Ferroptosis is an autophagic cell death process
Open accessAbstract
Ferroptosis is an iron-dependent form of regulated necrosis. It is implicated in various human diseases, including ischemic organ damage and cancer. Here, we report the crucial role of autophagy, particularly autophagic degradation of cellular iron storage proteins (a process known as ferritinophagy), in ferroptosis. Using RNAi screening coupled with subsequent genetic analysis, we identified multiple autophagy-related genes as positive regulators of ferroptosis. Ferroptosis induction led to autophagy activation and consequent degradation of ferritin and ferritinophagy cargo receptor NCOA4. Consistently, inhibition of ferritinophagy by blockage of autophagy or knockdown of NCOA4 abrogated the accumulation of ferroptosis-associated cellular labile iron and reactive oxygen species, as well as eventual ferroptotic cell death. Therefore, ferroptosis is an autophagic cell death process, and NCOA4-mediated ferritinophagy supports ferroptosis by controlling cellular iron homeostasis.
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Ferroptosis is promoted by autophagic degradation of ferritin (ferritinophagy).
“ferroptosis, which is promoted by the autophagic degradation of ferritin (ferritinophagy) [573, 574]”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [574]
Erastin induces ferroptosis through silencing SLC7A11 and enhances iron bioavailability through autophagic/lysosomal degradation of ferritin and NCOA4.
“Erastin induces ferroptosis through silencing SLC7A11 [84] and was recently demonstrated to enhance iron bioavailability through autophagic/lysosomal degradation of ferritin and its cargo receptor NCOA4 [63].”
From Iron accumulation in senescent cells is coupled with impaired ferritinophagy and inhibition of ferroptosis (2018) · cites this paper as [63]
Ferroptosis is an iron-dependent autophagic cell death program that can be inhibited in MEFs by genetically inactivating autophagy or ferritinophagy.
“an iron-dependent autophagic cell death program [62], [63], [64] that can be inhibited in MEFs by genetically inactivating autophagy or ferritinophagy [65].”
From Iron accumulation in senescent cells is coupled with impaired ferritinophagy and inhibition of ferroptosis (2018) · cites this paper as [63]
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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
Repertoires of Autophagy in the Pathogenesis of Ocular Diseases
Li, Y., Jiang, Q. L., Cao, G.-F., Yao, J., & Yan, B. (2015) · Cellular Physiology and Biochemistry · doi:10.1159/000373980 · Cited by 16,351 · 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
Cillà, S. D., Farruggio, S., Vujosevic, S., Raina, G., Filippini, D. A., Gatti, V., Clemente, N., Mary, D., Vezzola, D., Casini, G., et al. (2017) · Cellular Physiology and Biochemistry · doi:10.1159/000479441 · Cited by 5,153 · see citing works
Danial, N. N., & Korsmeyer, S. J. (2004) · Cell · doi:10.1016/s0092-8674(04)00046-7 · Cited by 4,651 · see citing works
Autophagy: process and functionPreprint
Mizushima, N. (2007) · Genes & Development · doi:10.1101/gad.1599207 · Cited by 3,964 · 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
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
The Pathophysiology of Mitochondrial Cell Death
Green, D. R., & Kroemer, G. (2004) · Science · doi:10.1126/science.1099320 · Cited by 3,416 · 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
Pyroptosis: host cell death and inflammation
Bergsbaken, T., Fink, S. L., & Cookson, B. T. (2009) · Nature Reviews Microbiology · doi:10.1038/nrmicro2070 · Cited by 3,185 · 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
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
Rahman, I., Kode, A., & Biswas, S. K. (2006) · Nature Protocols · doi:10.1038/nprot.2006.378 · Cited by 2,262 · see citing works
Dixon, S. J., Patel, D. N., Welsch, M., Skouta, R., Lee, E. D., Hayano, M., Thomas, A. G., Gleason, C. E., Tatonetti, N. P., Slusher, B. S., et al. (2014) · eLife · doi:10.7554/elife.02523 · Cited by 2,088 · 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
Self-citationProgrammed Cell Death in Animal Development and Disease
Fuchs, Y., & Steller, H. (2011) · Cell · doi:10.1016/j.cell.2011.10.033 · Cited by 1,915 · see citing works
Mathew, R., Karantza-Wadsworth, V., & White, E. (2007) · Nature Reviews Cancer · doi:10.1038/nrc2254 · Cited by 1,798 · see citing works
Regulated necrosis: the expanding network of non-apoptotic cell death pathways
Berghe, T. V., Linkermann, A., Jouan-Lanhouet, S., Walczak, H., & Vandenabeele, P. (2014) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3737 · Cited by 1,735 · 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
Synchronized renal tubular cell death involves ferroptosis
Linkermann, A., Skouta, R., Himmerkus, N., Mulay, S. R., Dewitz, C., De Zen, F., Prokai, A., Zuchtriegel, G., Krombach, F., Welz, P.-S., et al. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1415518111 · Cited by 1,126 · 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
Another way to die: autophagic programmed cell death
Tsujimoto, Y., & Shimizu, S. (2005) · Cell Death and Differentiation · doi:10.1038/sj.cdd.4401777 · Cited by 755 · see citing works
Autosis and autophagic cell death: the dark side of autophagy
Liu, Y., & Levine, B. (2014) · Cell Death and Differentiation · doi:10.1038/cdd.2014.143 · Cited by 746 · see citing works
Autophagic programmed cell death by selective catalase degradation
Yu, L., Wan, F., Dutta, S., Welsh, S., Liu, Z., Freundt, E. C., Baehrecke, E. H., & Lenardo, M. J. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0511288103 · Cited by 668 · see citing works
Andrews, N. C., & Schmidt, P. J. (2006) · Annual Review of Physiology · doi:10.1146/annurev.physiol.69.031905.164337 · Cited by 640 · see citing works
Liu, Y., Shoji-Kawata, S., Sumpter, R. M., Wei, Y., Ginet, V., Zhang, L., Posner, B., Tran, K. A., Green, D. R., Xavier, R. J., et al. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1319661110 · Cited by 607 · see citing works
Mancias, J. D., Pontano Vaites, L., Nissim, S., Biancur, D. E., Kim, A. J., Wang, X., Liu, Y., Goessling, W., Kimmelman, A. C., & Harper, J. W. (2015) · eLife · doi:10.7554/elife.10308 · Cited by 552 · see citing works
The Role of the Kinases RIP1 and RIP3 in TNF-Induced Necrosis
Vandenabeele, P., Declercq, W., Van Herreweghe, F., & Vanden Berghe, T. (2010) · Science Signaling · doi:10.1126/scisignal.3115re4 · Cited by 482 · see citing works
RIP3: a molecular switch for necrosis and inflammationPreprint
Moriwaki, K., & Chan, F. K.-M. (2013) · Genes & Development · doi:10.1101/gad.223321.113 · Cited by 353 · see citing works
Alternative cell death mechanisms in development and beyondPreprint
Yuan, J., & Kroemer, G. (2010) · Genes & Development · doi:10.1101/gad.1984410 · Cited by 290 · see citing works
NCOA4 deficiency impairs systemic iron homeostasis
Bellelli, R., Federico, G., Matte’, A., Colecchia, D., Iolascon, A., Chiariello, M., Santoro, M., De Franceschi, L., & Carlomagno, F. (2016) · Cell Reports · doi:10.1016/j.celrep.2015.12.065 · Cited by 248 · see citing works
Autophagy in cellular metabolism and cancer
Jiang, X., Overholtzer, M., & Thompson, C. B. (2015) · Journal of Clinical Investigation · doi:10.1172/jci73942 · Cited by 198 · see citing works
Self-citationFlow cytometry measurement of the labile iron pool in human hematopoietic cells
Prus, E., & Fibach, E. (2007) · Cytometry Part A · doi:10.1002/cyto.a.20491 · Cited by 129 · see citing works
Metabolism and iron signaling in ferroptotic cell death
Gao, M., Monian, P., & Jiang, X. (2015) · Oncotarget · doi:10.18632/oncotarget.5671 · Cited by 71 · see citing works
Self-citationBlum, E. S., Abraham, M. C., Yoshimura, S., Lu, Y., & Shaham, S. (2012) · Science · doi:10.1126/science.1215156 · Cited by 70 · see citing works
Phospholipase D2 Is Required for Efficient Endocytic Recycling of Transferrin Receptors
Padrón, D., Tall, R. D., & Roth, M. G. (2005) · Molecular Biology of the Cell · doi:10.1091/mbc.e05-05-0389 · Cited by 58 · see citing works
Flagged first, then by citations
Research works printed but not linked: 1
- Danial NN, Korsmeyer SJ. Cell death: Critical control points. Cell 2004; 116:205-219.
Cited by
Sorted by citations
Ferroptosis: 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-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
Targeting Ferroptosis as a Vulnerability in Cancer
Lei, G., Zhuang, L., & Gan, B. (2022) · Nature reviews. Cancer · doi:10.1038/s41568-022-00459-0 · Cited by 2,252 · see citing works
Kastenhuber, E. R., & Lowe, S. W. (2017) · Cell · doi:10.1016/j.cell.2017.08.028 · Cited by 1,906 · see citing works
Role of GPX4 in ferroptosis and its pharmacological implication
Seibt, T. M., Proneth, B., & Conrad, M. (2019) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2018.09.014 · Cited by 1,520 · 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
Cysteine depletion induces pancreatic tumor ferroptosis in mice
Badgley, M. A., Kremer, D. M., Maurer, H. C., DelGiorno, K. E., Lee, H.-J., Purohit, V., Sagalovskiy, I. R., Ma, A., Kapilian, J., Firl, C. E. M., et al. (2020) · Science · doi:10.1126/science.aaw9872 · Cited by 1,294 · see citing works
Ferroptosis: Role of lipid peroxidation, iron and ferritinophagy
Latunde-Dada, G. O. (2017) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2017.05.019 · Cited by 892 · see citing works
The emerging role of ferroptosis in inflammation
Sun, Y., Chen, P., Zhai, B., Zhang, M., Xiang, Y., Fang, J., Xu, S., Gao, Y., Chen, X., Sui, X., et al. (2020) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2020.110108 · Cited by 739 · see citing works
Ferroptosis Inhibition: Mechanisms and Opportunities
Angeli, J. P. F., Shah, R., Pratt, D. A., & Conrad, M. (2017) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2017.02.005 · Cited by 563 · see citing works
Involvement of cigarette smoke-induced epithelial cell ferroptosis in COPD pathogenesis
Yoshida, M., Minagawa, S., Araya, J., Sakamoto, T., Hara, H., Tsubouchi, K., Hosaka, Y., Ichikawa, A., Saito, N., Kadota, T., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-10991-7 · Cited by 572 · 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
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
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
Torti, S. V., Manz, D. H., Paul, B. T., Blanchette-Farra, N., & Torti, F. M. (2018) · Annual Review of Nutrition · doi:10.1146/annurev-nutr-082117-051732 · Cited by 426 · see citing works
The chemistry and biology of ferroptosis
Stockwell, B. R., & Jiang, X. (2020) · Cell chemical biology · doi:10.1016/j.chembiol.2020.03.013 · Cited by 429 · see citing works
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Autophagy-dependent cell death—where.; how and why a cell eats itself to death
Bialik, S., Dasari, S. K., & Kimchi, A. (2018) · Journal of Cell Science · doi:10.1242/jcs.215152 · Cited by 295 · see citing works
Chemistry and biology of ferritin
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NCOA4-Mediated Ferritinophagy: A Potential Link to Neurodegeneration
Quiles del Rey, M., & Mancias, J. D. (2019) · Frontiers in Neuroscience · doi:10.3389/fnins.2019.00238 · Cited by 227 · see citing works
Chaudhary, N., Choudhary, B. S., Shah, S. G., Khapare, N., Dwivedi, N., Gaikwad, A., Joshi, N., Raichanna, J., Basu, S., Gurjar, M., et al. (2021) · International Journal of Cancer · doi:10.1002/ijc.33711 · Cited by 185 · see citing works
Iron in the Tumor Microenvironment-Connecting the Dots
Pfeifhofer-Obermair, C., Tymoszuk, P., Petzer, V., Weiss, G., & Nairz, M. (2018) · Frontiers in Oncology · doi:10.3389/fonc.2018.00549 · Cited by 151 · see citing works
Wei, X.-B., Jiang, W.-Q., Zeng, J.-H., Huang, L.-Q., Ding, H.-G., Jing, Y.-W., Han, Y.-L., Li, Y.-C., & Chen, S.-L. (2022) · Molecular Neurobiology · doi:10.1007/s12035-022-02738-1 · Cited by 123 · see citing works
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Dasari, S. K., Bialik, S., Levin-Zaidman, S., Levin-Salomon, V., Merrill, A. H., Futerman, A. H., & Kimchi, A. (2017) · Cell Death & Differentiation · doi:10.1038/cdd.2017.80 · Cited by 95 · 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
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Wang, T., Xu, S.-F., Fan, Y.-G., Li, L.-B., & Guo, C. (2019) · Advances in experimental medicine and biology · doi:10.1007/978-981-13-9589-5_5 · Cited by 64 · 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
The interplay of autophagy and non-apoptotic cell death pathways
(2020) · International Review of Cell and Molecular Biology · doi:10.1016/bs.ircmb.2019.12.004 · Cited by 50 · see citing works
Cheng, X., Zhao, F., Ke, B., Chen, D., & Liu, F. (2023) · Cancers · doi:10.3390/cancers15215209 · Cited by 44 · 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
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- Authors
- Gao, M., Monian, P., Pan, Q., Zhang, W., Xiang, J., & Jiang, X.
- Affiliations
- Tongji University (CN)
- Memorial Sloan Kettering Cancer Center (US)
- Weill Cornell Medicine (US)
- Corresponding author
- Gao, Minghui
- Jiang, Xuejun
- Venue
- Cell Research
- Published
- 2016-08-12
- Volume
- 26
- Issue
- 9
- Pages
- 1021-1032
- ISSN
- 1001-0602 (ISSN-L)
- 1748-7838
- PMC
- PMC5034113
- OpenAlex
- W2518357275
- Cited by
- 1,899
- References
- 38
- Citations by year
- 2026: 225 · 2025: 286 · 2024: 321 · 2023: 297 · 2022: 272 · 2021: 213 · 2020: 115 · 2019: 78 · 2018: 52 · 2017: 34 · 2016: 5
- FWCI
- 50.38
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Cell Research (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (CA008748)
- National Cancer Institute (CA008748, R01CA166413, P30CA008748)
- National Institute of General Medical Sciences (R01GM113013)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Ferroptosis and cancer prognosis
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Keywords
- ferroptosis, autophagy, ferritinophagy, NCOA4, ferritin degradation, cellular iron homeostasis, labile iron, reactive oxygen species, regulated necrosis, autophagy-related genes, RNAi screening
- MeSH terms
- Animals, Autophagy, Ferritins, Genetic Testing, Homeostasis, Humans, Iron, Apoptosis, Reactive Oxygen Species, RNA Interference, Mice, Nuclear Receptor Coactivators
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