferroptosis, a novel pharmacological mechanism of anti-cancer drugs
Su, Y., Zhao, B., Zhou, L., Zhang, Z., Shen, Y., Lv, H., AlQudsy, L. H. H., & Shang, P. (2020) · Cancer Letters · doi:10.1016/j.canlet.2020.02.015 · Cited by 580 · see citing works
Ferroptosis and Cancer: Mitochondria Meet the “Iron Maiden” Cell Death
Battaglia, A. M., Chirillo, R., Aversa, I., Sacco, A., Costanzo, F. S., & Biamonte, F. (2020) · Cells · doi:10.3390/cells9061505 · Cited by 574 · see citing works
Kell, D. B. (2009) · BMC Medical Genomics · doi:10.1186/1755-8794-2-2 · Cited by 554 · see citing works
p53 in ferroptosis regulation: The new weapon for the old guardian
Liu, Y., & Gu, W. (2022) · Cell Death & Differentiation · doi:10.1038/s41418-022-00943-y · Cited by 540 · see citing works
Iron and cancer: recent insights
Manz, D. H., Blanchette, N. L., Paul, B. T., Torti, F. M., & Torti, S. V. (2016) · Annals of the New York Academy of Sciences · doi:10.1111/nyas.13008 · Cited by 507 · see citing works
Regulation of lipid peroxidation and ferroptosis in diverse species
Conrad, M., Kagan, V. E., Bayir, H., Pagnussat, G. C., Head, B., Traber, M. G., & Stockwell, B. R. (2018) · Genes & Development · doi:10.1101/gad.314674.118 · Cited by 544 · see citing works
Self-citationIdentification of artesunate as a specific activator of ferroptosis in pancreatic cancer cells
Eling, N., Reuter, L., Hazin, J., Hamacher-Brady, A., & Brady, N. R. (2015) · Oncoscience · doi:10.18632/oncoscience.160 · Cited by 524 · see citing works
Mechanisms of Ferroptosis and Relations With Regulated Cell Death: A Review
Lei, P., Bai, T., & Sun, Y. (2019) · Frontiers in Physiology · doi:10.3389/fphys.2019.00139 · Cited by 535 · see citing works
Oxidative Damage and Antioxidant Defense in Ferroptosis
Kuang, F., Liu, J., Tang, D., & Kang, R. (2020) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.586578 · Cited by 539 · see citing works
Xu, C., Sun, S., Johnson, T. S., Qi, R. A., Zhang, S., Zhang, J., & Yang, K. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.109235 · Cited by 528 · 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
Selective covalent targeting of GPX4 using masked nitrile-oxide electrophiles
Eaton, J. K., Furst, L., Ruberto, R. A., Moosmayer, D., Hilpmann, A., Ryan, M. J., Zimmermann, K. C., Cai, L. L., Niehues, M., Badock, V., et al. (2020) · Nature Chemical Biology · doi:10.1038/s41589-020-0501-5 · Cited by 510 · see citing works
Reactive Oxygen Species (ROS) Regulates Different Types of Cell Death by Acting as a Rheostat
Villalpando-Rodriguez, G. E., & Gibson, S. B. (2021) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2021/9912436 · Cited by 498 · see citing works
Striking while the iron is hot: Iron metabolism and ferroptosis in neurodegeneration
Masaldan, S., Bush, A. I., Devos, D., Rolland, A., & Moreau, C. (2018) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2018.09.033 · Cited by 485 · see citing works
Yan, Y., Xie, Y., Cao, L., Yang, L., Yang, M., Lotze, M. T., Zeh, H. J., Kang, R., & Tang, D. (2015) · Molecular & Cellular Oncology · doi:10.1080/23723556.2015.1054549 · Cited by 467 · 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
Ferroptosis and Its Role in Diverse Brain Diseases
Weiland, A., Wang, Y., Wu, W., Lan, X., Han, X., Li, Q., & Wang, J. (2018) · Molecular Neurobiology · doi:10.1007/s12035-018-1403-3 · Cited by 469 · see citing works
A Dual Role of Heme Oxygenase-1 in Cancer Cells
Chiang, S.-K., Chen, S., & Chang, L. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms20010039 · Cited by 466 · see citing works
The Role of Erastin in Ferroptosis and Its Prospects in Cancer Therapy
Zhao, Y., Li, Y., Zhang, R., Wang, F., Wang, T., & Jiao, Y. (2020) · OncoTargets and Therapy · doi:10.2147/ott.s254995 · Cited by 459 · see citing works
Redox-Directed Cancer Therapeutics: Molecular Mechanisms and Opportunities
Wondrak, G. T. (2009) · Antioxidants & Redox Signaling · doi:10.1089/ars.2009.2541 · Cited by 462 · see citing works
Hayano, M., Yang, W., Corn, C. K., Pagano, N. C., & Stockwell, B. R. (2015) · Cell Death and Differentiation · doi:10.1038/cdd.2015.93 · Cited by 462 · see citing works
Self-citationmiR-137 regulates ferroptosis by targeting glutamine transporter SLC1A5 in melanoma
Luo, M., Wu, L., Zhang, K., Wang, H., Zhang, T., Gutierrez, L., O’Connell, D., Zhang, P., Li, Y., Gao, T., et al. (2018) · Cell Death and Differentiation · doi:10.1038/s41418-017-0053-8 · Cited by 455 · see citing works
The multifaceted role of reactive oxygen species in tumorigenesis
Kirtonia, A., Sethi, G., & Garg, M. (2020) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-020-03536-5 · Cited by 452 · see citing works
The diversified role of mitochondria in ferroptosis in cancer
Liu, Y., Lu, S.-P., Wu, L., Yang, L., Wang, J., & Wang, J. (2023) · Cell Death and Disease · doi:10.1038/s41419-023-06045-y · Cited by 473 · see citing works
Regulated cell death in myocardial ischemia–reperfusion injury
Xiang, Q., Yi, X., Zhu, X., Wei, X., & Jiang, D. (2023) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2023.10.010 · Cited by 459 · see citing works
Masaldan, S., Clatworthy, S. A. S., Gamell, C., Meggyesy, P. M., Rigopoulos, A.-T., Haupt, S., Haupt, Y., Denoyer, D., Adlard, P. A., Bush, A. I., et al. (2018) · Redox Biology · doi:10.1016/j.redox.2017.08.015 · Cited by 452 · see citing works
Lipoxygenase‐mediated generation of lipid peroxides enhances ferroptosis induced by erastin and RSL3
Shintoku, R., Takigawa, Y., Yamada, K., Kubota, C., Yoshimoto, Y., Takeuchi, T., Koshiishi, I., & Torii, S. (2017) · Cancer Science · doi:10.1111/cas.13380 · Cited by 453 · see citing works
The Role of Ferroptosis in Cancer Development and Treatment Response
Lu, B., Chen, X. B., Ying, M. D., He, Q. J., Cao, J., & Yang, B. (2018) · Frontiers in Pharmacology · doi:10.3389/fphar.2017.00992 · Cited by 444 · see citing works
Breakdown of an Ironclad Defense System: The Critical Role of NRF2 in Mediating Ferroptosis
Anandhan, A., Dodson, M. B., Schmidlin, C. J., Liu, P., & Zhang, D. D. (2020) · Cell chemical biology · doi:10.1016/j.chembiol.2020.03.011 · Cited by 439 · see citing works
- Authors
- Yang, W. S., & Stockwell, B. R.
- Affiliations
- Columbia University (US)
- Corresponding author
- Stockwell, Brent R.
- Venue
- Chemistry & Biology
- Publisher
- Elsevier BV
- Published
- 2008-03
- Volume
- 15
- Issue
- 3
- Pages
- 234-245
- ISSN
- 1074-5521 (ISSN-L)
- PMC
- PMC2683762
- OpenAlex
- W2114138419
- Cited by
- 1,876
- References
- 35
- Citations by year
- 2026: 138 · 2025: 231 · 2024: 319 · 2023: 312 · 2022: 271 · 2021: 202 · 2020: 135 · 2019: 66 · 2018: 58 · 2017: 38 · 2016: 35 · 2015: 19 · 2014: 11 · 2013: 7 · 2012: 10
- FWCI
- 3.16
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Chemistry & Biology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (R01CA097061)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Ferroptosis and cancer prognosis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- synthetic lethality, oncogenic Ras, RSL3, erastin, non-apoptotic cell death, iron-dependent cell death, oxidative cell death, VDAC3, voltage-dependent anion channel, transferrin receptor 1, ferritin, iron metabolism, small molecule screening, cancer cell death
- MeSH terms
- Drug Evaluation, Preclinical, Humans, Iron, Mutation, Neoplasms, Piperazines, Substrate Specificity, Gene Expression Regulation, Neoplastic, Proto-Oncogene Proteins p21(ras), Cell Death, Apoptosis, Cell Line, Tumor, Voltage-Dependent Anion Channels, Small Molecule Libraries
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