T cell lipid peroxidation induces ferroptosis and prevents immunity to infection
Open accessAbstract
The selenoenzyme glutathione peroxidase 4 (Gpx4) is a major scavenger of phospholipid hydroperoxides. Although Gpx4 represents a key component of the reactive oxygen species-scavenging network, its relevance in the immune system is yet to be defined. Here, we investigated the importance of Gpx4 for physiological T cell responses by using T cell–specific Gpx4-deficient mice. Our results revealed that, despite normal thymic T cell development, CD8+ T cells from TΔGpx4/ΔGpx4 mice had an intrinsic defect in maintaining homeostatic balance in the periphery. Moreover, both antigen-specific CD8+ and CD4+ T cells lacking Gpx4 failed to expand and to protect from acute lymphocytic choriomeningitis virus and Leishmania major parasite infections, which were rescued with diet supplementation of high dosage of vitamin E. Notably, depletion of the Gpx4 gene in the memory phase of viral infection did not affect T cell recall responses upon secondary infection. Ex vivo, Gpx4-deficient T cells rapidly accumulated membrane lipid peroxides and concomitantly underwent cell death driven by ferroptosis but not necroptosis. These studies unveil an essential role of Gpx4 for T cell immunity.
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Inducible or tissue-specific ablation of Gpx4 in mice provokes acute renal or hepatic injury, neurodegeneration, and defective immunity to infection, all preventable or mitigated by ferroptosis-inhibiting strategies.
“the inducible or tissue-specific ablation of Gpx4 in mice provokes a variety of pathological conditions, including acute renal or hepatic injury [547, 563, 589], neurodegeneration [550, 590, 591], and defective immunity to infection [567], all of which can be prevented or mitigated by ferroptosis-inhibiting strategies.”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [567]
GPX4 is essential for the survival and expansion of recently activated T cells.
“GPX4 is essential for the survival and expansion of recently activated T cells, indicating the importance of preventing lipid peroxidation and of iron dysregulation resulting in ferroptosis, in T cell proliferation (Matsushita et al., 2015).”
From The Role of Iron Regulation in Immunometabolism and Immune-Related Disease (2019) · cites this paper as Matsushita et al., 2015
Preventing lipid peroxidation and iron dysregulation resulting in ferroptosis is important in T cell proliferation.
“GPX4 is essential for the survival and expansion of recently activated T cells, indicating the importance of preventing lipid peroxidation and of iron dysregulation resulting in ferroptosis, in T cell proliferation (Matsushita et al., 2015).”
From The Role of Iron Regulation in Immunometabolism and Immune-Related Disease (2019) · cites this paper as Matsushita et al., 2015
Gpx4 is crucial for the survival of CD8+ T cells and for the expansion of both CD4+ and CD8+ T cells upon T cell receptor triggering in response to infection by preventing membrane lipid peroxidation and ferroptosis.
“Gpx4 exerts important effects on the immune system as it is crucial for the survival of CD8+ T cells and for the expansion of both CD4+ and CD8+ T cells upon T cell receptor triggering in response to infection by preventing membrane lipid peroxidation and ferroptosis”
From Iron in immune cell function and host defense (2021) · cites this paper as [112]
High levels of reactive oxygen species in T cells impair cytotoxicity, perhaps mediated by T cell lipid peroxidation, resulting in failure to control viruses.
“and high levels of reactive oxygen species in T cells impair cytotoxicity, perhaps mediated by T cell lipid peroxidation, resulting in failure to control viruses (Henson et al. 2014; Matsushita et al. 2015).”
From Is immunosenescence influenced by our lifetime “dose” of exercise? (2016) · cites this paper as Matsushita et al. 2015
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BackgroundActivated human CD4+ T cells express transporters for both cysteine and cystine
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“Earlier studies have suggested that Gpx4 inactivation in murine fibroblasts result in apoptosis-inducing factor (AIF)-mediated cell death as a consequence of lipid peroxide accumulation catalyzed specifically by 12/15-lipoxygenase in vitro (Seiler et al., 2008; Schneider et al., 2010).”
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“Moreover, mitochondria are a major source of ROS and mitochondrial ROS is essential for T cell activation, expansion and effector function (Sena et al., 2013; Yi et al., 2006).”
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“As it has been reported that normoxia increases oxygen radicals and promotes hydrogen peroxides generation (Fan et al., 2008), the effect in vitro suggests that the Gpx4deficient T cells acquire damage already ex vivo as a consequence of high oxygen levels in normoxic conditions, which provoked the…”
BackgroundCoxsackievirus B3-resistant mice become susceptible in Se/vitamin E deficiency
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“Also, studies have suggested a synergistic relationship between selenium and vitamin E to inhibit lipid peroxidation (Navarro et al., 1998; Beck et al., 2003).”
BackgroundExpression of 5‐lipoxygenase (5‐LOX) in T lymphocytes
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“Concurrently, it is well appreciated that ROS are at the interface of several cell signaling pathways that regulate cell proliferation, differentiation, and death (D’Autréaux and Toledano, 2007; Finkel, 2011; Ray et al., 2012).”
BackgroundImmune and inflammatory mechanisms
Castellano, G., Cafiero, C., Divella, C., Sallustio, F., Gigante, M., Gesualdo, L., Kirsch, A. H., Smaczny, N., Riegelbauer, V., Sedej, S., et al. (2013) · Nephrology Dialysis Transplantation · doi:10.1093/ndt/gft142 · Cited by 4 · see citing works
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Ferroptosis: mechanisms, biology and role in disease
Jiang, X., Stockwell, B. R., & Conrad, M. (2021) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-020-00324-8 · Cited by 7,698 · 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
“acute renal or hepatic injury [547, 563, 589], neurodegeneration [550, 590, 591], and defective immunity to infection [567], all of which can be prevented or mitigated by ferroptosis-inhibiting strategies.”
BackgroundSelf-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
Self-citationFerroptosis: molecular mechanisms and health implications
Tang, D., Chen, X., Kang, R., & Kroemer, G. (2020) · Cell Research · doi:10.1038/s41422-020-00441-1 · Cited by 4,332 · 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
“Thus, the most important objective in the study of ferroptosis is to identify the downstream signaling pathways or executors of iron-dependent ROS metabolism to distinguish ferroptosis from other types of RCD. Induction of ferroptosis by drugs has been shown to inhibit cancer cell growth in both a Ras-dependent and -i…”
BackgroundInfluentialFerroptosis: 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
“In addition, conditional deletion of Gpx4 in T cells in mice resulted in T cell ferroptosis, resulting in lack of an immune response to infection [46]; this suggests that Gpx4 is essential for a functional T-cell-mediated immune response.”
BackgroundOxidized 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-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
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
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
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
Self-citationCao, 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
“However, both antigenspecific CD8 and CD4 T cells failed to expand and to protect from acute infections, and CD8 T cells had an intrinsic defect in maintaining homeostatic balance in the periphery,(190) which can be rescued with a high dosage of vitamin E.(190) Ferroptosis also plays a significant role in CD8 T cell-i…”
BackgroundThe 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
Self-citationFerroptosis at the crossroads of cancer-acquired drug resistance and immune evasion
Angeli, J. P. F., Krysko, D. V., & Conrad, M. (2019) · Nature reviews. Cancer · doi:10.1038/s41568-019-0149-1 · Cited by 1,262 · see citing works
Self-citationEmerging 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
“5 days post conception (dpc), conditional-Gpx4-mutant mice revealed that GPX4 loss not only induces ferroptosis, but also results in neurodegeneration [19], loss of antiviral immunity [61], infertility, and ischemia/reperfusion injury in kidney and liver [27,28,62,63].”
BackgroundIdentification of ACSL4 as a biomarker and contributor of ferroptosis
Yuan, H., Li, X., Zhang, X., Kang, R., & Tang, D. (2016) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2016.08.124 · Cited by 1,071 · 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
Ma, X., Xiao, L., Liu, L., Ye, L., Pan, S., Bi, E., Wang, Q., Yang, M., Qian, J., & Yi, Q. (2021) · Cell Metabolism · doi:10.1016/j.cmet.2021.02.015 · Cited by 1,022 · see citing works
The Tumor Suppressor p53 Limits Ferroptosis by Blocking DPP4 Activity
Xie, Y., Zhu, S., Song, X., Sun, X., Fan, Y., Liu, J., Zhong, M., Yuan, H., Zhang, L., Billiar, T. R., et al. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.07.055 · Cited by 952 · see citing works
“…prevents nuclear accumulation of DPP4 and then triggers membrane-associated DPP4-mediated lipid peroxidation, which finally results in ferroptosis. are sensitive to erastin (Friedmann Angeli et al., 2014; Jiang et al., 2015; Linkermann et al., 2014; Matsushita et al., 2015; Skouta et al., 2014).”
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
Ferroptosis in cancer: from molecular mechanisms to therapeutic strategies
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
“35,42 However, genetic deletion of Alox15 in Gpx4 knockout mice failed to avert ferroptosis in vivo, 8 and Alox12/15 failed to restore the viability of Gpx4 de fi cient T cells, 79 suggesting the existence of alternative mechanisms in certain contexts of ferroptosis.”
BackgroundRegulators of Iron Homeostasis: New Players in Metabolism, Cell Death, and Disease
Bogdan, A. R., Miyazawa, M., Hashimoto, K., & Tsuji, Y. (2015) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2015.11.012 · Cited by 897 · see citing works
“peroxidase 4 (GPX4) [42,50,51], and the glutamate-cystine antiporter (also known as system xc, and is crucial for glutathione biosynthesis) [52] (Figure 2).”
BackgroundInfluentialALOX12 is required for p53-mediated tumour suppression through a distinct ferroptosis pathway
Chu, B., Kon, N., Chen, D., Li, T., Liu, T., Jiang, L., Song, S., Tavana, O., & Gu, W. J. (2019) · Nature Cell Biology · doi:10.1038/s41556-019-0305-6 · Cited by 885 · see citing works
Hambright, W. S., Fonseca, R. S., Chen, L., Na, R., & Ran, Q. (2017) · Redox Biology · doi:10.1016/j.redox.2017.01.021 · Cited by 851 · see citing works
“Subsequently, it was shown that ablation of Gpx4 induces ferroptosis in cell types such as renal tubular cells and T lymphocytes [13,18].”
BackgroundPlasticity of ether lipids promotes ferroptosis susceptibility and evasion
Zou, Y., Henry, W. S., Ricq, E. L., Graham, E. T., Phadnis, V. V., Maretich, P., Paradkar, S., Boehnke, N., Deik, A., Reinhardt, F., et al. (2020) · Nature · doi:10.1038/s41586-020-2732-8 · Cited by 849 · see citing works
Ferroptosis in infection, inflammation, and immunity
Chen, X., Kang, R., Kroemer, G., & Tang, D. (2021) · The Journal of Experimental Medicine · doi:10.1084/jem.20210518 · Cited by 828 · see citing works
“Third, the genetic depletion of Gpx4 or treatment with GPX4 inhibitors (e.g., RSL3, ML162, and ML210) induces lipid peroxidation and concomitantly ferroptotic cell death in T cells in vitro (Drijvers et al., 2021; Matsushita et al., 2015).”
BackgroundInfluentialXu, S., Chaudhary, O., Rodríguez-Morales, P., Sun, X., Chen, D., Zappasodi, R., Xu, Z. Z., Pinto, A. F. M., Williams, A. E., Schulze, I., et al. (2021) · Immunity · doi:10.1016/j.immuni.2021.05.003 · Cited by 815 · 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
“Notably, the conditional depletion of GPX4 in tissues or cells can cause oxidative injury or cell death in both ferroptosis-dependent and -independent manners (Canli et al., 2016; Cole-Ezea et al., 2012; Friedmann Angeli et al., 2014; Kang et al., 2018a; Matsushita et al., 2015; Ran et al., 2006; Ran et al., 2004; Ran…”
BackgroundSignaling 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
Mechanisms controlling cellular and systemic iron homeostasis
Galy, B., Conrad, M., & Muckenthaler, M. U. (2023) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-023-00648-1 · Cited by 806 · see citing works
Self-citationZhou, N., & Bao, J. (2020) · Database · doi:10.1093/database/baaa021 · Cited by 787 · see citing works
“Acute lymphocytic choriomeningitis virus and Leishmania major parasite infections benefit from ferroptosis (8).”
BackgroundResolving 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
AMPK-Mediated BECN1 Phosphorylation Promotes Ferroptosis by Directly Blocking System Xc– Activity
Song, X., Zhu, S., Chen, P., Hou, W., Wen, Q., Liu, J., Xie, Y., Liu, J., Klionsky, D. J., Kroemer, G., et al. (2018) · Current Biology · doi:10.1016/j.cub.2018.05.094 · Cited by 753 · 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
A non-canonical vitamin K cycle is a potent ferroptosis suppressor
Mishima, E., Ito, J., Wu, Z., Nakamura, T., Wahida, A., Doll, S. G., Tonnus, W., Nepachalovich, P., Eggenhofer, E., Aldrovandi, M., et al. (2022) · Nature · doi:10.1038/s41586-022-05022-3 · Cited by 730 · see citing works
Self-citationGPx4, 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
“For instance, suf-ficient a -tocopherol content in the mouse chow or supra-nutritional a -tocopherol supplementation was demonstrated to compensate for the loss of GPx4 in endothelial cells (115), CD8 + T cells (72), and hepatocytes of newborn pups (18).”
Self-citationThe 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
“15-LOX modulates the ferroptotic endurance in macrophages, similar to that in tumor cells,(115,117) while solely knocking out 12/15-LOX is insufficient to prevent lipid peroxidation in T cells.(11,118) Instead, 5LOX may be responsible for toxic lipid peroxidation in T cells lacking GPX4.”
BackgroundCold and hot tumors: from molecular mechanisms to targeted therapy
Wu, B., Zhang, B., Li, B., Wu, H., & Jiang, M. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-01979-x · Cited by 751 · see citing works
Metallothionein‐1G facilitates sorafenib resistance through inhibition of ferroptosis
Sun, X., Niu, X., Chen, R., He, W., Chen, D., Kang, R., & Tang, D. (2016) · Hepatology · doi:10.1002/hep.28574 · Cited by 707 · see citing works
“In addition to cancer therapy,((28)) impaired ferroptosis involves tissue injury,((26,35)) immunity tolerance,((36)) and stem cell division.”
BackgroundThe 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
“Genetic depletion of GPX4 can trigger ferroptosis in an iron-, MEK-, and ROS-dependent manner in vitro or in vivo [23,24,31].”
Redox lipid reprogramming commands susceptibility of macrophages and microglia to ferroptotic death
Kapralov, A. A., Yang, Q., Dar, H. H., Tyurina, Y. Y., Anthonymuthu, T. S., Kim, R., Croix, C. M. S., Mikulska‐Ruminska, K., Liu, B., Shrivastava, I. H., et al. (2020) · Nature Chemical Biology · doi:10.1038/s41589-019-0462-8 · Cited by 657 · see citing works
Amino Assets: How Amino Acids Support Immunity
Kelly, B. L., & Pearce, E. L. (2020) · Cell Metabolism · doi:10.1016/j.cmet.2020.06.010 · Cited by 653 · see citing works
GPX4 in cell death, autophagy, and disease
Xie, Y., Kang, R., Klionsky, D. J., & Tang, D. (2023) · Autophagy · doi:10.1080/15548627.2023.2218764 · Cited by 652 · see citing works
“A mouse model with conditional knockout of Gpx4 in T cells displays a phenotype of accumulated membrane lipid peroxides, leading to an intrinsic defect in protecting against acute lymphocytic choriomeningitis virus and Leishmania major parasite infections [28].”
BackgroundInfluentialRegulated 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-citationFerroptosis 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
“The cystine uptake inhibitor erastin has been shown to block GSH activation leading to accumulation of ROS and ferroptosis.(23,33)We found that both erastin and the combination of siramesine and lapatinib-induced cell death was promoted by inhibition of cystine transport.”
BackgroundLipid 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
Lipid Peroxidation Drives Gasdermin D-Mediated Pyroptosis in Lethal Polymicrobial Sepsis
Kang, R., Zeng, L., Zhu, S., Xie, Y., Liu, J., Wen, Q., Cao, L., Xie, M., Ran, Q., Kroemer, G., et al. (2018) · Cell Host & Microbe · doi:10.1016/j.chom.2018.05.009 · Cited by 620 · see citing works
“, 2015), viral and parasitic infections (Matsushita et al., 2015), male subfertility (Brutsch et al.”
BackgroundTargeting 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
“85 With respect to B cells, various B cell populations have been shown to respond differently to ferroptosis induction.”
BackgroundSepsis-induced immunosuppression: mechanisms, diagnosis and current treatment options
Liu, D., Huang, S., Sun, J., Zhang, H., Cai, Q., Gao, C., Li, L., Cao, J., Xu, F., Zhou, Y., et al. (2022) · Military Medical Research · doi:10.1186/s40779-022-00422-y · Cited by 633 · see citing works
“T-cell-specific Gpx4-deficient mice are more sensitive to viral and parasitic infections due to T-cell death caused by ferroptosis [65].”
BackgroundMitochondrial regulation of ferroptosis
Gan, B. (2021) · The Journal of Cell Biology · doi:10.1083/jcb.202105043 · Cited by 615 · see citing works
HSPA5 Regulates Ferroptotic Cell Death in Cancer Cells
Zhu, S., Zhang, Q., Sun, X., Zeh, H. J., Lotze, M. T., Kang, R., & Tang, D. (2017) · Cancer Research · doi:10.1158/0008-5472.can-16-1979 · Cited by 576 · see citing works
“Conditional knockout of GPX4 in mice enhances ferroptosis in vivo (5-7).”
BackgroundLei, G., Zhuang, L., & Gan, B. (2024) · Cancer Cell · doi:10.1016/j.ccell.2024.03.011 · Cited by 615 · 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
Self-citationIron 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-citationMechanisms 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
GPX4: The hub of lipid oxidation, ferroptosis, disease and treatment
Liu, Y., Wan, Y., Jiang, Y., Zhang, L., & Cheng, W. (2023) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2023.188890 · Cited by 536 · see citing works
Glutathione primes t cell metabolism for inflammation
Mak, T. W., Grusdat, M., Duncan, G. S., Dostert, C., Nonnenmacher, Y., Cox, M., Binsfeld, C., Hao, Z., Brüstle, A., Itsumi, M., et al. (2017) · Immunity · doi:10.1016/j.immuni.2017.03.019 · Cited by 511 · see citing works
“Prevention of lipid oxidationbyglutathioneperoxidase 4 (Gpx4) is crucial for T cell survival and activation (Matsushita et al., 2015).”
BackgroundManganese Oxide Nanomaterials: Synthesis, Properties, and Theranostic Applications
Ding, B., Zheng, P., Ma, P., & Lin, J. (2020) · Advanced Materials · doi:10.1002/adma.201905823 · Cited by 523 · see citing works
Li, Y., Cao, Y., Xiao, J., Shang, J., Tan, Q., Feng, P., Huang, W.-F., Wu, F., Zhang, H., & Zhang, X. (2020) · Cell Death and Differentiation · doi:10.1038/s41418-020-0528-x · Cited by 512 · see citing works
“This finding is in line with results from previous studies suggesting that ferroptosis is involved in the pathogenesis of human diseases such as Huntington’s disease, periventricular leukomalacia, and kidney dysfunction [25], as well as I/R injury [13, 25] and infectious diseases [26].”
ResultCISD1 inhibits ferroptosis by protection against mitochondrial lipid peroxidation
Yuan, H., Li, X., Zhang, X., Kang, R., & Tang, D. (2016) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2016.08.034 · Cited by 507 · see citing works
Redox regulation of immunometabolism
Muri, J., & Köpf, M. (2020) · Nature reviews. Immunology · doi:10.1038/s41577-020-00478-8 · Cited by 501 · 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
“Aberrant ferroptosis activation in T cells of the immune system has been shown to affect their ability to mount a response to Leishmania parasite infection [140].”
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
“(29) demonstrated that Gpx4 is essential for neuroprotection in hippocampus, cortex, cerebellum and motor neurons (29,64–66), as well as for photoreceptor cells (67), kidney tubular cells (6), and CD8-positive T cells (68).”
BackgroundSelf-citationGlutathione peroxidase 4–regulated neutrophil ferroptosis induces systemic autoimmunity
Li, P., Jiang, M., Li, K., Li, H., Zhou, Y., Xiao, X., Xu, Y., Krishfield, S., Lipsky, P. E., Tsokos, G. C., et al. (2021) · Nature Immunology · doi:10.1038/s41590-021-00993-3 · Cited by 445 · see citing works
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“2014), CD8 T cells (Matsushita et al., 2015), vascular endothelial cells (Wortmann et al.”
BackgroundSwitching Apoptosis to Ferroptosis: Metal–Organic Network for High-Efficiency Anticancer Therapy
Zheng, D., Lei, Q., Zhu, J., Fan, J., Li, C., Li, C., Xu, Z., Cheng, S., & Zhang, X. (2016) · Nano Letters · doi:10.1021/acs.nanolett.6b04060 · Cited by 434 · see citing works
Paradoxical Roles of Antioxidant Enzymes: Basic Mechanisms and Health Implications
Lei, X. G., Zhu, J., Cheng, W.-H., Bao, Y., Ho, Y.-S., Reddi, A. R., Holmgren, A., & Arnér, E. S. J. (2015) · Physiological Reviews · doi:10.1152/physrev.00010.2014 · Cited by 437 · see citing works
The application of Ferroptosis in diseases
Qiu, Y., Cao, Y., Cao, W., Jia, Y., & Lu, N. (2020) · Pharmacological Research · doi:10.1016/j.phrs.2020.104919 · Cited by 415 · see citing works
Metabolic regulation of the immune system in health and diseases: mechanisms and interventions
Hu, T., Liu, C., Lei, M., Zeng, Q., Li, L., Tang, H., & Zhang, N. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-01954-6 · Cited by 425 · see citing works
Selenium–GPX4 axis protects follicular helper T cells from ferroptosis
Yao, Y., Chen, Z., Zhang, H., Chen, C., Zeng, M., Yunis, J., Wei, Y., Wan, Y., Wang, N., Zhou, M., et al. (2021) · Nature Immunology · doi:10.1038/s41590-021-00996-0 · Cited by 386 · see citing works
Oxidative Stress: Signaling Pathways, Biological Functions, and Disease
Liu, S., Liu, J., Wang, Y., Deng, F., & Deng, Z. (2025) · MedComm · doi:10.1002/mco2.70268 · Cited by 435 · see citing works
Ferroptosis and necroinflammation, a yet poorly explored link
Proneth, B., & Conrad, M. (2018) · Cell Death and Differentiation · doi:10.1038/s41418-018-0173-9 · Cited by 378 · see citing works
“lethality caused by the systemic loss of GPX4 [85], and the defects in the viability of GPX4 deficient T cells [41].”
BackgroundSelf-citationFerroptosis in Cancer Cell Biology
Bebber, C. M., Müller, F., Clemente, L. P., Weber, J., & von Karstedt, S. (2020) · Cancers · doi:10.3390/cancers12010164 · Cited by 360 · see citing works
Myeloid Cell-Derived Reactive Oxygen Species Induce Epithelial Mutagenesis
Canli, Ö., Nicolas, A. M., Gupta, J. R. P., Finkelmeier, F., Goncharova, O., Pesic, M. H., Neumann, T., Horst, D. A., Löwer, M., Şahin, U., et al. (2017) · Cancer Cell · doi:10.1016/j.ccell.2017.11.004 · Cited by 364 · see citing works
“Recently, we and other groups have demonstrated that genetic ablation ofGpx4 causes spontaneous ferroptosis or necroptosis depending on the cell type (Canli et al., 2016; Matsushita et al., 2015; Seiler et al., 2008; Ueta et al., 2012; Yang et al., 2014).”
BackgroundFerroptosis in health and disease
Berndt, C., Alborzinia, H., Skafar, V., Ayton, S., Barayeu, U., Bartelt, A., Bayır, H., Bebber, C. M., Birsoy, K., Böttcher, J. P., et al. (2024) · Redox Biology · doi:10.1016/j.redox.2024.103211 · Cited by 354 · see citing works
Self-citationQi, J., Kim, J.-W., Zhou, Z., Lim, C.-W., & Kim, B. (2020) · The American Journal of Pathology · doi:10.1016/j.ajpath.2019.09.011 · Cited by 338 · see citing works
Emerging mechanisms of lipid peroxidation in regulated cell death and its physiological implications
Zheng, Y., Sun, J., Luo, Z., Li, Y., & Huang, Y. (2024) · Cell Death and Disease · doi:10.1038/s41419-024-07244-x · Cited by 349 · see citing works
“A T cell-speci fi c GPX4-de fi cient mice displays a phenotype of accumulated lipid peroxides, leading to an intrinsic defect in defending acute lymphocytic choriomeningitis virus (LCMV) and Leishmania major parasite infections [256].”
Reactive Oxygen Species Regulate T Cell Immune Response in the Tumor Microenvironment
Chen, X., Song, M., Zhang, B., & Zhang, Y. (2016) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2016/1580967 · Cited by 326 · see citing works
Dixon, S. J. (2017) · Immunological Reviews · doi:10.1111/imr.12533 · Cited by 314 · see citing works
Programmed Cell Death Tunes Tumor Immunity
Liu, J., Hong, M., Li, Y., Chen, D., Wu, Y., & Hu, Y. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.847345 · 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
“As reported in earlier studies [6,13], vitamin E can compensate for Gpx4 loss in some tissues in vivo (i.”
BackgroundSelf-citationFerroptosis Detection: From Approaches to Applications
Zeng, F., Nijiati, S., Tang, L., Ye, J., Zhou, Z., & Chen, X. S. (2023) · Angewandte Chemie International Edition · doi:10.1002/anie.202300379 · Cited by 312 · see citing works
The Role of Iron Regulation in Immunometabolism and Immune-Related Disease
Cronin, S. J. F., Woolf, C. J., Weiss, G., & Penninger, J. M. (2019) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2019.00116 · Cited by 299 · see citing works
“GPX4 is essential for the survival and expansion of recently activated T cells, indicating the importance of preventing lipid peroxidation and of iron dysregulation resulting in ferroptosis, in T cell proliferation (Matsushita et al., 2015).”
BackgroundZhang, X., Sui, S., Wang, L., Li, H., Zhang, L., Xu, S., & Zheng, X. (2020) · Journal of Cellular Physiology · doi:10.1002/jcp.29232 · Cited by 293 · see citing works
“Furthermore, ferroptosis was discovered to associate with other biological processes such as autophagy (Kang, Zhu, Zeh, Klionsky, & Tang, 2018), metabolism (Murphy, 2018), and immune (Matsushita et al., 2015) in cancer cells, indicating that maybe ferroptosis could be used to enhance other anticancer therapies.”
BackgroundFerroptosis in the tumor microenvironment: perspectives for immunotherapy
Xu, H., Ye, D., Ren, M., Zhang, H., & Bi, F. (2021) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2021.06.014 · Cited by 301 · see citing works
A guideline on the molecular ecosystem regulating ferroptosis
Dai, E., Chen, X., Linkermann, A., Jiang, X., Kang, R., Kagan, V. E., Bayır, H., Yang, W. S., García‐Sáez, A. J., Ioannou, M. S., et al. (2024) · Nature Cell Biology · doi:10.1038/s41556-024-01360-8 · Cited by 308 · see citing works
“Conditional knockout of Gpx4 in various tissues (for example, kidney 8 ) or cells (for example, T cells 10 or B cells 9 ) can cause ferroptotic damage, highlighting its role in developmental biology.”
BackgroundJiang, Y., Mao, C., Yang, R., Yan, B., Shi, Y., Liu, X., Lai, W., Liu, Y., Wang, X., Xiao, D., et al. (2017) · Theranostics · doi:10.7150/thno.19988 · Cited by 293 · see citing works
“Vitamin E is regarded as a high efficient ferroptosis inhibitor[53, 54].”
BackgroundFerroptosis and Its Potential Role in Human Diseases
Han, C., Liu, Y., Dai, R., Ismail, N., Su, W., & Li, B. (2020) · Frontiers in Pharmacology · doi:10.3389/fphar.2020.00239 · Cited by 274 · see citing works
GPX4-independent ferroptosis—a new strategy in disease’s therapy
Ma, T., Du, J., Zhang, Y., Wang, Y., Wang, B., & Zhang, T. (2022) · Cell Death Discovery · doi:10.1038/s41420-022-01212-0 · Cited by 275 · see citing works
“INOS/NO PATHWAY It has been found that ferroptosis plays a role in different mammalian cells, but some specific types of cells, especially cells of the innate immune system (such as macrophages), show significant resistance to ferroptosis [44].”
BackgroundWeaver, K., & Skouta, R. (2022) · Biomedicines · doi:10.3390/biomedicines10040891 · Cited by 273 · see citing works
Mechanism of Ferroptosis and Its Role in Type 2 Diabetes Mellitus
Sha, W., Hu, F., Yang, X., Chu, Y., & Bu, S. (2021) · Journal of Diabetes Research · doi:10.1155/2021/9999612 · Cited by 273 · see citing works
Persister cancer cells: Iron addiction and vulnerability to ferroptosis
Rodriguez, R., Schreiber, S. L., & Conrad, M. (2021) · Molecular Cell · doi:10.1016/j.molcel.2021.12.001 · Cited by 271 · see citing works
Self-citationRethinking peripheral T cell tolerance: checkpoints across a T cell’s journey
ElTanbouly, M. A., & Noelle, R. J. (2020) · Nature reviews. Immunology · doi:10.1038/s41577-020-00454-2 · Cited by 267 · see citing works
Role of Selenoproteins in Redox Regulation of Signaling and the Antioxidant System: A Review
Zhang, Y., Roh, Y. J., Han, S.-J., Park, I., Lee, H. M., Ok, Y. S., Lee, B. C., & Lee, S.-R. (2020) · Antioxidants · doi:10.3390/antiox9050383 · Cited by 267 · see citing works
“It has also been reported that GPx dysfunction is associated with the incidence of various types of cancer [40,41], muscle disorders [42], CVDs [43,44], hepatopathies [45], renal failure [46,47], neurological disorders (such as Alzheimer’s disease (AD) and Parkinson’s disease (PD)) [48–50], immune defense dysfunction…”
BackgroundThe complexity of p53-mediated metabolic regulation in tumor suppression
Liu, Y., & Gu, W. J. (2021) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2021.03.010 · Cited by 260 · see citing works
- Authors
- Matsushita, M., Freigang, S., Schneider, C., Conrad, M., Bornkamm, G. W., & Kopf, M.
- Affiliations
- ETH Zurich (CH)
- Helmholtz Munich (DE)
- Molecular Biomedicine, Institute of Molecular Health Science, Department of Biology, ETH Zurich, 8093 Zurich, Switzerland 1
- Venue
- Journal of Experimental Medicine
- Publisher
- Rockefeller University Press
- Published
- 2015-03-30
- Volume
- 212
- Issue
- 4
- Pages
- 555-568
- ISSN
- 0022-1007 (ISSN-L)
- 1540-9538
- PMC
- PMC4387287
- OpenAlex
- W2065934830
- Cited by
- 672
- References
- 57
- Citations by year
- 2026: 65 · 2025: 77 · 2024: 90 · 2023: 90 · 2022: 95 · 2021: 92 · 2020: 56 · 2019: 28 · 2018: 25 · 2017: 22 · 2016: 24 · 2015: 8
- FWCI
- 12.96
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Experimental Medicine (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Repository for Publications and Research Data (ETH Zurich) (publishedVersion, cc-by-nc-sa)
- Bern Open Repository and Information System (University of Bern) (submittedVersion, cc-by-nc-sa)
- Site cant be reached (submittedVersion)
- PuSH - Publication Server of Helmholtz Zentrum München (submittedVersion)
- ETH Zürich Research Collection
- Funders
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (141175, 310030B_141175/1)
- National Institutes of Health
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Ferroptosis and cancer prognosis
- Health Sciences › Nursing › Nutrition and Dietetics › Selenium in Biological Systems
- Keywords
- GPX4, ferroptosis, lipid peroxidation, T cell immunity, CD8+ T cells, CD4+ T cells, phospholipid hydroperoxides, vitamin E, lymphocytic choriomeningitis virus, Leishmania major, antiviral immunity, antiparasitic immunity, T cell homeostasis, T cell-specific knockout mice
- MeSH terms
- Phospholipid Hydroperoxide Glutathione Peroxidase, Animals, Cell Membrane, Glutathione Peroxidase, Immunologic Memory, Lymphocytic Choriomeningitis, Lymphocytic choriomeningitis virus, Thymus Gland, Vitamin E, Vitamins, Lipid Peroxidation, CD4-Positive T-Lymphocytes, Leishmaniasis, Cutaneous, Cell Death, Leishmania major, Mice, Knockout, CD8-Positive T-Lymphocytes, Mice
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