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Review

GPX4 in cell death, autophagy, and disease

, , ORCID Icon & ORCID Icon
Pages 2621-2638 | Received 17 Mar 2023, Accepted 22 May 2023, Published online: 04 Jun 2023

References

  • Rock KL, Kono H. The inflammatory response to cell death. Annu Rev Pathol. 2008;3:99–126.
  • Tang D, Kang R, Berghe TV, et al. The molecular machinery of regulated cell death. Cell Res. 2019;29:347–364.
  • Ryter SW, Kim HP, Hoetzel A, et al. Mechanisms of cell death in oxidative stress. Antioxid Redox Signal. 2007;9:49–89.
  • Kayagaki N, Kornfeld OS, Lee BL, et al. NINJ1 mediates plasma membrane rupture during lytic cell death. Nature. 2021;591:131–136.
  • Gaschler MM, Stockwell BR. Lipid peroxidation in cell death. Biochem Biophys Res Commun. 2017;482:419–425.
  • Denton D, Kumar S. Autophagy-dependent cell death. Cell Death Differ. 2019;26:605–616.
  • Flohe L, Toppo S, Orian L. The glutathione peroxidase family: discoveries and mechanism. Free Radic Biol Med. 2022;187:113–122.
  • Weaver K, Skouta R. The selenoprotein glutathione peroxidase 4: from molecular mechanisms to novel therapeutic opportunities. Biomedicines. 2022;10:891.
  • Brigelius-Flohe R, Flohe L. Regulatory phenomena in the glutathione peroxidase superfamily. Antioxid Redox Signal. 2020;33:498–516.
  • Ursini F, Maiorino M, Valente M, et al. Purification from pig liver of a protein which protects liposomes and biomembranes from peroxidative degradation and exhibits glutathione peroxidase activity on phosphatidylcholine hydroperoxides. Biochim Biophys Acta. 1982;710:197–211.
  • Yant LJ, Ran Q, Rao L, et al. The selenoprotein GPX4 is essential for mouse development and protects from radiation and oxidative damage insults. Free Radic Biol Med. 2003;34:496–502.
  • Imai H, Hirao F, Sakamoto T, et al. Early embryonic lethality caused by targeted disruption of the mouse PHGPx gene. Biochem Biophys Res Commun. 2003;305:278–286.
  • Ran Q, Van Remmen H, Gu M, et al. Embryonic fibroblasts from Gpx4± mice: a novel model for studying the role of membrane peroxidation in biological processes. Free Radic Biol Med. 2003;35:1101–1109.
  • Scimeca MS, Lisk DJ, Prolla T, et al. Effects of gpx4 haploid insufficiency on GPx4 activity, selenium concentration, and paraquat-induced protein oxidation in murine tissues. Exp Biol Med (Maywood). 2005;230:709–714.
  • Ran Q, Liang H, Ikeno Y, et al. Reduction in glutathione peroxidase 4 increases life span through increased sensitivity to apoptosis. J Gerontol A Biol Sci Med Sci. 2007;62:932–942.
  • Garry MR, Kavanagh TJ, Faustman EM, et al. Sensitivity of mouse lung fibroblasts heterozygous for GPx4 to oxidative stress. Free Radic Biol Med. 2008;44:1075–1087.
  • Conrad M, Moreno SG, Sinowatz F, et al. The nuclear form of phospholipid hydroperoxide glutathione peroxidase is a protein thiol peroxidase contributing to sperm chromatin stability. Mol Cell Biol. 2005;25:7637–7644.
  • Puglisi R, Maccari I, Pipolo S, et al. The nuclear form of glutathione peroxidase 4 is associated with sperm nuclear matrix and is required for proper paternal chromatin decondensation at fertilization. J Cell Physiol. 2012;227:1420–1427.
  • Azuma K, Koumura T, Iwamoto R, et al. Mitochondrial glutathione peroxidase 4 is indispensable for photoreceptor development and survival in mice. J Biol Chem. 2022;298:101824.
  • Seiler A, Schneider M, Forster H, et al. Glutathione peroxidase 4 senses and translates oxidative stress into 12/15-lipoxygenase dependent- and AIF-mediated cell death. Cell Metab. 2008;8:237–248.
  • Friedmann Angeli JP, Schneider M, Proneth B, et al. Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice. Nat Cell Biol. 2014;16:1180–1191.
  • Liang H, Yoo SE, Na R, et al. Short form glutathione peroxidase 4 is the essential isoform required for survival and somatic mitochondrial functions. J Biol Chem. 2009;284:30836–30844.
  • Schneider M, Forster H, Boersma A, et al. Mitochondrial glutathione peroxidase 4 disruption causes male infertility. Faseb J. 2009;23:3233–3242.
  • Imai H, Hakkaku N, Iwamoto R, et al. Depletion of selenoprotein GPx4 in spermatocytes causes male infertility in mice. J Biol Chem. 2009;284:32522–32532.
  • Sengupta A, Lichti UF, Carlson BA, et al. Targeted disruption of glutathione peroxidase 4 in mouse skin epithelial cells impairs postnatal hair follicle morphogenesis that is partially rescued through inhibition of COX-2. J Invest Dermatol. 2013;133:1731–1741.
  • Ingold I, Aichler M, Yefremova E, et al. Expression of a catalytically inactive mutant form of glutathione peroxidase 4 (Gpx4) confers a dominant-negative effect in male fertility. J Biol Chem. 2015;290:14668–14678.
  • Brutsch SH, Wang CC, Li L, et al. Expression of inactive glutathione peroxidase 4 leads to embryonic lethality, and inactivation of the Alox15 gene does not rescue such knock-in mice. Antioxid Redox Signal. 2015;22:281–293.
  • Matsushita M, Freigang S, Schneider C, et al. T cell lipid peroxidation induces ferroptosis and prevents immunity to infection. J Exp Med. 2015;212:555–568.
  • Chen L, Hambright WS, Na R, et al. Ablation of the ferroptosis inhibitor glutathione peroxidase 4 in neurons results in rapid motor neuron degeneration and paralysis. J Biol Chem. 2015;290:28097–28106.
  • Canli O, Alankus YB, Grootjans S, et al. Glutathione peroxidase 4 prevents necroptosis in mouse erythroid precursors. Blood. 2016;127:139–148.
  • Carlson BA, Tobe R, Yefremova E, et al. Glutathione peroxidase 4 and vitamin E cooperatively prevent hepatocellular degeneration. Redox Biol. 2016;9:22–31.
  • Hambright WS, Fonseca RS, Chen L, et al. Ablation of ferroptosis regulator glutathione peroxidase 4 in forebrain neurons promotes cognitive impairment and neurodegeneration. Redox Biol. 2017;12:8–17.
  • Kang R, Zeng L, Zhu S, et al. Lipid peroxidation drives gasdermin D-mediated pyroptosis in lethal polymicrobial sepsis. Cell Host Microbe. 2018;24:97–108 e4.
  • Ingold I, Berndt C, Schmitt S, et al. Selenium utilization by GPX4 is required to prevent hydroperoxide-induced ferroptosis. Cell. 2018;172:409–22 e21.
  • Muri J, Thut H, Bornkamm GW, et al. B1 and marginal zone B cells but not follicular B2 cells require Gpx4 to prevent lipid peroxidation and ferroptosis. Cell Rep. 2019;29:2731–44 e4.
  • Liu K, Liu J, Zou B, et al. Trypsin-mediated sensitization to ferroptosis increases the severity of pancreatitis in mice. Cell Mol Gastroenterol Hepatol. 2022;13:483–500.
  • Dai E, Han L, Liu J, et al. Ferroptotic damage promotes pancreatic tumorigenesis through a TMEM173/STING-dependent DNA sensor pathway. Nat Commun. 2020;11:6339.
  • Piattini F, Matsushita M, Muri J, et al. Differential sensitivity of inflammatory macrophages and alternatively activated macrophages to ferroptosis. Eur J Immunol. 2021;51:2417–2429.
  • Li J, Liu J, Xu Y, et al. Tumor heterogeneity in autophagy-dependent ferroptosis. Autophagy. 2021;17:3361–3374.
  • Yao Y, Chen Z, Zhang H, et al. Selenium-GPX4 axis protects follicular helper T cells from ferroptosis. Nat Immunol. 2021;22:1127–1139.
  • Wang S, Li W, Zhang P, et al. Mechanical overloading induces GPX4-regulated chondrocyte ferroptosis in osteoarthritis via Piezo1 channel facilitated calcium influx. J Adv Res. 2022;41:63–75.
  • Tosatto SC, Bosello V, Fogolari F, et al. The catalytic site of glutathione peroxidases. Antioxid Redox Signal. 2008;10:1515–1526.
  • Roveri A, Flohe L, Maiorino M, et al. Phospholipid-hydroperoxide glutathione peroxidase in sperm. Methods Enzymol. 2002;347:208–212.
  • Vuckovic AM, Venerando R, Tibaldi E, et al. Aerobic pyruvate metabolism sensitizes cells to ferroptosis primed by GSH depletion. Free Radic Biol Med. 2021;167:45–53.
  • Mao C, Liu X, Zhang Y, et al. DHODH-mediated ferroptosis defence is a targetable vulnerability in cancer. Nature. 2021;593:586–590.
  • Arai M, Imai H, Sumi D, et al. Import into mitochondria of phospholipid hydroperoxide glutathione peroxidase requires a leader sequence. Biochem Biophys Res Commun. 1996;227:433–439.
  • Pfeifer H, Conrad M, Roethlein D, et al. Identification of a specific sperm nuclei selenoenzyme necessary for protamine thiol cross-linking during sperm maturation. Faseb J. 2001;15:1236–1238.
  • Tong J, Li D, Meng H, et al. Targeting a novel inducible GPX4 alternative isoform to alleviate ferroptosis and treat metabolic-associated fatty liver disease. Acta Pharm Sin B. 2022;12:3650–3666.
  • Maiorino M, Thomas JP, Girotti AW, et al. Reactivity of phospholipid hydroperoxide glutathione peroxidase with membrane and lipoprotein lipid hydroperoxides. Free Radic Res Commun. 1991;12-13(Pt 1):131–135.
  • Thomas JP, Maiorino M, Ursini F, et al. Protective action of phospholipid hydroperoxide glutathione peroxidase against membrane-damaging lipid peroxidation. In situ reduction of phospholipid and cholesterol hydroperoxides. J Biol Chem. 1990;265:454–461.
  • Cozza G, Rossetto M, Bosello-Travain V, et al. Glutathione peroxidase 4-catalyzed reduction of lipid hydroperoxides in membranes: the polar head of membrane phospholipids binds the enzyme and addresses the fatty acid hydroperoxide group toward the redox center. Free Radic Biol Med. 2017;112:1–11.
  • Schnurr K, Belkner J, Ursini F, et al. The selenoenzyme phospholipid hydroperoxide glutathione peroxidase controls the activity of the 15-lipoxygenase with complex substrates and preserves the specificity of the oxygenation products. J Biol Chem. 1996;271:4653–4658.
  • Mendieta-Serrano MA, Schnabel D, Lomeli H, et al. Spatial and temporal expression of zebrafish glutathione peroxidase 4 a and b genes during early embryo development. Gene Expr Patterns. 2015;19:98–107.
  • Rong X, Zhou Y, Liu Y, et al. Glutathione peroxidase 4 inhibits Wnt/beta-catenin signaling and regulates dorsal organizer formation in zebrafish embryos. Development. 2017;144:1687–1697.
  • Borchert A, Wang CC, Ufer C, et al. The role of phospholipid hydroperoxide glutathione peroxidase isoforms in murine embryogenesis. J Biol Chem. 2006;281:19655–19664.
  • Peng JJ, Yue SY, Fang YH, et al. Mechanisms affecting the biosynthesis and incorporation rate of selenocysteine. Molecules. 2021;26:7120.
  • Yuan J, Palioura S, Salazar JC, et al. RNA-dependent conversion of phosphoserine forms selenocysteine in eukaryotes and archaea. Proc Natl Acad Sci U S A. 2006;103:18923–18927.
  • Viswanathan VS, Ryan MJ, Dhruv HD, et al. Dependency of a therapy-resistant state of cancer cells on a lipid peroxidase pathway. Nature. 2017;547:453–457.
  • Weitzel F, Ursini F, Wendel A. Phospholipid hydroperoxide glutathione peroxidase in various mouse organs during selenium deficiency and repletion. Biochim Biophys Acta. 1990;1036:88–94.
  • Kerins MJ, Milligan J, Wohlschlegel JA, et al. Fumarate hydratase inactivation in hereditary leiomyomatosis and renal cell cancer is synthetic lethal with ferroptosis induction. Cancer Sci. 2018;109:2757–2766.
  • Grossman EA, Ward CC, Spradlin JN, et al. Covalent ligand discovery against druggable hotspots targeted by anti-cancer natural products. Cell Chem Biol. 2017;24:1368–76 e4.
  • Chen X, Yu C, Kang R, et al. Cellular degradation systems in ferroptosis. Cell Death Differ. 2021;28:1135–1148.
  • Yang L, Chen X, Yang Q, et al. Broad spectrum deubiquitinase inhibition induces both apoptosis and ferroptosis in cancer cells. Front Oncol. 2020;10:949.
  • Ding Y, Chen X, Liu C, et al. Identification of a small molecule as inducer of ferroptosis and apoptosis through ubiquitination of GPX4 in triple negative breast cancer cells. J Hematol Oncol. 2021;14:19.
  • Sakamoto K, Sogabe S, Kamada Y, et al. Discovery of GPX4 inhibitory peptides from random peptide T7 phage display and subsequent structural analysis. Biochem Biophys Res Commun. 2017;482:195–201.
  • Zhang W, Jiang B, Liu Y, et al. Bufotalin induces ferroptosis in non-small cell lung cancer cells by facilitating the ubiquitination and degradation of GPX4. Free Radic Biol Med. 2022;180:75–84.
  • Tian P, Xu ZY, Guo JR, et al. BPDE induces human trophoblast cell ferroptosis by up-regulating iron metabolism and promoting GPX4 proteasomal degradatio. Ecotoxicol Environ Saf. 2021;228:113028.
  • Hauser DN, Dukes AA, Mortimer AD, et al. Dopamine quinone modifies and decreases the abundance of the mitochondrial selenoprotein glutathione peroxidase 4. Free Radic Biol Med. 2013;65:419–427.
  • Fradejas-Villar N, Zhao W, Reuter U, et al. Missense mutation in selenocysteine synthase causes cardio-respiratory failure and perinatal death in mice which can be compensated by selenium-independent GPX4. Redox Biol. 2021;48:102188.
  • Liu H, Forouhar F, Seibt T, et al. Characterization of a patient-derived variant of GPX4 for precision therapy. Nat Chem Biol. 2022;18:91–100.
  • Wu Z, Geng Y, Lu X, et al. Chaperone-mediated autophagy is involved in the execution of ferroptosis. Proc Natl Acad Sci U S A. 2019;116:2996–3005.
  • Thayyullathil F, Cheratta AR, Alakkal A, et al. Acid sphingomyelinase-dependent autophagic degradation of GPX4 is critical for the execution of ferroptosis. Cell Death Dis. 2021;12:26.
  • Chen C, Wang D, Yu Y, et al. Legumain promotes tubular ferroptosis by facilitating chaperone-mediated autophagy of GPX4 in AKI. Cell Death Dis. 2021;12:65.
  • Sun Y, Berleth N, Wu W, et al. Fin56-induced ferroptosis is supported by autophagy-mediated GPX4 degradation and functions synergistically with mTOR inhibition to kill bladder cancer cells. Cell Death Dis. 2021;12:1028.
  • Yu S, Li Z, Zhang Q, et al. GPX4 degradation via chaperone-mediated autophagy contributes to antimony-triggered neuronal ferroptosis. Ecotoxicol Environ Saf. 2022;234:113413.
  • Liu J, Liu Y, Wang Y, et al. TMEM164 is a new determinant of autophagy-dependent ferroptosis. Autophagy. 2023;19:945–956.
  • Zhu S, Zhang Q, Sun X, et al. HSPA5 regulates ferroptotic cell death in cancer cells. Cancer Res. 2017;77:2064–2077.
  • Han L, Bai L, Fang X, et al. SMG9 drives ferroptosis by directly inhibiting GPX4 degradation. Biochem Biophys Res Commun. 2021;567:92–98.
  • Dong K, Wei R, Jin T, et al. HOIP modulates the stability of GPx4 by linear ubiquitination. Proc Natl Acad Sci U S A. 2022;119:e2214227119.
  • Vuckovic AM, Bosello Travain V, Bordin L, et al. Inactivation of the glutathione peroxidase GPx4 by the ferroptosis-inducing molecule RSL3 requires the adaptor protein 14-3-3epsilon. FEBS Lett. 2020;594:611–624.
  • Liu H, Forouhar F, Lin AJ, et al. Small-molecule allosteric inhibitors of GPX4. Cell Chem Biol. 2022;29:1680–1693.e9.
  • Hochstein P, Ernster L. Adp-activated lipid peroxidation coupled to the Tpnh oxidase system of microsomes. Biochem Biophys Res Commun. 1963;12:388–394.
  • Ayala A, Munoz MF, Arguelles S. Lipid peroxidation: production, metabolism, and signaling mechanisms of malondialdehyde and 4-hydroxy-2-nonenal. Oxid Med Cell Longev. 2014;2014:360438.
  • Wu G, Fang YZ, Yang S, et al. Glutathione metabolism and its implications for health. J Nutr. 2004;134:489–492.
  • Yang WS, SriRamaratnam R, Welsch ME, et al. Regulation of ferroptotic cancer cell death by GPX4. Cell. 2014;156:317–331.
  • Imai H, Koumura T, Nakajima R, et al. Protection from inactivation of the adenine nucleotide translocator during hypoglycaemia-induced apoptosis by mitochondrial phospholipid hydroperoxide glutathione peroxidase. Biochem J. 2003;371:799–809.
  • Zhang Y, Swanda RV, Nie L, et al. mTORC1 couples cyst(e)ine availability with GPX4 protein synthesis and ferroptosis regulation. Nat Commun. 2021;12:1589.
  • Liu Y, Wang Y, Liu J, et al. Interplay between MTOR and GPX4 signaling modulates autophagy-dependent ferroptotic cancer cell death. Cancer Gene Ther. 2021;28:55–63.
  • Buczynski MW, Dumlao DS, Dennis EA. Thematic review series: proteomics. An integrated omics analysis of eicosanoid biology. J Lipid Res. 2009;50:1015–1038.
  • Wang T, Fu X, Chen Q, et al. Arachidonic acid metabolism and kidney inflammation. Int J Mol Sci. 2019;20:20.
  • Li C, Deng X, Xie X, et al. Activation of glutathione peroxidase 4 as a novel anti-inflammatory strategy. Front Pharmacol. 2018;9:1120.
  • Schwarzler J, Mayr L, Vich Vila A, et al. PUFA-Induced metabolic enteritis as a fuel for Crohn’s disease. Gastroenterology. 2022;162:1690–1704.
  • Mayr L, Grabherr F, Schwarzler J, et al. Dietary lipids fuel GPX4-restricted enteritis resembling Crohn’s disease. Nat Commun. 2020;11:1775.
  • Kryukov GV, Castellano S, Novoselov SV, et al. Characterization of mammalian selenoproteomes. Science. 2003;300:1439–1443.
  • Daniels LA. Selenium metabolism and bioavailability. Biol Trace Elem Res. 1996;54:185–199.
  • Li Z, Ferguson L, Deol KK, et al. Ribosome stalling during selenoprotein translation exposes a ferroptosis vulnerability. Nat Chem Biol. 2022;18:751–761.
  • Elmore S. Apoptosis: a review of programmed cell death. Toxicol Pathol. 2007;35:495–516.
  • Galluzzi L, Vitale I, Aaronson SA, et al. Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. Cell Death Differ. 2018;25:486–541.
  • Singh R, Letai A, Sarosiek K. Regulation of apoptosis in health and disease: the balancing act of BCL-2 family proteins. Nat Rev Mol Cell Biol. 2019;20:175–193.
  • Nomura K, Imai H, Koumura T, et al. Mitochondrial phospholipid hydroperoxide glutathione peroxidase suppresses apoptosis mediated by a mitochondrial death pathway. J Biol Chem. 1999;274:29294–29302.
  • Brielmeier M, Bechet JM, Suppmann S, et al. Cloning of phospholipid hydroperoxide glutathione peroxidase (PHGPx) as an anti-apoptotic and growth promoting gene of Burkitt lymphoma cells. BioFactors. 2001;14:179–190.
  • Ran Q, Liang H, Gu M, et al. Transgenic mice overexpressing glutathione peroxidase 4 are protected against oxidative stress-induced apoptosis. J Biol Chem. 2004;279:55137–55146.
  • Hurst R, Korytowski W, Kriska T, et al. Hyperresistance to cholesterol hydroperoxide-induced peroxidative injury and apoptotic death in a tumor cell line that overexpresses glutathione peroxidase isotype-4. Free Radic Biol Med. 2001;31:1051–1065.
  • Huang HS, Chang WC, Chen CJ. Involvement of reactive oxygen species in arsenite-induced downregulation of phospholipid hydroperoxide glutathione peroxidase in human epidermoid carcinoma A431 cells. Free Radic Biol Med. 2002;33:864–873.
  • Kriska T, Korytowski W, Girotti AW. Hyperresistance to photosensitized lipid peroxidation and apoptotic killing in 5-aminolevulinate-treated tumor cells overexpressing mitochondrial GPX4. Free Radic Biol Med. 2002;33:1389–1402.
  • Nomura K, Imai H, Koumura T, et al. Mitochondrial phospholipid hydroperoxide glutathione peroxidase inhibits the release of cytochrome c from mitochondria by suppressing the peroxidation of cardiolipin in hypoglycaemia-induced apoptosis. Biochem J. 2000;351:183–193.
  • Doll S, Freitas FP, Shah R, et al. FSP1 is a glutathione-independent ferroptosis suppressor. Nature. 2019;575:693–698.
  • Ufer C, Wang CC, Fahling M, et al. Translational regulation of glutathione peroxidase 4 expression through guanine-rich sequence-binding factor 1 is essential for embryonic brain development. Genes Dev. 2008;22:1838–1850.
  • Liu P, Zhu J, Yuan G, et al. The effects of selenium on GPX4-mediated lipid peroxidation and apoptosis in germ cells. J Appl Toxicol. 2022;42:1016–1028.
  • Weinlich R, Oberst A, Beere HM, et al. Necroptosis in development, inflammation and disease. Nat Rev Mol Cell Biol. 2017;18:127–136.
  • Degterev A, Huang Z, Boyce M, et al. Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury. Nat Chem Biol. 2005;1:112–119.
  • Xie Y, Zhu S, Zhong M, et al. Inhibition of aurora kinase a induces necroptosis in pancreatic carcinoma. Gastroenterology. 2017;153:1429–43 e5.
  • Vandenabeele P, Galluzzi L, Vanden Berghe T, et al. Molecular mechanisms of necroptosis: an ordered cellular explosion. Nat Rev Mol Cell Biol. 2010;11:700–714.
  • Zhang Y, Su SS, Zhao S, et al. RIP1 autophosphorylation is promoted by mitochondrial ROS and is essential for RIP3 recruitment into necrosome. Nat Commun. 2017;8:14329.
  • Basit F, van Oppen LM, Schockel L, et al. Mitochondrial complex I inhibition triggers a mitophagy-dependent ROS increase leading to necroptosis and ferroptosis in melanoma cells. Cell Death Dis. 2017;8:e2716.
  • Xue Y, Enosi Tuipulotu D, Tan WH, et al. Emerging activators and regulators of inflammasomes and pyroptosis. Trends Immunol. 2019;40:1035–1052.
  • Kayagaki N, Stowe IB, Lee BL, et al. Caspase-11 cleaves gasdermin D for non-canonical inflammasome signalling. Nature. 2015;526:666–671.
  • Zou J, Zheng Y, Huang Y, et al. The versatile gasdermin family: their function and roles in diseases. Front Immunol. 2021;12:751533.
  • Wu R, Wang N, Comish PB, et al. Inflammasome-dependent coagulation activation in sepsis. Front Immunol. 2021;12:641750.
  • Gu X, Wang Y, He Y, et al. MiR-1656 targets GPX4 to trigger pyroptosis in broilers kidney tissues by activating NLRP3 inflammasome under Se deficiency. J Nutr Biochem. 2022;105:109001.
  • Gong Z, Li Q, Yang J, et al. Identification of a pyroptosis-related gene signature for predicting the immune status and prognosis in lung adenocarcinoma. Front Bioeng Biotechnol. 2022;10:852734.
  • Chen Y, Liao Y, Du Q, et al. Roles of pyroptosis-related gene signature in prediction of endometrial cancer outcomes. Front Med. 2022;9:822806.
  • Tan S, Schubert D, Maher P. Oxytosis: a novel form of programmed cell death. Curr Top Med Chem. 2001;1:497–506.
  • Dixon SJ, Lemberg KM, Lamprecht MR, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell. 2012;149:1060–1072.
  • Jiang X, Stockwell BR, Conrad M. Ferroptosis: mechanisms, biology and role in disease. Nat Rev Mol Cell Biol. 2021;22:266–282.
  • Chen X, Huang J, Yu C, et al. A noncanonical function of EIF4E limits ALDH1B1 activity and increases susceptibility to ferroptosis. Nat Commun. 2022;13:6318.
  • Yuan H, Li X, Zhang X, et al. Identification of ACSL4 as a biomarker and contributor of ferroptosis. Biochem Biophys Res Commun. 2016;478:1338–1343.
  • Kagan VE, Mao G, Qu F, et al. Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis. Nat Chem Biol. 2017;13:81–90.
  • Doll S, Proneth B, Tyurina YY, et al. ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition. Nat Chem Biol. 2017;13:91–98.
  • Liu J, Kang R, Tang D. Signaling pathways and defense mechanisms of ferroptosis. FEBS J. 2022;289:7038–7050.
  • Xie Y, Hou W, Song X, et al. Ferroptosis: process and function. Cell Death Differ. 2016;23:369–379.
  • Chen X, Li J, Kang R, et al. Ferroptosis: machinery and regulation. Autophagy. 2021;17:2054–2081.
  • Gaschler MM, Andia AA, Liu H, et al. FINO2 initiates ferroptosis through GPX4 inactivation and iron oxidation. Nat Chem Biol. 2018;14:507–515.
  • Tang D, Chen X, Kang R, et al. Ferroptosis: molecular mechanisms and health implications. Cell Res. 2021;31:107–125.
  • Tang D, Kroemer G, Kang R. Ferroptosis in hepatocellular carcinoma: from bench to bedside. Hepatology. 2023;Publish Ahead of Print. DOI: 10.1097/HEP.0000000000000390
  • Chen X, Kang R, Kroemer G, et al. Targeting ferroptosis in pancreatic cancer: a double-edged sword. Trends Cancer. 2021;7:891–901.
  • Yu T, Robotham JL, Yoon Y. Increased production of reactive oxygen species in hyperglycemic conditions requires dynamic change of mitochondrial morphology. Proc Natl Acad Sci U S A. 2006;103:2653–2658.
  • Andrabi SA, Kim NS, Yu SW, et al. Poly(adp-ribose) (PAR) polymer is a death signal. Proc Natl Acad Sci U S A. 2006;103:18308–18313.
  • Liu L, Liu B, Guan G, et al. Cyclophosphamide-induced GPX4 degradation triggers parthanatos by activating AIFM1. Biochem Biophys Res Commun. 2022;606:68–74.
  • Xie Y, Li J, Kang R, et al. Interplay between lipid metabolism and autophagy. Front Cell Dev Biol. 2020;8:431.
  • Dikic I, Elazar Z. Mechanism and medical implications of mammalian autophagy. Nat Rev Mol Cell Biol. 2018;19:349–364.
  • Klionsky DJ, Abdel-Aziz AK, Abdelfatah S, et al. Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition) (1). Autophagy. 2021;17:1–382.
  • Xie Y, Kang R, Sun X, et al. Posttranslational modification of autophagy-related proteins in macroautophagy. Autophagy. 2015;11:28–45.
  • Vernon PJ, Tang D. Eat-me: autophagy, phagocytosis, and reactive oxygen species signaling. Antioxid Redox Signal. 2013;18:677–691.
  • Hou W, Xie Y, Song X, et al. Autophagy promotes ferroptosis by degradation of ferritin. Autophagy. 2016;12:1425–1428.
  • Gao M, Monian P, Pan Q, et al. Ferroptosis is an autophagic cell death process. Cell Res. 2016;26:1021–1032.
  • Yang M, Chen P, Liu J, et al. Clockophagy is a novel selective autophagy process favoring ferroptosis. Sci Adv. 2019;5:eaaw2238.
  • Bai Y, Meng L, Han L, et al. Lipid storage and lipophagy regulates ferroptosis. Biochem Biophys Res Commun. 2019;508:997–1003.
  • Song X, Zhu S, Chen P, et al. AMPK-Mediated BECN1 phosphorylation promotes ferroptosis by directly blocking system Xc– activity. Curr Biol. 2018;28(15):2388–2399.e5. DOI:10.1016/j.cub.2018.05.094
  • Kang R, Zhu S, Zeh HJ, et al. BECN1 is a new driver of ferroptosis. Autophagy. 2018;14:2173–2175.
  • Chen X, Song X, Li J, et al. Identification of HPCAL1 as a specific autophagy receptor involved in ferroptosis. Autophagy. 2023;19:54–74.
  • Xue Q, Kang R, Klionsky DJ, et al. Copper metabolism in cell death and autophagy. Autophagy. 2023;1–21. DOI:10.1080/15548627.2023.2200554.
  • Wu K, Yan M, Liu T, et al. Creatine kinase B suppresses ferroptosis by phosphorylating GPX4 through a moonlighting function. Nat Cell Biol. 2023;25:714–725.
  • Rubio N, Coupienne I, Di Valentin E, et al. Spatiotemporal autophagic degradation of oxidatively damaged organelles after photodynamic stress is amplified by mitochondrial reactive oxygen species. Autophagy. 2012;8:1312–1324.
  • Jiang W, Li Y, Zhao Y, et al. L-carnitine supplementation during in vitro culture regulates oxidative stress in embryos from bovine aged oocytes. Theriogenology. 2020;143:64–73.
  • Morgan AH, Hammond VJ, Sakoh-Nakatogawa M, et al. A novel role for 12/15-lipoxygenase in regulating autophagy. Redox Biol. 2015;4:40–47.
  • Liu J, Kuang F, Kroemer G, et al. Autophagy-dependent ferroptosis: machinery and regulation. Cell Chem Biol. 2020;27:420–435.
  • Stockwell BR, Friedmann Angeli JP, Bayir H, et al. Ferroptosis: a regulated cell death nexus linking metabolism, redox biology, and disease. Cell. 2017;171:273–285.
  • Chen X, Kang R, Kroemer G, et al. Broadening horizons: the role of ferroptosis in cancer. Nat Rev Clin Oncol. 2021;18:280–296.
  • Yang C, Zhang Y, Lin S, et al. Correction for: suppressing the KIF20A/NUAK1/Nrf2/GPX4 signaling pathway induces ferroptosis and enhances the sensitivity of colorectal cancer to oxaliplatin. Aging. 2021;13:19077.
  • Ni J, Chen K, Zhang J, et al. Inhibition of GPX4 or mTOR overcomes resistance to Lapatinib via promoting ferroptosis in NSCLC cells. Biochem Biophys Res Commun. 2021;567:154–160.
  • Wang Q, Bin C, Xue Q, et al. GSTZ1 sensitizes hepatocellular carcinoma cells to sorafenib-induced ferroptosis via inhibition of NRF2/GPX4 axis. Cell Death Dis. 2021;12:426.
  • Yuan L, Li S, Chen Q, et al. EBV infection-induced GPX4 promotes chemoresistance and tumor progression in nasopharyngeal carcinoma. Cell Death Differ. 2022;29:1513–1527.
  • Zheng J, Sato M, Mishima E, et al. Sorafenib fails to trigger ferroptosis across a wide range of cancer cell lines. Cell Death Dis. 2021;12:698.
  • Wiernicki B, Maschalidi S, Pinney J, et al. Cancer cells dying from ferroptosis impede dendritic cell-mediated anti-tumor immunity. Nat Commun. 2022;13:3676.
  • Hangauer MJ, Viswanathan VS, Ryan MJ, et al. Drug-tolerant persister cancer cells are vulnerable to GPX4 inhibition. Nature. 2017;551:247–250.
  • Liu S, Zhao X, Shui S, et al. PDTAC: targeted photodegradation of GPX4 triggers ferroptosis and potent antitumor immunity. J Med Chem. 2022;65:12176–12187.
  • Luo T, Zheng Q, Shao L, et al. Intracellular delivery of glutathione peroxidase degrader induces ferroptosis in vivo. Angew Chem Int Ed Engl. 2022;61:e202206277.
  • Han L, Bai L, Qu C, et al. PPARG-mediated ferroptosis in dendritic cells limits antitumor immunity. Biochem Biophys Res Commun. 2021;576:33–39.
  • Kim R, Hashimoto A, Markosyan N, et al. Ferroptosis of tumour neutrophils causes immune suppression in cancer. Nature. 2022;612:338–346.
  • Xu C, Sun S, Johnson T, et al. The glutathione peroxidase Gpx4 prevents lipid peroxidation and ferroptosis to sustain Treg cell activation and suppression of antitumor immunity. Cell Rep. 2021;35:109235.
  • Dai E, Han L, Liu J, et al. Autophagy-dependent ferroptosis drives tumor-associated macrophage polarization via release and uptake of oncogenic KRAS protein. Autophagy. 2020;16:2069–2083.
  • Liu J, Zhu S, Zeng L, et al. DCN released from ferroptotic cells ignites AGER-dependent immune responses. Autophagy. 2022;18:2036–2049.
  • Wirth EK, Conrad M, Winterer J, et al. Neuronal selenoprotein expression is required for interneuron development and prevents seizures and neurodegeneration. Faseb J. 2010;24:844–852.
  • Wirth EK, Bharathi BS, Hatfield D, et al. Cerebellar hypoplasia in mice lacking selenoprotein biosynthesis in neurons. Biol Trace Elem Res. 2014;158:203–210.
  • Jakaria M, Belaidi AA, Bush AI, et al. Ferroptosis as a mechanism of neurodegeneration in Alzheimer’s disease. J Neurochem. 2021;159:804–825.
  • Ko CJ, Gao SL, Lin TK, et al. Ferroptosis as a major factor and therapeutic target for neuroinflammation in Parkinson’s disease. Biomedicines. 2021;9:1679.
  • Banning A, Schnurr K, Bol GF, et al. Inhibition of basal and interleukin-1-induced VCAM-1 expression by phospholipid hydroperoxide glutathione peroxidase and 15-lipoxygenase in rabbit aortic smooth muscle cells. Free Radic Biol Med. 2004;36:135–144.
  • Rayman MP, Taylor EW, Zhang J. The relevance of selenium to viral disease with special reference to SARS-CoV-2 and COVID-19. Proc Nutr Soc. 2023;2022:1–12.
  • Bedford J, Enria D, Giesecke J, et al. COVID-19: towards controlling of a pandemic. Lancet. 2020;395:1015–1018.
  • Khoso PA, Yang Z, Liu C, et al. Selenium deficiency downregulates selenoproteins and suppresses immune function in chicken thymus. Biol Trace Elem Res. 2015;167:48–55.
  • Drijvers JM, Gillis JE, Muijlwijk T, et al. Pharmacologic screening identifies metabolic vulnerabilities of CD8(+) T cells. Cancer Immunol Res. 2021;9:184–199.
  • Zhang RX, Kang R, Tang DL. STING1 in sepsis: mechanisms, functions, and implications. Chin J Traumatol. 2022;25:1–10.
  • Zhang R, Kang R, Tang D. The STING1 network regulates autophagy and cell death. Signal Transduct Target Ther. 2021;6:208.
  • Jia M, Qin D, Zhao C, et al. Redox homeostasis maintained by GPX4 facilitates STING activation. Nat Immunol. 2020;21:727–735.
  • Li C, Liu J, Hou W, et al. STING1 promotes ferroptosis through MFN1/2-dependent mitochondrial fusion. Front Cell Dev Biol. 2021;9:698679.
  • Foresta C, Flohe L, Garolla A, et al. Male fertility is linked to the selenoprotein phospholipid hydroperoxide glutathione peroxidase. Biol Reprod. 2002;67:967–971.
  • Chen X, Kang R, Kroemer G, et al. Ferroptosis in infection, inflammation, and immunity. J Exp Med. 2021;218. DOI:10.1084/jem.20210518
  • Dabkowski ER, Williamson CL, Hollander JM. Mitochondria-specific transgenic overexpression of phospholipid hydroperoxide glutathione peroxidase (GPx4) attenuates ischemia/reperfusion-associated cardiac dysfunction. Free Radic Biol Med. 2008;45:855–865.
  • Sun W, Shi R, Guo J, et al. MiR-135b-3p promotes cardiomyocyte ferroptosis by targeting GPX4 and aggravates myocardial Ischemia/reperfusion injury. Front Cardiovasc Med. 2021;8:663832.
  • Kromer A, Moosmann B. Statin-induced liver injury involves cross-talk between cholesterol and selenoprotein biosynthetic pathways. Mol Pharmacol. 2009;75:1421–1429.
  • Luo Y, Chen H, Liu H, et al. Protective effects of ferroptosis inhibition on high fat diet-induced liver and renal injury in mice. Int J Clin Exp Pathol. 2020;13:2041–2049.
  • Yang Y, Chen J, Gao Q, et al. Study on the attenuated effect of Ginkgolide B on ferroptosis in high fat diet induced nonalcoholic fatty liver disease. Toxicology. 2020;445:152599.
  • Zhao T, Yu Z, Zhou L, et al. Regulating Nrf2-GPx4 axis by bicyclol can prevent ferroptosis in carbon tetrachloride-induced acute liver injury in mice. Cell Death Discov. 2022;8:380.
  • Zhu K, Zhu X, Liu S, et al. Glycyrrhizin attenuates hypoxic-ischemic brain damage by inhibiting ferroptosis and neuroinflammation in neonatal rats via the HMGB1/GPX4 pathway. Oxid Med Cell Longev. 2022;2022:1–18.
  • Fukai M, Hayashi T, Yokota R, et al. Lipid peroxidation during ischemia depends on ischemia time in warm ischemia and reperfusion of rat liver. Free Radic Biol Med. 2005;38:1372–1381.
  • Weiwer M, Bittker JA, Lewis TA, et al. Development of small-molecule probes that selectively kill cells induced to express mutant RAS. Bioorg Med Chem Lett. 2012;22:1822–1826.
  • Eaton JK, Furst L, Ruberto RA, et al. Selective covalent targeting of GPX4 using masked nitrile-oxide electrophiles. Nat Chem Biol. 2020;16:497–506.
  • Cheff DM, Huang C, Scholzen KC, et al. The ferroptosis inducing compounds RSL3 and ML162 are not direct inhibitors of GPX4 but of TXNRD1. Redox Biol. 2023;14:9401–9418.
  • Shimada K, Skouta R, Kaplan A, et al. Global survey of cell death mechanisms reveals metabolic regulation of ferroptosis. Nat Chem Biol. 2016;12:497–503.
  • Muller T, Dewitz C, Schmitz J, et al. Necroptosis and ferroptosis are alternative cell death pathways that operate in acute kidney failure. Cell Mol Life Sci. 2017;74:3631–3645.
  • Su LJ, Zhang JH, Gomez H, et al. Reactive oxygen species-induced lipid peroxidation in apoptosis, autophagy, and ferroptosis. Oxid Med Cell Longev. 2019;2019:5080843.
  • Blaner WS, Shmarakov IO, Traber MG. Vitamin a and vitamin E: will the real antioxidant please stand up? Annu Rev Nutr. 2021;41:105–131.
  • Maiorino M, Coassin M, Roveri A, et al. Microsomal lipid peroxidation: effect of vitamin E and its functional interaction with phospholipid hydroperoxide glutathione peroxidase. Lipids. 1989;24:721–726.
  • Zhang R, Kang R, Tang D. Reductive cell death: the other side of the coin. Cancer Gene Ther. 2023. DOI:10.1038/s41417-023-00612-3