Current Pharmaceutical BiotechnologyCurrent Pharmaceutical BiotechnologyCurrent Pharmaceutical Biotechnology1389-20101873-4316Bentham Science64479210.2174/1389201024666230823091144BiotechnologyResearch ArticleAdvances on the Role of Ferroptosis in Ionizing Radiation ResponseWangFanginfo@benthamscience.netDaiQingHuiinfo@benthamscience.netXuLuhaninfo@benthamscience.netGanLuinfo@benthamscience.netShiYidiinfo@benthamscience.netYangMingjuninfo@benthamscience.netYangShuhonginfo@benthamscience.netSchool of Life Science and Engineering, Lanzhou University of TechnologyInstitute of Modern Physics,, Chinese Academy of Sciences1502202425439641007012025Copyright ©; 2024, Bentham Science Publishers2024Bentham Science Publishershttps://journals.eco-vector.com/1389-2010/article/view/644792

Ferroptosis is an iron-dependent programmed cell death mode that is distinct from other cell death modes, and radiation is able to stimulate cellular oxidative stress and induce the production of large amounts of reactive oxygen radicals, which in turn leads to the accumulation of lipid peroxide and the onset of ferroptosis. In this review, from the perspective of the role of ferroptosis in generating a radiation response following cellular irradiation, the relationship between ferroptosis induced by ionizing radiation stress and the response to ionizing radiation is reviewed, including the roles of MAPK and Nrf2 signaling pathways in ferroptosis, resulting from the oxidative stress response to ionizing radiation, the metabolic regulatory role of the p53 gene in ferroptosis, and regulatory modes of action of iron metabolism and iron metabolism-related regulatory proteins in promoting and inhibiting ferroptosis. It provides some ideas for the follow-up research to explore the specific mechanism and regulatory network of ferroptosis in response to ionizing radiation.

Ionizing radiation responseferroptosislipid peroxidesregulation of iron metabolismreactive oxygen radicalsradiotherapy.Wang, K.; Tepper, J.E. Radiation therapy-associated toxicity: Etiology, management, and prevention. CA Cancer J. Clin., 2021, 71(5), 437-454. doi: 10.3322/caac.21689 PMID: 34255347Zeng, J.; Harris, T.J.; Lim, M.; Drake, C.G.; Tran, P.T. (2013) Immune modulation and stereotactic radiation: improving local and abscopal responses. BioMed Res. Int., 2013, 658126. doi: 10.1155/2013/658126 PMID: 24324970Tang, D.; Chen, X.; Kang, R.; Kroemer, G. Ferroptosis: Molecular mechanisms and health implications. Cell Res., 2021, 31(2), 107-125. doi: 10.1038/s41422-020-00441-1 PMID: 33268902Helm, J.S.; Rudel, R.A. Adverse outcome pathways for ionizing radiation and breast cancer involve direct and indirect DNA damage, oxidative stress, inflammation, genomic instability, and interaction with hormonal regulation of the breast. Arch. Toxicol., 2020, 94(5), 1511-1549. doi: 10.1007/s00204-020-02752-z PMID: 32399610Noda, A. Radiation-induced unrepairable DSBs: Their role in the late effects of radiation and possible applications to biodosimetry. J. Radiat. Res., 2018, 59(2), ii114-ii120. doi: 10.1093/jrr/rrx074 PMID: 29281054Yu, C.; Peng, R.Y. Biological effects and mechanisms of shortwave radiation: A review. Mil. Med. Res., 2017, 4(1), 24. doi: 10.1186/s40779-017-0133-6 PMID: 28729909Chen, X.; Kang, R.; Kroemer, G.; Tang, D. Broadening horizons: The role of ferroptosis in cancer. Nat. Rev. Clin. Oncol., 2021, 18(5), 280-296. doi: 10.1038/s41571-020-00462-0 PMID: 33514910Gan, B. DUBbing ferroptosis in cancer cells. Cancer Res., 2019, 79(8), 1749-1750. doi: 10.1158/0008-5472.CAN-19-0487 PMID: 30987975Dixon, 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.; Morrison, B., III; Stockwell, B.R. Ferroptosis: An iron-dependent form of nonapoptotic cell death. Cell, 2012, 149(5), 1060-1072. doi: 10.1016/j.cell.2012.03.042 PMID: 22632970Tang, D.; Kroemer, G. Ferroptosis. Curr. Biol., 2020, 30(21), R1292-R1297. doi: 10.1016/j.cub.2020.09.068 PMID: 33142092Stockwell, B.R. Ferroptosis turns 10: Emerging mechanisms, physiological functions, and therapeutic applications. Cell, 2022, 185(14), 2401-2421. doi: 10.1016/j.cell.2022.06.003 PMID: 35803244Yuan, H.; Pratte, J.; Giardina, C. Ferroptosis and its potential as a therapeutic target. Biochem. Pharmacol., 2021, 186, 114486. doi: 10.1016/j.bcp.2021.114486 PMID: 33631189Jiang, X.; Stockwell, B.R.; Conrad, M. Ferroptosis: Mechanisms, biology and role in disease. Nat. Rev. Mol. Cell Biol., 2021, 22(4), 266-282. doi: 10.1038/s41580-020-00324-8 PMID: 33495651Feng, H.; Schorpp, K.; Jin, J.; Yozwiak, C.E.; Hoffstrom, B.G.; Decker, A.M.; Rajbhandari, P.; Stokes, M.E.; Bender, H.G.; Csuka, J.M.; Upadhyayula, P.S.; Canoll, P.; Uchida, K.; Soni, R.K.; Hadian, K.; Stockwell, B.R. Transferrin receptor is a specific ferroptosis marker. Cell Rep., 2020, 30(10), 3411-3423.e7. doi: 10.1016/j.celrep.2020.02.049 PMID: 32160546Luo, M.; Yan, J.; Hu, X.; Li, H.; Li, H.; Liu, Q.; Chen, Y.; Zou, Z. Targeting lipid metabolism for ferroptotic cancer therapy. Apoptosis, 2022, •••, 18. doi: 10.1007/s10495-022-01795-0 PMID: 36399287Zheng, J.; Conrad, M. The metabolic underpinnings of ferroptosis. Cell Metab., 2020, 32(6), 920-937. doi: 10.1016/j.cmet.2020.10.011 PMID: 33217331Dahlmanns, M.; Yakubov, E.; Chen, D.; Sehm, T.; Rauh, M.; Savaskan, N.; Wrosch, J.K. Chemotherapeutic xCT inhibitors sorafenib and erastin unraveled with the synaptic optogenetic function analysis tool. Cell Death Discov., 2017, 3(1), 17030. doi: 10.1038/cddiscovery.2017.30 PMID: 28835855Zhang, Y.; Shi, J.; Liu, X.; Feng, L.; Gong, Z.; Koppula, P.; Sirohi, K.; Li, X.; Wei, Y.; Lee, H.; Zhuang, L.; Chen, G.; Xiao, Z.D.; Hung, M.C.; Chen, J.; Huang, P.; Li, W.; Gan, B. BAP1 links metabolic regulation of ferroptosis to tumour suppression. Nat. Cell Biol., 2018, 20(10), 1181-1192. doi: 10.1038/s41556-018-0178-0 PMID: 30202049Li, J.; Cao, F.; Yin, H.; Huang, Z.; Lin, Z.; Mao, N.; Sun, B.; Wang, G. Ferroptosis: Past, present and future. Cell Death Dis., 2020, 11(2), 88. doi: 10.1038/s41419-020-2298-2 PMID: 32015325Bogdan, A.R.; Miyazawa, M.; Hashimoto, K.; Tsuji, Y. Regulators of Iron homeostasis: New players in metabolism, cell death, and disease. Trends Biochem. Sci., 2016, 41(3), 274-286. doi: 10.1016/j.tibs.2015.11.012 PMID: 26725301Lei, G.; Mao, C.; Yan, Y.; Zhuang, L.; Gan, B. Ferroptosis, radiotherapy, and combination therapeutic strategies. Protein Cell, 2021, 12(11), 836-857. doi: 10.1007/s13238-021-00841-y PMID: 33891303Valashedi, M.R.; Bamshad, C.; Najafi-Ghalehlou, N.; Nikoo, A.; Tomita, K.; Kuwahara, Y.; Sato, T.; Roushandeh, A.M.; Roudkenar, M.H. Non-coding RNAs in ferroptotic cancer cell death pathway: Meet the new masters. Hum. Cell, 2022, 35(4), 972-994. doi: 10.1007/s13577-022-00699-0 PMID: 35415781Liu, P.; Feng, Y.; Li, H.; Chen, X.; Wang, G.; Xu, S.; Li, Y.; Zhao, L. Ferrostatin-1 alleviates lipopolysaccharide-induced acute lung injury via inhibiting ferroptosis. Cell. Mol. Biol. Lett., 2020, 25(1), 10. doi: 10.1186/s11658-020-00205-0 PMID: 32161620Dächert, J.; Ehrenfeld, V.; Habermann, K.; Dolgikh, N.; Fulda, S. Targeting ferroptosis in rhabdomyosarcoma cells. Int. J. Cancer, 2020, 146(2), 510-520. doi: 10.1002/ijc.32496 PMID: 31173656Feng, S-Q.; Yao, X.; Zhang, Y.; Hao, J.; Duan, H-Q.; Zhao, C-X.; Sun, C.; Li, B.; Fan, B-Y.; Wang, X.; Li, W-X.; Fu, X-H.; Hu, Y.; Liu, C.; Kong, X-H. Deferoxamine promotes recovery of traumatic spinal cord injury by inhibiting ferroptosis. Neural Regen. Res., 2019, 14(3), 532-541. doi: 10.4103/1673-5374.245480 PMID: 30539824Cao, Y.; Li, Y.; He, C.; Yan, F.; Li, J.R.; Xu, H.Z.; Zhuang, J.F.; Zhou, H.; Peng, Y.C.; Fu, X.J.; Lu, X.Y.; Yao, Y.; Wei, Y.Y.; Tong, Y.; Zhou, Y.F.; Wang, L. Selective ferroptosis inhibitor liproxstatin-1 attenuates neurological deficits and neuroinflammation after subarachnoid hemorrhage. Neurosci. Bull., 2021, 37(4), 535-549. doi: 10.1007/s12264-020-00620-5 PMID: 33421025Jiang, T.; Chu, J.; Chen, H.; Cheng, H.; Su, J.; Wang, X.; Cao, Y.; Tian, S.; Li, Q. Gastrodin inhibits H2O2-induced ferroptosis through its antioxidative effect in rat glioma cell line C6. Biol. Pharm. Bull., 2020, 43(3), 480-487. doi: 10.1248/bpb.b19-00824 PMID: 32115506Xiao, F.J.; Zhang, D.; Wu, Y.; Jia, Q.H.; Zhang, L.; Li, Y.X.; Yang, Y.F.; Wang, H.; Wu, C.T.; Wang, L.S. miRNA-17-92 protects endothelial cells from erastin-induced ferroptosis through targeting the A20-ACSL4 axis. Biochem. Biophys. Res. Commun., 2019, 515(3), 448-454. doi: 10.1016/j.bbrc.2019.05.147 PMID: 31160087Sun, X.; Ou, Z.; Chen, R.; Niu, X.; Chen, D.; Kang, R.; Tang, D. Activation of the p62Keap1NRF2 pathway protects against ferroptosis in hepatocellular carcinoma cells. Hepatology, 2016, 63(1), 173-184. doi: 10.1002/hep.28251 PMID: 26403645Wang, B.; Hou, D.; Liu, Q.; Wu, T.; Guo, H.; Zhang, X.; Zou, Y.; Liu, Z.; Liu, J.; Wei, J.; Gong, Y.; Shao, C. Artesunate sensitizes ovarian cancer cells to cisplatin by downregulating RAD51. Cancer Biol. Ther., 2015, 16(10), 1548-1556. doi: 10.1080/15384047.2015.1071738 PMID: 26176175Gaschler, M.M.; Andia, A.A.; Liu, H.; Csuka, J.M.; Hurlocker, B.; Vaiana, C.A.; Heindel, D.W.; Zuckerman, D.S.; Bos, P.A.O.; Reznik, E.; Ye, L.F.; Tyurina, Y.Y.; Lin, A.J.; Shchepinov, M.S.; Chan, A.Y.; Peguero-Pereira, E.; Fomich, M.A.; Daniels, J.D.; Bekish, A.V.; Shmanai, V.A.O.; Kagan, V.E.; Mahal, L.K.; Woerpel, K.A.; Stockwell, B.R. FINO2 initiates ferroptosis through GPX4 inactivation and iron oxidation. Nat. Chem. Biol., 2018, 14(5), 507-515. doi: 10.1038/s41589-018-0031-6 PMID: 29610484Ma, S.; Henson, E.S.; Chen, Y.; Gibson, S.B. Ferroptosis is induced following siramesine and lapatinib treatment of breast cancer cells. Cell Death Dis., 2016, 7(7), e2307. doi: 10.1038/cddis.2016.208 PMID: 27441659Du, Y.; Bao, J.; Zhang, M.; Li, L.; Xu, X.L.; Chen, H.; Feng, Y.; Peng, X.; Chen, F. Targeting ferroptosis contributes to ATPR-induced AML differentiation via ROS-autophagy-lysosomal pathway. Gene, 2020, 755, 144889. doi: 10.1016/j.gene.2020.144889 PMID: 32534056Chen, X.; Xu, S.; Zhao, C.; Liu, B. Role of TLR4/NADPH oxidase 4 pathway in promoting cell death through autophagy and ferroptosis during heart failure. Biochem. Biophys. Res. Commun., 2019, 516(1), 37-43. doi: 10.1016/j.bbrc.2019.06.015 PMID: 31196626Mikulska-Ruminska, K.; Anthonymuthu, T.; Levkina, A.; Shrivastava, I.; Kapralov, A. Bayır, H.; Kagan, V.; Bahar, I. NO● represses the oxygenation of arachidonoyl PE by 15LOX/PEBP1: Mechanism and role in ferroptosis. Int. J. Mol. Sci., 2021, 22(10), 5253. doi: 10.3390/ijms22105253 PMID: 34067535Badgley, 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.; Decker, A.R.; Sastra, S.A.; Palermo, C.F.; Andrade, L.R.; Sajjakulnukit, P.; Zhang, L.; Tolstyka, Z.P.; Hirschhorn, T.; Lamb, C.; Liu, T.; Gu, W.; Seeley, E.S.; Stone, E.; Georgiou, G.; Manor, U.; Iuga, A.; Wahl, G.M.; Stockwell, B.R.; Lyssiotis, C.A.; Olive, K.P. Cysteine depletion induces pancreatic tumor ferroptosis in mice. Sci., 2020, 368(6486), 85-89. doi: 10.1126/science.aaw9872 PMID: 32241947Eaton, J.K.; Furst, L.; Ruberto, R.A.; Moosmayer, D.; Hilpmann, A.; Ryan, M.J.; Zimmermann, K.; Cai, L.L.; Niehues, M.; Badock, V.; Kramm, A.; Chen, S.; Hillig, R.C.; Clemons, P.A.; Gradl, S.; Montagnon, C.; Lazarski, K.E.; Christian, S.; Bajrami, B.; Neuhaus, R.; Eheim, A.L.; Viswanathan, V.S.; Schreiber, S.L. Selective covalent targeting of GPX4 using masked nitrile-oxide electrophiles. Nat. Chem. Biol., 2020, 16(5), 497-506. doi: 10.1038/s41589-020-0501-5 PMID: 32231343NaveenKumar, S.K.; Hemshekhar, M.; Kemparaju, K.; Girish, K.S. Hemin-induced platelet activation and ferroptosis is mediated through ROS-driven proteasomal activity and inflammasome activation: Protection by Melatonin. Biochim. Biophys. Acta Mol. Basis Dis., 2019, 1865(9), 2303-2316. doi: 10.1016/j.bbadis.2019.05.009 PMID: 31102787Doll, S.; Freitas, F.P.; Shah, R.; Aldrovandi, M.; da Silva, M.C.; Ingold, I.; Goya Grocin, A.; Xavier da Silva, T.N.; Panzilius, E.; Scheel, C.H.; Mourão, A.; Buday, K.; Sato, M.; Wanninger, J.; Vignane, T.; Mohana, V.; Rehberg, M.; Flatley, A.; Schepers, A.; Kurz, A.; White, D.; Sauer, M.; Sattler, M.; Tate, E.W.; Schmitz, W.; Schulze, A.; O’Donnell, V.; Proneth, B.; Popowicz, G.M.; Pratt, D.A.; Angeli, J.P.F.; Conrad, M. FSP1 is a glutathione-independent ferroptosis suppressor. Nature, 2019, 575(7784), 693-698. doi: 10.1038/s41586-019-1707-0 PMID: 31634899Yu, Y.; Huang, Z.; Chen, Q.; Zhang, Z.; Jiang, H.; Gu, R.; Ding, Y.; Hu, Y. Iron-based nanoscale coordination polymers synergistically induce immunogenic ferroptosis by blocking dihydrofolate reductase for cancer immunotherapy. Biomaterials, 2022, 288, 121724. doi: 10.1016/j.biomaterials.2022.121724 PMID: 36038420Wang, S.; Li, F.; Qiao, R.; Hu, X.; Liao, H.; Chen, L.; Wu, J.; Wu, H.; Zhao, M.; Liu, J.; Chen, R.; Ma, X.; Kim, D.; Sun, J.; Davis, T.P.; Chen, C.; Tian, J.; Hyeon, T.; Ling, D. Arginine-rich manganese silicate nanobubbles as a ferroptosis-inducing agent for tumor-targeted theranostics. ACS Nano, 2018, 12(12), 12380-12392. doi: 10.1021/acsnano.8b06399 PMID: 30495919Hsieh, C.H.; Hsieh, H.C.; Shih, F.H.; Wang, P.W.; Yang, L.X.; Shieh, D.B.; Wang, Y.C. An innovative NRF2 nano-modulator induces lung cancer ferroptosis and elicits an immunostimulatory tumor microenvironment. Theranostics, 2021, 11(14), 7072-7091. doi: 10.7150/thno.57803 PMID: 34093872Huo, M.; Wang, L.; Wang, Y.; Chen, Y.; Shi, J. Nanocatalytic tumor therapy by single-atom catalysts. ACS Nano., 2019, 13(2), acsnano.9b00457.. doi: 10.1021/acsnano.9b00457 PMID: 30753056Miao, M.Z.; Xiao, P.G.; Yue, G.; Wen, J.; Dong, L. A review of the effects of ionizing radiation on cell membrane. J. Radiat. Res. Radiat. Technol., 2017, 35(4), 040103-040107. doi: 10.11889/j.1000-3436.2017.rrj.35.040103Hassannia, B.; Van Coillie, S.; Vanden Berghe, T. Ferroptosis: Biological rust of lipid membranes. Antioxid. Redox Signal., 2021, 35(6), 487-509. doi: 10.1089/ars.2020.8175 PMID: 32808533Stockwell, 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.; Noel, K.; Jiang, X.; Linkermann, A.; Murphy, M.E.; Overholtzer, M.; Oyagi, A.; Pagnussat, G.C.; Park, J.; Ran, Q.; Rosenfeld, C.S.; Salnikow, K.; Tang, D.; Torti, F.M.; Torti, S.V.; Toyokuni, S.; Woerpel, K.A.; Zhang, D.D. Ferroptosis: A regulated cell death nexus linking metabolism, redox biology, and disease. Cell, 2017, 171(2), 273-285. doi: 10.1016/j.cell.2017.09.021 PMID: 28985560Wang, Y.; Liu, Z.G.; Yuan, H.; Deng, W.; Li, J.; Huang, Y.; Kim, B.Y.S.; Story, M.D.; Jiang, W. The reciprocity between radiotherapy and cancer immunotherapy. Clin. Cancer Res., 2019, 25(6), 1709-1717. doi: 10.1158/1078-0432.CCR-18-2581 PMID: 30413527Lang, X.; Green, M.D.; Wang, W.; Yu, J.; Choi, J.E.; Jiang, L.; Liao, P.; Zhou, J.; Zhang, Q.; Dow, A.; Saripalli, A.L.; Kryczek, I.; Wei, S.; Szeliga, W.; Vatan, L.; Stone, E.M.; Georgiou, G.; Cieslik, M.; Wahl, D.R.; Morgan, M.A.; Chinnaiyan, A.M.; Lawrence, T.S.; Zou, W. Radiotherapy and immunotherapy promote tumoral lipid oxidation and ferroptosis via synergistic repression of SLC7A11. Cancer Discov., 2019, 9(12), 1673-1685. doi: 10.1158/2159-8290.CD-19-0338 PMID: 31554642Wang, W.; Green, M.; Choi, J.E.; Gijón, M.; Kennedy, P.D.; Johnson, J.K.; Liao, P.; Lang, X.; Kryczek, I.; Sell, A.; Xia, H.; Zhou, J.; Li, G.; Li, J.; Li, W.; Wei, S.; Vatan, L.; Zhang, H.; Szeliga, W.; Gu, W.; Liu, R.; Lawrence, T.S.; Lamb, C.; Tanno, Y.; Cieslik, M.; Stone, E.; Georgiou, G.; Chan, T.A.; Chinnaiyan, A.; Zou, W. CD8+ T cells regulate tumour ferroptosis during cancer immunotherapy. Nature, 2019, 569(7755), 270-274. doi: 10.1038/s41586-019-1170-y PMID: 31043744Wang, H.; Mu, X.; He, H.; Zhang, X.D. Cancer radiosensitizers. Trends Pharmacol. Sci., 2018, 39(1), 24-48. doi: 10.1016/j.tips.2017.11.003 PMID: 29224916Cadenas, S. ROS and redox signaling in myocardial ischemia-reperfusion injury and cardioprotection. Free Radic. Biol. Med., 2018, 117, 76-89. doi: 10.1016/j.freeradbiomed.2018.01.024 PMID: 29373843Santivasi, W.L.; Xia, F. Ionizing radiation-induced DNA damage, response, and repair. Antioxid. Redox Signal., 2014, 21(2), 251-259. doi: 10.1089/ars.2013.5668 PMID: 24180216Yan, B.; Ai, Y.; Sun, Q.; Ma, Y.; Cao, Y.; Wang, J.; Zhang, Z.; Wang, X. Membrane damage during ferroptosis is caused by oxidation of phospholipids catalyzed by the oxidoreductases POR and CYB5R1. Mol. Cell, 2021, 81(2), 355-369.e10. doi: 10.1016/j.molcel.2020.11.024 PMID: 33321093Panzetta, V.; La Verde, G.; Pugliese, M.; Artiola, V.; Arrichiello, C.; Muto, P.; La Commara, M.; Netti, P.A.; Fusco, S. Adhesion and migration response to radiation therapy of mammary epithelial and adenocarcinoma cells interacting with different stiffness substrates. Cancers, 2020, 12(5), 1170. doi: 10.3390/cancers12051170 PMID: 32384675Imai, H.; Matsuoka, M.; Kumagai, T.; Sakamoto, T.; Koumura, T. Lipid peroxidation-dependent cell death regulated by GPx4 and ferroptosis. Curr. Top. Microbiol. Immunol., 2016, 403, 143-170. doi: 10.1007/82_2016_508 PMID: 28204974Ye, L.F.; Chaudhary, K.R.; Zandkarimi, F.; Harken, A.D.; Kinslow, C.J.; Upadhyayula, P.S.; Dovas, A.; Higgins, D.M.; Tan, H.; Zhang, Y.; Buonanno, M.; Wang, T.J.C.; Hei, T.K.; Bruce, J.N.; Canoll, P.D.; Cheng, S.K.; Stockwell, B.R. Radiation-induced lipid peroxidation triggers ferroptosis and synergizes with ferroptosis inducers. ACS Chem. Biol., 2020, 15(2), 469-484. doi: 10.1021/acschembio.9b00939 PMID: 31899616Dixon, S.J.; Winter, G.E.; Musavi, L.S.; Lee, E.D.; Snijder, B.; Rebsamen, M.; Superti-Furga, G.; Stockwell, B.R. Human haploid cell genetics reveals roles for lipid metabolism genes in nonapoptotic cell death. ACS Chem. Biol., 2015, 10(7), 1604-1609. doi: 10.1021/acschembio.5b00245 PMID: 25965523Nakamura, T.; Naguro, I.; Ichijo, H. Iron homeostasis and iron-regulated ROS in cell death, senescence and human diseases. Biochim. Biophys. Acta, Gen. Subj., 2019, 1863(9), 1398-1409. doi: 10.1016/j.bbagen.2019.06.010 PMID: 31229492Lin, Z.; Liu, J.; Kang, R.; Yang, M.; Tang, D. Lipid metabolism in ferroptosis. Adv. Biol., 2021, 5(8), 2100396. doi: 10.1002/adbi.202100396 PMID: 34015188Chen, X.; Yu, C.; Kang, R.; Tang, D. Iron metabolism in ferroptosis. Front. Cell Dev. Biol., 2020, 8, 590226. doi: 10.3389/fcell.2020.590226 PMID: 33117818Zou, Y.; Henry, W.S.; Ricq, E.L.; Graham, E.T.; Phadnis, V.V.; Maretich, P.; Paradkar, S.; Boehnke, N.; Deik, A.A.; Reinhardt, F.; Eaton, J.K.; Ferguson, B.; Wang, W.; Fairman, J.; Keys, H.R. Dančík, V.; Clish, C.B.; Clemons, P.A.; Hammond, P.T.; Boyer, L.A.; Weinberg, R.A.; Schreiber, S.L. Plasticity of ether lipids promotes ferroptosis susceptibility and evasion. Nature, 2020, 585(7826), 603-608. doi: 10.1038/s41586-020-2732-8 PMID: 32939090Chang, L.C.; Chiang, S.K.; Chen, S.E.; Yu, Y.L.; Chou, R.H.; Chang, W.C. Heme oxygenase-1 mediates BAY 11–7085 induced ferroptosis. Cancer Lett., 2018, 416, 124-137. doi: 10.1016/j.canlet.2017.12.025 PMID: 29274359Ursini, F.; Maiorino, M. Lipid peroxidation and ferroptosis: The role of GSH and GPx4. Free Radic. Biol. Med., 2020, 152, 175-185. doi: 10.1016/j.freeradbiomed.2020.02.027 PMID: 32165281Sun, Y.; Berleth, N.; Wu, W.; Schlütermann, D.; Deitersen, J.; Stuhldreier, F.; Berning, L.; Friedrich, A.; Akgün, S.; Mendiburo, M.J.; Wesselborg, S.; Conrad, M.; Berndt, C.; Stork, B. 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(11), 1028. doi: 10.1038/s41419-021-04306-2 PMID: 34716292Kabilan, U.; Graber, T.E.; Alain, T.; Klokov, D. Ionizing radiation and translation control: A link to radiation hormesis? Int. J. Mol. Sci., 2020, 21(18), 6650. doi: 10.3390/ijms21186650 PMID: 32932812Zhang, X.; Xing, X.; Liu, H.; Feng, J.; Tian, M.; Chang, S.; Liu, P.; Zhang, H. Ionizing radiation induces ferroptosis in granulocyte-macrophage hematopoietic progenitor cells of murine bone marrow. Int. J. Radiat. Biol., 2020, 96(5), 584-595. doi: 10.1080/09553002.2020.1708993 PMID: 31906761Li, X.Y.; Leung, P.S. Erastin-induced ferroptosis is a regulator for the growth and function of human pancreatic islet-like cell clusters. Cell Regen., 2020, 9(1), 16. doi: 10.1186/s13619-020-00055-3 PMID: 32893325Regon, P.; Dey, S.; Chowardhara, B.; Saha, B.; Kar, S.; Tanti, B.; Panda, S.K. Physio-biochemical and molecular assessment of Iron (Fe2+) toxicity responses in contrasting indigenous aromatic joha rice cultivars of Assam, India. Protoplasma, 2021, 258(2), 289-299. doi: 10.1007/s00709-020-01574-1 PMID: 33070240Bersuker, K.; Hendricks, J.M.; Li, Z.; Magtanong, L.; Ford, B.; Tang, P.H.; Roberts, M.A.; Tong, B.; Maimone, T.J.; Zoncu, R.; Bassik, M.C.; Nomura, D.K.; Dixon, S.J.; Olzmann, J.A. The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis. Nature, 2019, 575(7784), 688-692. doi: 10.1038/s41586-019-1705-2 PMID: 31634900Chen, L.; Xie, J. Ferroptosis suppressor protein 1: A potential neuroprotective target for combating ferroptosis. Mov. Disord., 2020, 35(3), 400. doi: 10.1002/mds.27990 PMID: 32027037Vogt, A.C.S.; Arsiwala, T.; Mohsen, M.; Vogel, M.; Manolova, V.; Bachmann, M.F. On iron metabolism and its regulation. Int. J. Mol. Sci., 2021, 22(9), 4591. doi: 10.3390/ijms22094591 PMID: 33925597Gao, J.; Luo, T.; Wang, J. Gene interfered-ferroptosis therapy for cancers. Nat. Commun., 2021, 12(1), 5311. doi: 10.1038/s41467-021-25632-1 PMID: 34493724Bao, W.D.; Pang, P.; Zhou, X.T.; Hu, F.; Xiong, W.; Chen, K.; Wang, J.; Wang, F.; Xie, D.; Hu, Y.Z.; Han, Z.T.; Zhang, H.H.; Wang, W.X.; Nelson, P.T.; Chen, J.G.; Lu, Y.; Man, H.Y.; Liu, D.; Zhu, L.Q. Loss of ferroportin induces memory impairment by promoting ferroptosis in Alzheimer’s disease. Cell Death Differ., 2021, 28(5), 1548-1562. doi: 10.1038/s41418-020-00685-9 PMID: 33398092Sporn, M.B.; Liby, K.T. NRF2 and cancer: The good, the bad and the importance of context. Nat. Rev. Cancer, 2012, 12(8), 564-571. doi: 10.1038/nrc3278 PMID: 22810811Ke, K.; Li, L.; Lu, C.; Zhu, Q.; Wang, Y.; Mou, Y.; Wang, H.; Jin, W. The crosstalk effect between ferrous and other ions metabolism in ferroptosis for therapy of cancer. Front. Oncol., 2022, 12, 916082. doi: 10.3389/fonc.2022.916082 PMID: 36033459Gan, B. Mitochondrial regulation of ferroptosis. J. Cell Biol., 2021, 220(9), e202105043. doi: 10.1083/jcb.202105043 PMID: 34328510Shui, S.; Zhao, Z.; Wang, H.; Conrad, M.; Liu, G. Non-enzymatic lipid peroxidation initiated by photodynamic therapy drives a distinct ferroptosis-like cell death pathway. Redox Biol., 2021, 45, 102056. doi: 10.1016/j.redox.2021.102056 PMID: 34229160Lu, J.; Holmgren, A. Selenoproteins. J. Biol. Chem., 2009, 284(2), 723-727. doi: 10.1074/jbc.R800045200 PMID: 18757362Short, S.P.; Williams, C.S. Selenoproteins in tumorigenesis and cancer progression. Adv. Cancer Res., 2017, 136, 49-83. doi: 10.1016/bs.acr.2017.08.002 PMID: 29054422Wu, H.; Luan, Y.; Wang, H.; Zhang, P.; Liu, S.; Wang, P.; Cao, Y.; Sun, H.; Wu, L. Selenium inhibits ferroptosis and ameliorates autistic-like behaviors of BTBR mice by regulating the Nrf2/GPx4 pathway. Brain Res. Bull., 2022, 183, 38-48. doi: 10.1016/j.brainresbull.2022.02.018 PMID: 35227767Angeli, F.J.P.; Conrad, M. Selenium and GPX4, a vital symbiosis. Free Radic. Biol. Med., 2018, 127, 153-159. doi: 10.1016/j.freeradbiomed.2018.03.001 PMID: 29522794Liu, L.; Wang, M.; Gong, N.; Tian, P.; Deng, H. Se improves GPX4 expression and SOD activity to alleviate heat-stress-induced ferroptosis-like death in goat mammary epithelial cells. Anim. Cells Syst., 2021, 25(5), 283-295. doi: 10.1080/19768354.2021.1988704 PMID: 34745435Dineley, K.E.; Votyakova, T.V.; Reynolds, I.J. Zinc inhibition of cellular energy production: Implications for mitochondria and neurodegeneration. J. Neurochem., 2003, 85(3), 563-570. doi: 10.1046/j.1471-4159.2003.01678.x PMID: 12694382Lee, S.R. Critical role of zinc as either an antioxidant or a prooxidant in cellular systems. Oxid. Med. Cell. Longev., 2018, 2018, 1-11. doi: 10.1155/2018/9156285 PMID: 29743987Wang, B.; Li, D.; Kovalchuk, O. p53 Ser15 phosphorylation and histone modifications contribute to IR-induced miR-34a transcription in mammary epithelial cells. Cell Cycle, 2013, 12(13), 2073-2083. doi: 10.4161/cc.25135 PMID: 23759592Chen, J.; Zhang, D.; Qin, X.; Owzar, K.; McCann, J.J.; Kastan, M.B. DNA-damage-induced alternative splicing of p53. Cancers, 2021, 13(2), 251. doi: 10.3390/cancers13020251 PMID: 33445417Hassin, O.; Oren, M. Drugging p53 in cancer: One protein, many targets. Nat. Rev. Drug Discov., 2022, •••, 1-18. doi: 10.1038/s41573-022-00571-8 PMID: 36216888Chen, S.L.; Zhang, C.Z.; Liu, L.L.; Lu, S.X.; Pan, Y.H.; Wang, C.H.; He, Y.F.; Lin, C.S.; Yang, X.; Xie, D.; Yun, J.P.A. GYS2/p53 negative feedback loop restricts tumor growth in HBV-related hepatocellular carcinoma. Cancer Res., 2019, 79(3), 534-545. doi: 10.1158/0008-5472.CAN-18-2357 PMID: 30584071O’Connor, P.M.; Jackman, J.; Bae, I.; Myers, T.G.; Fan, S.; Mutoh, M.; Scudiero, D.A.; Monks, A.; Sausville, E.A.; Weinstein, J.N.; Friend, S.; Fornace, A.J., Jr; Kohn, K.W. Characterization of the p53 tumor suppressor pathway in cell lines of the national cancer institute anticancer drug screen and correlations with the growth-inhibitory potency of 123 anticancer agents. Cancer Res., 1997, 57(19), 4285-4300. PMID: 9331090Werbrouck, C.; Evangelista, C.C.S.; Lobón-Iglesias, M.J.; Barret, E.; Le Teuff, G.; Merlevede, J.; Brusini, R.; Kergrohen, T.; Mondini, M.; Bolle, S.; Varlet, P.; Beccaria, K.; Boddaert, N.; Puget, S.; Grill, J.; Debily, M.A.; Castel, D. TP53 pathway alterations drive radioresistance in diffuse intrinsic pontine gliomas (DIPG). Clin. Cancer Res., 2019, 25(22), 6788-6800. doi: 10.1158/1078-0432.CCR-19-0126 PMID: 31481512Chen, X.; Zhang, T.; Su, W.; Dou, Z.; Zhao, D.; Jin, X.; Lei, H.; Wang, J.; Xie, X.; Cheng, B.; Li, Q.; Zhang, H.; Di, C. Mutant p53 in cancer: From molecular mechanism to therapeutic modulation. Cell Death Dis., 2022, 13(11), 974. doi: 10.1038/s41419-022-05408-1 PMID: 36400749Ou, Y.; Wang, S.J.; Li, D.; Chu, B.; Gu, W. Activation of SAT1 engages polyamine metabolism with p53-mediated ferroptotic responses. Proc. Natl. Acad. Sci., 2016, 113(44), E6806-E6812. doi: 10.1073/pnas.1607152113 PMID: 27698118Wang, P.Y.; Ma, W.; Park, J.Y.; Celi, F.S.; Arena, R.; Choi, J.W.; Ali, Q.A.; Tripodi, D.J.; Zhuang, J.; Lago, C.U.; Strong, L.C.; Talagala, S.L.; Balaban, R.S.; Kang, J.G.; Hwang, P.M. Increased oxidative metabolism in the Li-Fraumeni syndrome. N. Engl. J. Med., 2013, 368(11), 1027-1032. doi: 10.1056/NEJMoa1214091 PMID: 23484829Xie, Y.; Zhu, S.; Song, X.; Sun, X.; Fan, Y.; Liu, J.; Zhong, M.; Yuan, H.; Zhang, L.; Billiar, T.R.; Lotze, M.T.; Zeh, H.J., III; Kang, R.; Kroemer, G.; Tang, D. The tumor suppressor p53 limits ferroptosis by blocking DPP4 activity. Cell Rep., 2017, 20(7), 1692-1704. doi: 10.1016/j.celrep.2017.07.055 PMID: 28813679Simanshu, D.K.; Nissley, D.V.; McCormick, F. RAS proteins and their regulators in human disease. Cell, 2017, 170(1), 17-33. doi: 10.1016/j.cell.2017.06.009 PMID: 28666118Shi, Z.; Liu, J.; Sun, D. Let-7a targets Rsf-1 to modulate radiotherapy response of non-small cell lung cancer cells through Ras-MAPK pathway. J. BUON, 2021, 26(4), 1422-1431. PMID: 34565000Levada, K.; Guldiken, N.; Zhang, X.; Vella, G.; Mo, F.R.; James, L.P.; Haybaeck, J.; Kessler, S.M.; Kiemer, A.K.; Ott, T.; Hartmann, D.; Hüser, N.; Ziol, M.; Trautwein, C.; Strnad, P. Hsp72 protects against liver injury via attenuation of hepatocellular death, oxidative stress, and JNK signaling. J. Hepatol., 2018, 68(5), 996-1005. doi: 10.1016/j.jhep.2018.01.003 PMID: 29331340Wang, X.; Zhang, C.; Zou, N.; Chen, Q.; Wang, C.; Zhou, X.; Luo, L.; Qi, H.; Li, J.; Liu, Z.; Yi, J.; Li, J.; Liu, W. Lipocalin-2 silencing suppresses inflammation and oxidative stress of acute respiratory distress syndrome by ferroptosis via inhibition of MAPK/ERK pathway in neonatal mice. Bioengineered, 2022, 13(1), 508-520. doi: 10.1080/21655979.2021.2009970 PMID: 34969358Krayem, M.; Sabbah, M.; Najem, A.; Wouters, A.; Lardon, F.; Simon, S.; Sales, F.; Journe, F.; Awada, A.; Ghanem, G.E.; Van Gestel, D. The benefit of reactivating p53 under mapk inhibition on the efficacy of radiotherapy in Melanoma. Cancers, 2019, 11(8), 1093. doi: 10.3390/cancers11081093 PMID: 31374895Tonelli, C.; Chio, I.I.C.; Tuveson, D.A. Transcriptional regulation by Nrf2. Antioxid. Redox Signal., 2018, 29(17), 1727-1745. doi: 10.1089/ars.2017.7342 PMID: 28899199Kobayashi, M.; Yamamoto, M. Nrf2–Keap1 regulation of cellular defense mechanisms against electrophiles and reactive oxygen species. Adv. Enzyme Regul., 2006, 46(1), 113-140. doi: 10.1016/j.advenzreg.2006.01.007 PMID: 16887173Sato, Y.; Yoshizato, T.; Shiraishi, Y.; Maekawa, S.; Okuno, Y.; Kamura, T.; Shimamura, T.; Sato-Otsubo, A.; Nagae, G.; Suzuki, H.; Nagata, Y.; Yoshida, K.; Kon, A.; Suzuki, Y.; Chiba, K.; Tanaka, H.; Niida, A.; Fujimoto, A.; Tsunoda, T.; Morikawa, T.; Maeda, D.; Kume, H.; Sugano, S.; Fukayama, M.; Aburatani, H.; Sanada, M.; Miyano, S.; Homma, Y.; Ogawa, S. Integrated molecular analysis of clear-cell renal cell carcinoma. Nat. Genet., 2013, 45(8), 860-867. doi: 10.1038/ng.2699 PMID: 23797736Kim, B.; Nam, H.J.; Pyo, K.E.; Jang, M.J.; Kim, I.S.; Kim, D.; Boo, K.; Lee, S.H.; Yoon, J.B.; Baek, S.H.; Kim, J.H. Breast cancer metastasis suppressor 1 (BRMS1) is destabilized by the Cul3–SPOP E3 ubiquitin ligase complex. Biochem. Biophys. Res. Commun., 2011, 415(4), 720-726. doi: 10.1016/j.bbrc.2011.10.154 PMID: 22085717Liu, Q.; Wang, K. The induction of ferroptosis by impairing STAT3/Nrf2/GPx4 signaling enhances the sensitivity of osteosarcoma cells to cisplatin. Cell Biol. Int., 2019, 43(11), 1245-1256. doi: 10.1002/cbin.11121 PMID: 30811078Liu, N.; Lin, X.; Huang, C. Activation of the reverse transsulfuration pathway through NRF2/CBS confers erastin-induced ferroptosis resistance. Br. J. Cancer, 2020, 122(2), 279-292. doi: 10.1038/s41416-019-0660-x PMID: 31819185Jiao, Y.; Cao, F.; Liu, H. Radiation-induced cell death and its mechanisms. Health Phys., 2022, 123(5), 376-386. doi: 10.1097/HP.0000000000001601 PMID: 36069830Dodson, M.; Castro-Portuguez, R.; Zhang, D.D. NRF2 plays a critical role in mitigating lipid peroxidation and ferroptosis. Redox Biol., 2019, 23, 101107. doi: 10.1016/j.redox.2019.101107 PMID: 30692038Huang, W.M.; Li, Z.X.; Wu, Y.H.; Shi, Z.L.; Mi, J.L.; Hu, K.; Wang, R.S. m6A demethylase FTO renders radioresistance of nasopharyngeal carcinoma via promoting OTUB1-mediated anti-ferroptosis. Transl. Oncol., 2023, 27, 101576. doi: 10.1016/j.tranon.2022.101576 PMID: 36343416Lei, G.; Zhang, Y.; Koppula, P.; Liu, X.; Zhang, J.; Lin, S.H.; Ajani, J.A.; Xiao, Q.; Liao, Z.; Wang, H.; Gan, B. The role of ferroptosis in ionizing radiation-induced cell death and tumor suppression. Cell Res., 2020, 30(2), 146-162. doi: 10.1038/s41422-019-0263-3 PMID: 31949285Beretta, G.L.; Zaffaroni, N. Radiotherapy-induced ferroptosis for cancer treatment. Front. Mol. Biosci., 2023, 10, 1216733. doi: 10.3389/fmolb.2023.1216733 PMID: 37388241Zhang, Z.; Lu, M.; Chen, C.; Tong, X.; Li, Y.; Yang, K.; Lv, H.; Xu, J.; Qin, L. Holo-lactoferrin: The link between ferroptosis and radiotherapy in triple-negative breast cancer. Theranostics, 2021, 11(7), 3167-3182. doi: 10.7150/thno.52028 PMID: 33537080Du, J.; Wang, T.; Li, Y.; Zhou, Y.; Wang, X.; Yu, X.; Ren, X.; An, Y.; Wu, Y.; Sun, W.; Fan, W.; Zhu, Q.; Wang, Y.; Tong, X. DHA inhibits proliferation and induces ferroptosis of leukemia cells through autophagy dependent degradation of ferritin. Free Radic. Biol. Med., 2019, 131, 356-369. doi: 10.1016/j.freeradbiomed.2018.12.011 PMID: 30557609Yuan, S.; Wei, C.; Liu, G.; Zhang, L.; Li, J.; Li, L.; Cai, S.; Fang, L. Sorafenib attenuates liver fibrosis by triggering hepatic stellate cell ferroptosis via HIF1α/SLC7A11 pathway. Cell Prolif., 2022, 55(1), e13158. doi: 10.1111/cpr.13158 PMID: 34811833Su, Y.; Zhao, B.; Zhou, L.; Zhang, Z.; Shen, Y.; Lv, H.; AlQudsy, L.H.H.; Shang, P. Ferroptosis, a novel pharmacological mechanism of anti-cancer drugs. Cancer Lett., 2020, 483, 127-136. doi: 10.1016/j.canlet.2020.02.015 PMID: 32067993Sui, X.; Zhang, R.; Liu, S.; Duan, T.; Zhai, L.; Zhang, M.; Han, X.; Xiang, Y.; Huang, X.; Lin, H.; Xie, T. RSL3 drives ferroptosis through gpx4 inactivation and ros production in colorectal cancer. Front. Pharmacol., 2018, 9, 1371. doi: 10.3389/fphar.2018.01371 PMID: 30524291Yao, X.; Xie, R.; Cao, Y.; Tang, J.; Men, Y.; Peng, H.; Yang, W. Simvastatin induced ferroptosis for triple-negative breast cancer therapy. J. Nanobiotechnology, 2021, 19(1), 311. doi: 10.1186/s12951-021-01058-1 PMID: 34627266Li, Q.; Liu, C.; Deng, L.; Xie, E.; Yadav, N.; Tie, Y.; Cheng, Z.; Deng, J. Novel function of fluvastatin in attenuating oxidized low density lipoprotein induced endothelial cell ferroptosis in a glutathione peroxidase4 and cystine glutamate antiporter dependent manner. Exp. Ther. Med., 2021, 22(5), 1275. doi: 10.3892/etm.2021.10710 PMID: 34594412Zhang, Y.; Tan, Y.; Liu, S.; Yin, H.; Duan, J.; Fan, L.; Zhao, X.; Jiang, B. Implications of Withaferin A for the metastatic potential and drug resistance in hepatocellular carcinoma cells via Nrf2-mediated EMT and ferroptosis. Toxicol. Mech. Methods, 2022, 33(1), 47-55. doi: 10.1080/15376516.2022.2075297 PMID: 35592903Zhang, Y.; Tan, H.; Daniels, J.D.; Zandkarimi, F.; Liu, H.; Brown, L.M.; Uchida, K.; O’Connor, O.A.; Stockwell, B.R. Imidazole ketone erastin induces ferroptosis and slows tumor growth in a mouse lymphoma model. Cell Chem. Biol., 2019, 26(5), 623-633.e9. doi: 10.1016/j.chembiol.2019.01.008 PMID: 30799221Luo, Y.; Yan, P.; Li, X.; Hou, J.; Wang, Y.; Zhou, S. pH-Sensitive polymeric vesicles for GOx/BSO delivery and synergetic starvation-ferroptosis therapy of Tumor. Biomacromolecules, 2021, 22(10), 4383-4394. doi: 10.1021/acs.biomac.1c00960 PMID: 34533297Shin, D.; Kim, E.H.; Lee, J.; Roh, J.L. Nrf2 inhibition reverses resistance to GPX4 inhibitor-induced ferroptosis in head and neck cancer. Free Radic. Biol. Med., 2018, 129, 454-462. doi: 10.1016/j.freeradbiomed.2018.10.426 PMID: 30339884Motooka, Y.; Toyokuni, S. Ferroptosis as ultimate target of cancer therapy. Antioxid. Redox Signal., 2022. doi: 10.1089/ars.2022.0048 PMID: 35943875Zhao, Y.; Zhao, W.; Lim, Y.C.; Liu, T. Salinomycin-loaded gold nanoparticles for treating cancer stem cells by ferroptosis-induced Cell Death. Mol. Pharm., 2019, 16(6), 2532-2539. doi: 10.1021/acs.molpharmaceut.9b00132 PMID: 31009228Helbig, L.; Koi, L.; Brüchner, K.; Gurtner, K.; Hess-Stumpp, H.; Unterschemmann, K.; Baumann, M.; Zips, D.; Yaromina, A. BAY 87–2243, a novel inhibitor of hypoxia-induced gene activation, improves local tumor control after fractionated irradiation in a schedule-dependent manner in head and neck human xenografts. Radiat. Oncol., 2014, 9(1), 207. doi: 10.1186/1748-717X-9-207 PMID: 25234922Llabani, E.; Hicklin, R.W.; Lee, H.Y.; Motika, S.E.; Crawford, L.A.; Weerapana, E.; Hergenrother, P.J. Diverse compounds from pleuromutilin lead to a thioredoxin inhibitor and inducer of ferroptosis. Nat. Chem., 2019, 11(6), 521-532. doi: 10.1038/s41557-019-0261-6 PMID: 31086302