Open Access Review

Enhanced understanding of the involvement of ferroptosis in tumorigenesis: A review of recent research advancements

by Chunfeng Liu a  and  Lei Ren b,*
a
Institute of Pathology, Faculty of Medicine, Ludwig Maximilians University of Munich, Munich, Germany.
b
Klinikum rechts der Isar, Faculty of Medicine, Technical University of Munich, Munich, Germany.
*
Author to whom correspondence should be addressed.
CI  2023, 26; 3(1), 26; https://doi.org/10.58567/ci03010001
Received: 13 November 2023 / Accepted: 28 November 2023 / Published: 29 November 2023

Abstract

Ferroptosis, a recently identified form of programmed cell death, is characterized by the accumulation of lipid peroxidation, reactive oxygen species, and elevated free iron levels, involving the regulation of glutathione metabolism, iron metabolism, lipid metabolism, and oxidative stress biology. Tumor metastasis, a critical hallmark of malignancy and a key contributor to cancer recurrence and mortality, has been extensively linked to iron dysregulation, highlighting the potential of agents inducing iron-mediated cell death as promising strategies for preventing and treating metastasis. This review offers a comprehensive understanding the regulatory mechanisms underlying ferroptosis and its crucial role in the three distinct stages of metastasis: invasion, circulation, and colonization.


Copyright: © 2023 by Liu and Ren. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) (Creative Commons Attribution 4.0 International License). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

Share and Cite

ACS Style
Liu, C.; Ren, L. Enhanced understanding of the involvement of ferroptosis in tumorigenesis: A review of recent research advancements. Cancer Insight, 2024, 3, 26. https://doi.org/10.58567/ci03010001
AMA Style
Liu C, Ren L. Enhanced understanding of the involvement of ferroptosis in tumorigenesis: A review of recent research advancements. Cancer Insight; 2024, 3(1):26. https://doi.org/10.58567/ci03010001
Chicago/Turabian Style
Liu, Chunfeng; Ren, Lei 2024. "Enhanced understanding of the involvement of ferroptosis in tumorigenesis: A review of recent research advancements" Cancer Insight 3, no.1:26. https://doi.org/10.58567/ci03010001
APA style
Liu, C., & Ren, L. (2024). Enhanced understanding of the involvement of ferroptosis in tumorigenesis: A review of recent research advancements. Cancer Insight, 3(1), 26. https://doi.org/10.58567/ci03010001

Article Metrics

Article Access Statistics

References

  1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F 2021. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA: a cancer journal for clinicians 71(3):209-249. DOI: https://doi.org/10.3322/caac.21660
  2. Wang YQ, Li HZ, Gong WW, Chen YY, Zhu C, Wang L, Zhong JM, Du LB 2021. Cancer incidence and mortality in Zhejiang Province, Southeast China, 2016: a population-based study. Chin Med J (Engl) 134(16):1959-1966. DOI: https://doi.org/10.1097/CM9.0000000000001666
  3. Hanahan D 2022. Hallmarks of Cancer: New Dimensions. Cancer Discov 12(1):31-46. DOI: https://doi.org/10.1158/2159-8290.CD-21-1059
  4. Thedieck K, Holzwarth B, Prentzell MT, Boehlke C, Klasener K, Ruf S, Sonntag AG, Maerz L, Grellscheid SN, Kremmer E, Nitschke R, Kuehn EW, Jonker JW, Groen AK, Reth M, Hall MN, Baumeister R 2013. Inhibition of mTORC1 by astrin and stress granules prevents apoptosis in cancer cells. Cell 154(4):859-874. DOI: https://doi.org/10.1016/j.cell.2013.07.031
  5. Green DR 2017. Cancer and Apoptosis: Who Is Built to Last? Cancer Cell 31(1):2-4. DOI: https://doi.org/10.1016/j.ccell.2016.12.007
  6. Endo S, Nakata K, Ohuchida K, Takesue S, Nakayama H, Abe T, Koikawa K, Okumura T, Sada M, Horioka K, Zheng B, Mizuuchi Y, Iwamoto C, Murata M, Moriyama T, Miyasaka Y, Ohtsuka T, Mizumoto K, Oda Y, Hashizume M, Nakamura M 2017. Autophagy Is Required for Activation of Pancreatic Stellate Cells, Associated With Pancreatic Cancer Progression and Promotes Growth of Pancreatic Tumors in Mice. Gastroenterology 152(6):1492-1506 e1424. DOI: https://doi.org/10.1053/j.gastro.2017.01.010
  7. Evavold CL, Hafner-Bratkovic I, Devant P, D'Andrea JM, Ngwa EM, Borsic E, Doench JG, LaFleur MW, Sharpe AH, Thiagarajah JR, Kagan JC 2021. Control of gasdermin D oligomerization and pyroptosis by the Ragulator-Rag-mTORC1 pathway. Cell 184(17):4495-4511 e4419. DOI: https://doi.org/10.1016/j.cell.2021.06.028
  8. Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, Patel DN, Bauer AJ, Cantley AM, Yang WS, Morrison B, 3rd, Stockwell BR 2012. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 149(5):1060-1072. DOI: https://doi.org/10.1016/j.cell.2012.03.042
  9. Yagoda N, von Rechenberg M, Zaganjor E, Bauer AJ, Yang WS, Fridman DJ, Wolpaw AJ, Smukste I, Peltier JM, Boniface JJ, Smith R, Lessnick SL, Sahasrabudhe S, Stockwell BR 2007. RAS-RAF-MEK-dependent oxidative cell death involving voltage-dependent anion channels. Nature 447(7146):864-868. DOI: https://doi.org/10.1038/nature05859
  10. Yang WS, Stockwell BR 2008. Synthetic lethal screening identifies compounds activating iron-dependent, nonapoptotic cell death in oncogenic-RAS-harboring cancer cells. Chem Biol 15(3):234-245. DOI: https://doi.org/10.1016/j.chembiol.2008.02.010
  11. Chen X, Kang R, Kroemer G, Tang D 2021. Broadening horizons: the role of ferroptosis in cancer. Nat Rev Clin Oncol 18(5):280-296. DOI: https://doi.org/10.1038/s41571-020-00462-0
  12. Stockwell BR, Friedmann Angeli JP, Bayir H, Bush AI, Conrad M, Dixon SJ, Fulda S, Gascon S, Hatzios SK, Kagan VE, Noel K, Jiang X, Linkermann A, Murphy ME, Overholtzer M, Oyagi A, Pagnussat GC, Park J, Ran Q, Rosenfeld CS, Salnikow K, Tang D, Torti FM, Torti SV, Toyokuni S, Woerpel KA, Zhang DD 2017. Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease. Cell 171(2):273-285. DOI: https://doi.org/10.1016/j.cell.2017.09.021
  13. Zhang T, Wu P, Budbazar E, Zhu Q, Sun C, Mo J, Peng J, Gospodarev V, Tang J, Shi H, Zhang JH 2019. Mitophagy Reduces Oxidative Stress Via Keap1 (Kelch-Like Epichlorohydrin-Associated Protein 1)/Nrf2 (Nuclear Factor-E2-Related Factor 2)/PHB2 (Prohibitin 2) Pathway After Subarachnoid Hemorrhage in Rats. Stroke 50(4):978-988. DOI: https://doi.org/10.1161/STROKEAHA.118.021590
  14. Banjac A, Perisic T, Sato H, Seiler A, Bannai S, Weiss N, Kolle P, Tschoep K, Issels RD, Daniel PT, Conrad M, Bornkamm GW 2008. The cystine/cysteine cycle: a redox cycle regulating susceptibility versus resistance to cell death. Oncogene 27(11):1618-1628. DOI: https://doi.org/10.1038/sj.onc.1210796
  15. Stockwell BR 2022. Ferroptosis turns 10: Emerging mechanisms, physiological functions, and therapeutic applications. Cell 185(14):2401-2421. DOI: https://doi.org/10.1016/j.cell.2022.06.003
  16. Zilka O, Shah R, Li B, Friedmann Angeli JP, Griesser M, Conrad M, Pratt DA 2017. On the Mechanism of Cytoprotection by Ferrostatin-1 and Liproxstatin-1 and the Role of Lipid Peroxidation in Ferroptotic Cell Death. ACS Cent Sci 3(3):232-243. DOI: https://doi.org/10.1021/acscentsci.7b00028
  17. Tang D, Kroemer G 2020. Ferroptosis. Curr Biol 30(21):R1292-R1297. DOI: https://doi.org/10.1016/j.cub.2020.09.068
  18. Carneiro BA, El-Deiry WS 2020. Targeting apoptosis in cancer therapy. Nat Rev Clin Oncol 17(7):395-417. DOI: https://doi.org/10.1038/s41571-020-0341-y
  19. Galluzzi L, Vitale I, Aaronson SA, Abrams JM, Adam D, Agostinis P, Alnemri ES, Altucci L, Amelio I, Andrews DW, Annicchiarico-Petruzzelli M, Antonov AV, Arama E, Baehrecke EH, Barlev NA, Bazan NG, Bernassola F, Bertrand MJM, Bianchi K, Blagosklonny MV, Blomgren K, Borner C, Boya P, Brenner C, Campanella M, Candi E, Carmona-Gutierrez D, Cecconi F, Chan FK, Chandel NS, Cheng EH, Chipuk JE, Cidlowski JA, Ciechanover A, Cohen GM, Conrad M, Cubillos-Ruiz JR, Czabotar PE, D'Angiolella V, Dawson TM, Da
  20. Hanahan D, Weinberg RA 2011. Hallmarks of cancer: the next generation. Cell 144(5):646-674. DOI: https://doi.org/10.1016/j.cell.2011.02.013
  21. Dolma S, Lessnick SL, Hahn WC, Stockwell BR 2003. Identification of genotype-selective antitumor agents using synthetic lethal chemical screening in engineered human tumor cells. Cancer Cell 3(3):285-296. DOI: https://doi.org/10.1016/s1535-6108(03)00050-3
  22. Tsoi J, Robert L, Paraiso K, Galvan C, Sheu KM, Lay J, Wong DJL, Atefi M, Shirazi R, Wang X, Braas D, Grasso CS, Palaskas N, Ribas A, Graeber TG 2018. Multi-stage Differentiation Defines Melanoma Subtypes with Differential Vulnerability to Drug-Induced Iron-Dependent Oxidative Stress. Cancer Cell 33(5):890-904 e895. DOI: https://doi.org/10.1016/j.ccell.2018.03.017
  23. Viswanathan VS, Ryan MJ, Dhruv HD, Gill S, Eichhoff OM, Seashore-Ludlow B, Kaffenberger SD, Eaton JK, Shimada K, Aguirre AJ, Viswanathan SR, Chattopadhyay S, Tamayo P, Yang WS, Rees MG, Chen S, Boskovic ZV, Javaid S, Huang C, Wu X, Tseng YY, Roider EM, Gao D, Cleary JM, Wolpin BM, Mesirov JP, Haber DA, Engelman JA, Boehm JS, Kotz JD, Hon CS, Chen Y, Hahn WC, Levesque MP, Doench JG, Berens ME, Shamji AF, Clemons PA, Stockwell BR, Schreiber SL 2017. Dependency of a therapy-resistant state of cance
  24. Kuang F, Liu J, Tang D, Kang R 2020. Oxidative Damage and Antioxidant Defense in Ferroptosis. Front Cell Dev Biol 8:586578. DOI: https://doi.org/10.3389/fcell.2020.586578
  25. Fonseca-Nunes A, Jakszyn P, Agudo A 2014. Iron and cancer risk-a systematic review and meta-analysis of the epidemiological evidence. Cancer Epidemiol Biomarkers Prev 23(1):12-31. DOI: https://doi.org/10.1158/1055-9965.EPI-13-0733
  26. Yang Y, Li X, Wang T, Guo Q, Xi T, Zheng L 2020. Emerging agents that target signaling pathways in cancer stem cells. Journal of hematology & oncology 13(1):60. DOI: https://doi.org/10.1186/s13045-020-00901-6
  27. Yang Y, Lu Y, Zhang C, Guo Q, Zhang W, Wang T, Xia Z, Liu J, Cheng X, Xi T, Jiang F, Zheng L 2022. Phenazine derivatives attenuate the stemness of breast cancer cells through triggering ferroptosis. Cellular and molecular life sciences : CMLS 79(7):360. DOI: https://doi.org/10.1007/s00018-022-04384-1
  28. Gao M, Monian P, Quadri N, Ramasamy R, Jiang X 2015. Glutaminolysis and Transferrin Regulate Ferroptosis. Mol Cell 59(2):298-308. DOI: https://doi.org/10.1016/j.molcel.2015.06.011
  29. Gao M, Monian P, Pan Q, Zhang W, Xiang J, Jiang X 2016. Ferroptosis is an autophagic cell death process. Cell Res 26(9):1021-1032. DOI: https://doi.org/10.1038/cr.2016.95
  30. Hou W, Xie Y, Song X, Sun X, Lotze MT, Zeh HJ, 3rd, Kang R, Tang D 2016. Autophagy promotes ferroptosis by degradation of ferritin. Autophagy 12(8):1425-1428. DOI: https://doi.org/10.1080/15548627.2016.1187366
  31. Mancias JD, Wang X, Gygi SP, Harper JW, Kimmelman AC 2014. Quantitative proteomics identifies NCOA4 as the cargo receptor mediating ferritinophagy. Nature 509(7498):105-109. DOI: https://doi.org/10.1038/nature13148
  32. Wang Y, Liu Y, Liu J, Kang R, Tang D 2020. NEDD4L-mediated LTF protein degradation limits ferroptosis. Biochem Biophys Res Commun 531(4):581-587. DOI: https://doi.org/10.1016/j.bbrc.2020.07.032
  33. Geng N, Shi BJ, Li SL, Zhong ZY, Li YC, Xua WL, Zhou H, Cai JH 2018. Knockdown of ferroportin accelerates erastin-induced ferroptosis in neuroblastoma cells. Eur Rev Med Pharmacol Sci 22(12):3826-3836. DOI: https://doi.org/10.26355/eurrev_201806_15267
  34. Brown CW, Amante JJ, Chhoy P, Elaimy AL, Liu H, Zhu LJ, Baer CE, Dixon SJ, Mercurio AM 2019. Prominin2 Drives Ferroptosis Resistance by Stimulating Iron Export. Dev Cell 51(5):575-586 e574. DOI: https://doi.org/10.1016/j.devcel.2019.10.007
  35. Alvarez SW, Sviderskiy VO, Terzi EM, Papagiannakopoulos T, Moreira AL, Adams S, Sabatini DM, Birsoy K, Possemato R 2017. NFS1 undergoes positive selection in lung tumours and protects cells from ferroptosis. Nature 551(7682):639-643. DOI: https://doi.org/10.1038/nature24637
  36. Du 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 2019. DHA inhibits proliferation and induces ferroptosis of leukemia cells through autophagy dependent degradation of ferritin. Free Radic Biol Med 131:356-369. DOI: https://doi.org/10.1016/j.freeradbiomed.2018.12.011
  37. Yuan H, Li X, Zhang X, Kang R, Tang D 2016. CISD1 inhibits ferroptosis by protection against mitochondrial lipid peroxidation. Biochem Biophys Res Commun 478(2):838-844. DOI: https://doi.org/10.1016/j.bbrc.2016.08.034
  38. Kim EH, Shin D, Lee J, Jung AR, Roh JL 2018. CISD2 inhibition overcomes resistance to sulfasalazine-induced ferroptotic cell death in head and neck cancer. Cancer Lett 432:180-190. DOI: https://doi.org/10.1016/j.canlet.2018.06.018
  39. Imoto S, Kono M, Suzuki T, Shibuya Y, Sawamura T, Mizokoshi Y, Sawada H, Ohbuchi A, Saigo K 2018. Haemin-induced cell death in human monocytic cells is consistent with ferroptosis. Transfus Apher Sci 57(4):524-531. DOI: https://doi.org/10.1016/j.transci.2018.05.028
  40. Do Van B, Gouel F, Jonneaux A, Timmerman K, Gele P, Petrault M, Bastide M, Laloux C, Moreau C, Bordet R, Devos D, Devedjian JC 2016. Ferroptosis, a newly characterized form of cell death in Parkinson's disease that is regulated by PKC. Neurobiol Dis 94:169-178. DOI: https://doi.org/10.1016/j.nbd.2016.05.011
  41. Conrad M, Pratt DA 2019. The chemical basis of ferroptosis. Nat Chem Biol 15(12):1137-1147. DOI: https://doi.org/10.1038/s41589-019-0408-1
  42. Jiang X, Stockwell BR, Conrad M 2021. Ferroptosis: mechanisms, biology and role in disease. Nat Rev Mol Cell Biol 22(4):266-282. DOI: https://doi.org/10.1038/s41580-020-00324-8
  43. Yang WS, Kim KJ, Gaschler MM, Patel M, Shchepinov MS, Stockwell BR 2016. Peroxidation of polyunsaturated fatty acids by lipoxygenases drives ferroptosis. Proc Natl Acad Sci USA 113(34):E4966-4975. DOI: https://doi.org/10.1073/pnas.1603244113
  44. Dixon SJ, Winter GE, Musavi LS, Lee ED, Snijder B, Rebsamen M, Superti-Furga G, Stockwell BR 2015. Human Haploid Cell Genetics Reveals Roles for Lipid Metabolism Genes in Nonapoptotic Cell Death. ACS Chem Biol 10(7):1604-1609. DOI: https://doi.org/10.1021/acschembio.5b00245
  45. Li Y, Feng D, Wang Z, Zhao Y, Sun R, Tian D, Liu D, Zhang F, Ning S, Yao J, Tian X 2019. Ischemia-induced ACSL4 activation contributes to ferroptosis-mediated tissue injury in intestinal ischemia/reperfusion. Cell Death Differ 26(11):2284-2299. DOI: https://doi.org/10.1038/s41418-019-0299-4
  46. Doll S, Proneth B, Tyurina YY, Panzilius E, Kobayashi S, Ingold I, Irmler M, Beckers J, Aichler M, Walch A, Prokisch H, Trumbach D, Mao G, Qu F, Bayir H, Fullekrug J, Scheel CH, Wurst W, Schick JA, Kagan VE, Angeli JP, Conrad M 2017. ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition. Nat Chem Biol 13(1):91-98. DOI: https://doi.org/10.1038/nchembio.2239
  47. Kagan VE, Mao G, Qu F, Angeli JP, Doll S, Croix CS, Dar HH, Liu B, Tyurin VA, Ritov VB, Kapralov AA, Amoscato AA, Jiang J, Anthonymuthu T, Mohammadyani D, Yang Q, Proneth B, Klein-Seetharaman J, Watkins S, Bahar I, Greenberger J, Mallampalli RK, Stockwell BR, Tyurina YY, Conrad M, Bayir H 2017. Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis. Nat Chem Biol 13(1):81-90. DOI: https://doi.org/10.1038/nchembio.2238
  48. Yuan H, Li X, Zhang X, Kang R, Tang D 2016. Identification of ACSL4 as a biomarker and contributor of ferroptosis. Biochem Biophys Res Commun 478(3):1338-1343. DOI: https://doi.org/10.1016/j.bbrc.2016.08.124
  49. Wenzel SE, Tyurina YY, Zhao J, St Croix CM, Dar HH, Mao G, Tyurin VA, Anthonymuthu TS, Kapralov AA, Amoscato AA, Mikulska-Ruminska K, Shrivastava IH, Kenny EM, Yang Q, Rosenbaum JC, Sparvero LJ, Emlet DR, Wen X, Minami Y, Qu F, Watkins SC, Holman TR, VanDemark AP, Kellum JA, Bahar I, Bayir H, Kagan VE 2017. PEBP1 Wardens Ferroptosis by Enabling Lipoxygenase Generation of Lipid Death Signals. Cell 171(3):628-641 e626. DOI: https://doi.org/10.1016/j.cell.2017.09.044
  50. Chu B, Kon N, Chen D, Li T, Liu T, Jiang L, Song S, Tavana O, Gu W 2019. ALOX12 is required for p53-mediated tumour suppression through a distinct ferroptosis pathway. Nat Cell Biol 21(5):579-591. DOI: https://doi.org/10.1038/s41556-019-0305-6
  51. Magtanong L, Ko PJ, To M, Cao JY, Forcina GC, Tarangelo A, Ward CC, Cho K, Patti GJ, Nomura DK, Olzmann JA, Dixon SJ 2019. Exogenous Monounsaturated Fatty Acids Promote a Ferroptosis-Resistant Cell State. Cell Chem Biol 26(3):420-432 e429. DOI: https://doi.org/10.1016/j.chembiol.2018.11.016
  52. Song X, Zhu S, Chen P, Hou W, Wen Q, Liu J, Xie Y, Liu J, Klionsky DJ, Kroemer G, Lotze MT, Zeh HJ, Kang R, Tang D 2018. AMPK-Mediated BECN1 Phosphorylation Promotes Ferroptosis by Directly Blocking System X(c)(-) Activity. Curr Biol 28(15):2388-2399 e2385. DOI: https://doi.org/10.1016/j.cub.2018.05.094
  53. Lee H, Zandkarimi F, Zhang Y, Meena JK, Kim J, Zhuang L, Tyagi S, Ma L, Westbrook TF, Steinberg GR, Nakada D, Stockwell BR, Gan B 2020. Energy-stress-mediated AMPK activation inhibits ferroptosis. Nat Cell Biol 22(2):225-234. DOI: https://doi.org/10.1038/s41556-020-0461-8
  54. Zou Y, Li H, Graham ET, Deik AA, Eaton JK, Wang W, Sandoval-Gomez G, Clish CB, Doench JG, Schreiber SL 2020. Cytochrome P450 oxidoreductase contributes to phospholipid peroxidation in ferroptosis. Nat Chem Biol 16(3):302-309. DOI: https://doi.org/10.1038/s41589-020-0472-6
  55. Yang WH, Ding CC, Sun T, Rupprecht G, Lin CC, Hsu D, Chi JT 2019. The Hippo Pathway Effector TAZ Regulates Ferroptosis in Renal Cell Carcinoma. Cell Rep 28(10):2501-2508 e2504. DOI: https://doi.org/10.1016/j.celrep.2019.07.107
  56. Yang WS, SriRamaratnam R, Welsch ME, Shimada K, Skouta R, Viswanathan VS, Cheah JH, Clemons PA, Shamji AF, Clish CB, Brown LM, Girotti AW, Cornish VW, Schreiber SL, Stockwell BR 2014. Regulation of ferroptotic cancer cell death by GPX4. Cell 156(1-2):317-331. DOI: https://doi.org/10.1016/j.cell.2013.12.010
  57. Hangauer MJ, Viswanathan VS, Ryan MJ, Bole D, Eaton JK, Matov A, Galeas J, Dhruv HD, Berens ME, Schreiber SL, McCormick F, McManus MT 2017. Drug-tolerant persister cancer cells are vulnerable to GPX4 inhibition. Nature 551(7679):247-250. DOI:https://doi.org/10.1038/nature24297
  58. Meister A 1982. Metabolism and function of glutathione: an overview. Biochem Soc Trans 10(2):78-79. DOI: https://doi.org/10.1042/bst0100078
  59. Lu SC 2009. Regulation of glutathione synthesis. Mol Aspects Med 30(1-2):42-59. DOI: https://doi.org/10.1016/j.mam.2008.05.005
  60. Bannai S 1986. Exchange of cystine and glutamate across plasma membrane of human fibroblasts. J Biol Chem 261(5):2256-2263.
  61. Ottestad-Hansen S, Hu QX, Follin-Arbelet VV, Bentea E, Sato H, Massie A, Zhou Y, Danbolt NC 2018. The cystine-glutamate exchanger (xCT, Slc7a11) is expressed in significant concentrations in a subpopulation of astrocytes in the mouse brain. Glia 66(5):951-970. DOI: https://doi.org/10.1002/glia.23294
  62. Bassi MT, Gasol E, Manzoni M, Pineda M, Riboni M, Martin R, Zorzano A, Borsani G, Palacin M 2001. Identification and characterisation of human xCT that co-expresses, with 4F2 heavy chain, the amino acid transport activity system xc. Pflugers Arch 442(2):286-296. DOI: https://doi.org/10.1007/s004240100537.
  63. Lin W, Wang C, Liu G, Bi C, Wang X, Zhou Q, Jin H 2020. SLC7A11/xCT in cancer: biological functions and therapeutic implications. Am J Cancer Res 10(10):3106-3126
  64. Polewski MD, Reveron-Thornton RF, Cherryholmes GA, Marinov GK, Cassady K, Aboody KS 2016. Increased Expression of System xc- in Glioblastoma Confers an Altered Metabolic State and Temozolomide Resistance. Mol Cancer Res 14(12):1229-1242. DOI: https://doi.org/10.1158/1541-7786.MCR-16-0028
  65. Arensman MD, Yang XS, Leahy DM, Toral-Barza L, Mileski M, Rosfjord EC, Wang F, Deng S, Myers JS, Abraham RT, Eng CH 2019. Cystine-glutamate antiporter xCT deficiency suppresses tumor growth while preserving antitumor immunity. Proc Natl Acad Sci USA 116(19):9533-9542. DOI: https://doi.org/10.1073/pnas.1814932116
  66. Fairweather SJ, Shah N, Brӧer S 2021. Heteromeric Solute Carriers: Function, Structure, Pathology and Pharmacology. Adv Exp Med Biol 21:13-127. DOI: https://doi.org/10.1007/5584_2020_584
  67. Fotiadis D, Kanai Y, Palacin M 2013. The SLC3 and SLC7 families of amino acid transporters. Mol Aspects Med 34(2-3):139-158. DOI: https://doi.org/10.1016/j.mam.2012.10.007
  68. Matsuo H, Kanai Y, Kim JY, Chairoungdua A, Kim DK, Inatomi J, Shigeta Y, Ishimine H, Chaekuntode S, Tachampa K, Choi HW, Babu E, Fukuda J, Endou H 2002. Identification of a novel Na+-independent acidic amino acid transporter with structural similarity to the member of a heterodimeric amino acid transporter family associated with unknown heavy chains. J Biol Chem 277(23):21017-21026. DOI: https://doi.org/10.1074/jbc.M200019200
  69. Feral CC, Nishiya N, Fenczik CA, Stuhlmann H, Slepak M, Ginsberg MH 2005. CD98hc (SLC3A2) mediates integrin signaling. Proc Natl Acad Sci USA 102(2):355-360. DOI: https://doi.org/10.1073/pnas.0404852102.
  70. Errasti-Murugarren E, Fort J, Bartoccioni P, Diaz L, Pardon E, Carpena X, Espino-Guarch M, Zorzano A, Ziegler C, Steyaert J, Fernandez-Recio J, Fita I, Palacin M 2019. L amino acid transporter structure and molecular bases for the asymmetry of substrate interaction. Nat Commun 10(1):1807. DOI: https://doi.org/10.1038/s41467-019-09837-z
  71. Closs EI, Boissel JP, Habermeier A, Rotmann A 2006. Structure and function of cationic amino acid transporters (CATs). J Membr Biol 213(2):67-77. DOI: https://doi.org/10.1007/s00232-006-0875-7
  72. Verrey F, Closs EI, Wagner CA, Palacin M, Endou H, Kanai Y 2004. CATs and HATs: the SLC7 family of amino acid transporters. Pflugers Arch 447(5):532-542. DOI: https://doi.org/10.1007/s00424-003-1086-z
  73. Yu D, Liu Y, Zhou Y, Ruiz-Rodado V, Larion M, Xu G, Yang C 2020. Triptolide suppresses IDH1-mutated malignancy via Nrf2-driven glutathione metabolism. Proc Natl Acad Sci USA 117(18):9964-9972. DOI: https://doi.org/10.1073/pnas.1913633117
  74. Lei G, Zhang Y, Hong T, Zhang X, Liu X, Mao C, Yan Y, Koppula P, Cheng W, Sood AK, Liu J, Gan B 2021. Ferroptosis as a mechanism to mediate p53 function in tumor radiosensitivity. Oncogene 40(20):3533-3547. DOI: https://doi.org/10.1038/s41388-021-01790-w
  75. Zhang Y, Shi J, Liu X, Feng L, Gong Z, Koppula P, Sirohi K, Li X, Wei Y, Lee H, Zhuang L, Chen G, Xiao ZD, Hung MC, Chen J, Huang P, Li W, Gan B 2018. BAP1 links metabolic regulation of ferroptosis to tumour suppression. Nature cell biology 20(10):1181-1192. DOI: https://doi.org/10.1038/s41556-018-0178-0
  76. Chen X, Yu C, Kang R, Kroemer G, Tang D 2021. Cellular degradation systems in ferroptosis. Cell Death Differ 28(4):1135-1148. DOI: https://doi.org/10.1038/s41418-020-00728-1
  77. Hayano M, Yang WS, Corn CK, Pagano NC, Stockwell BR 2016. Loss of cysteinyl-tRNA synthetase (CARS) induces the transsulfuration pathway and inhibits ferroptosis induced by cystine deprivation. Cell Death Differ 23(2):270-278. DOI: https://doi.org/10.1038/cdd.2015.93
  78. Tian T, Xiao L, Du J, Zhu X, Gu Y, Qin N, Yan C, Liu L, Ma H, Jiang Y, Chen J, Yu H, Dai J 2017. Polymorphisms in CARS are associated with gastric cancer risk: a two-stage case-control study in the Chinese population. Gastric Cancer 20(6):940-947. DOI: https://doi.org/10.1007/s10120-017-0717-6
  79. Bersuker K, Hendricks JM, Li Z, Magtanong L, Ford B, Tang PH, Roberts MA, Tong B, Maimone TJ, Zoncu R, Bassik MC, Nomura DK, Dixon SJ, Olzmann JA 2019. The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis. Nature 575(7784):688-692. DOI: https://doi.org/10.1038/s41586-019-1705-2
  80. Doll S, Freitas FP, Shah R, Aldrovandi M, da Silva MC, Ingold I, Goya Grocin A, Xavier da Silva TN, Panzilius E, Scheel CH, Mourao 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 EW, Schmitz W, Schulze A, O'Donnell V, Proneth B, Popowicz GM, Pratt DA, Angeli JPF, Conrad M 2019. FSP1 is a glutathione-independent ferroptosis suppressor. Nature 575(7784):693-698. DOI: https://doi.org/10.1038/s41586-019-1707-0
  81. Koppula P, Lei G, Zhang Y, Yan Y, Mao C, Kondiparthi L, Shi J, Liu X, Horbath A, Das M, Li W, Poyurovsky MV, Olszewski K, Gan B 2022. A targetable CoQ-FSP1 axis drives ferroptosis- and radiation-resistance in KEAP1 inactive lung cancers. Nat Commun 13(1):2206. DOI: https://doi.org/10.1038/s41467-022-29905-1
  82. Kraft VAN, Bezjian CT, Pfeiffer S, Ringelstetter L, Muller C, Zandkarimi F, Merl-Pham J, Bao X, Anastasov N, Kossl J, Brandner S, Daniels JD, Schmitt-Kopplin P, Hauck SM, Stockwell BR, Hadian K, Schick JA 2020. GTP Cyclohydrolase 1/Tetrahydrobiopterin Counteract Ferroptosis through Lipid Remodeling. ACS Cent Sci 6(1):41-53. DOI: https://doi.org/10.1021/acscentsci.9b01063
  83. Douglas G, Hale AB, Crabtree MJ, Ryan BJ, Hansler A, Watschinger K, Gross SS, Lygate CA, Alp NJ, Channon KM 2015. A requirement for Gch1 and tetrahydrobiopterin in embryonic development. Dev Biol 399(1):129-138. DOI: https://doi.org/10.1016/j.ydbio.2014.12.025
  84. Mao C, Liu X, Zhang Y, Lei G, Yan Y, Lee H, Koppula P, Wu S, Zhuang L, Fang B, Poyurovsky MV, Olszewski K, Gan B 2021. DHODH-mediated ferroptosis defence is a targetable vulnerability in cancer. Nature 593(7860):586-590. DOI: https://doi.org/10.1038/s41586-021-03539-7
  85. Lian F, Dong D, Pu J, Yang G, Yang J, Yang S, Wang Y, Zhao B, Lu M 2023. Ubiquitin-specific peptidase 10 attenuates the ferroptosis to promote thyroid cancer malignancy by facilitating GPX4 via elevating SIRT6. Environ Toxicol. DOI: https://doi.org/10.1002/tox.23992
  86. Li Q, Li K, Guo Q, Yang T 2023. CircRNA circSTIL inhibits ferroptosis in colorectal cancer via miR-431/SLC7A11 axis. Environ Toxicol 38(5):981-989. DOI: https://doi.org/10.1002/tox.23670
  87. Bi R, Hu R, Jiang L, Wen B, Jiang Z, Liu H, Mei J 2023. Butyrate enhances erastin-induced ferroptosis of lung cancer cells via modulating the ATF3/SLC7A11 pathway. Environ Toxicol. DOI: https://doi.org/10.1002/tox.23857
  88. Liang D, Minikes AM, Jiang X 2022. Ferroptosis at the intersection of lipid metabolism and cellular signaling. Mol Cell 82(12):2215-2227. DOI: https://doi.org/10.1016/j.molcel.2022.03.022
  89. Lee J, Shin D, Roh JL 2023. Lipid metabolism alterations and ferroptosis in cancer: Paving the way for solving cancer resistance. Eur J Pharmacol 941:175497. DOI: https://doi.org/10.1016/j.ejphar.2023.175497.
  90. Lv J, Wang Z, Liu H 2023. Erianin suppressed lung cancer stemness and chemotherapeutic sensitivity via triggering ferroptosis. Environ Toxicol. DOI: https://doi.org/10.1002/tox.23832
  91. Harayama T, Riezman H 2018. Understanding the diversity of membrane lipid composition. Nat Rev Mol Cell Biol 19(5):281-296. DOI: https://doi.org/10.1038/nrm.2017.138
  92. Khan W, Augustine D, Rao RS, Patil S, Awan KH, Sowmya SV, Haragannavar VC, Prasad K 2021. Lipid metabolism in cancer: A systematic review. J Carcinog 20:4. DOI: https://doi.org/10.4103/jcar.JCar_15_20.
  93. Rong X, Wang B, Palladino EN, de Aguiar Vallim TQ, Ford DA, Tontonoz P 2017. ER phospholipid composition modulates lipogenesis during feeding and in obesity. J Clin Invest 127(10):3640-3651. DOI: https://doi.org/10.1172/JCI93616
  94. Yu M, Alimujiang M, Hu L, Liu F, Bao Y, Yin J 2021. Berberine alleviates lipid metabolism disorders via inhibition of mitochondrial complex I in gut and liver. Int J Biol Sci 17(7):1693-1707. DOI: https://doi.org/10.7150/ijbs.54604
  95. Piccinin E, Cariello M, Moschetta A 2021. Lipid metabolism in colon cancer: Role of Liver X Receptor (LXR) and Stearoyl-CoA Desaturase 1 (SCD1). Mol Aspects Med 78:100933. DOI: https://doi.org/10.1016/j.mam.2020.100933
  96. Peck B, Schulze A 2016. Lipid desaturation - the next step in targeting lipogenesis in cancer? FEBS J 283(15):2767-2778. DOI: https://doi.org/10.1111/febs.13681
  97. Tracz-Gaszewska Z, Dobrzyn P 2019. Stearoyl-CoA Desaturase 1 as a Therapeutic Target for the Treatment of Cancer. Cancers (Basel) 11(7). DOI: https://doi.org/10.3390/cancers11070948.
  98. Wronski A, Wojcik P 2022. Impact of ROS-Dependent Lipid Metabolism on Psoriasis Pathophysiology. Int J Mol Sci 23(20). DOI: https://doi.org/10.3390/ijms232012137
  99. Zhao S, Zhang X, Shi Y, Cheng L, Song T, Wu B, Li J, Yang H 2020. MIEF2 over-expression promotes tumor growth and metastasis through reprogramming of glucose metabolism in ovarian cancer. J Exp Clin Cancer Res 39(1):286. DOI: https://doi.org/10.1186/s13046-020-01802-9
  100. Zhao S, Cheng L, Shi Y, Li J, Yun Q, Yang H 2021. MIEF2 reprograms lipid metabolism to drive progression of ovarian cancer through ROS/AKT/mTOR signaling pathway. Cell Death Dis 12(1):18. DOI: https://doi.org/10.1038/s41419-020-03336-6
  101. Tan Z, Xiao L, Tang M, Bai F, Li J, Li L, Shi F, Li N, Li Y, Du Q, Lu J, Weng X, Yi W, Zhang H, Fan J, Zhou J, Gao Q, Onuchic JN, Bode AM, Luo X, Cao Y 2018. Targeting CPT1A-mediated fatty acid oxidation sensitizes nasopharyngeal carcinoma to radiation therapy. Theranostics 8(9):2329-2347. DOI: https://doi.org/10.7150/thno.21451
  102. Li Y, Zeng X, Lu D, Yin M, Shan M, Gao Y 2021. Erastin induces ferroptosis via ferroportin-mediated iron accumulation in endometriosis. Hum Reprod 36(4):951-964. DOI: https://doi.org/10.1093/humrep/deaa363.
  103. Holohan C, Van Schaeybroeck S, Longley DB, Johnston PG 2013. Cancer drug resistance: an evolving paradigm. Nature reviews Cancer 13(10):714-726. DOI: https://doi.org/10.1038/nrc3599
  104. Holden DW 2015. Microbiology. Persisters unmasked. Science 347(6217):30-32. DOI: https://doi.org/10.1126/science.1262033
  105. Stratton MR, Campbell PJ, Futreal PA 2009. The cancer genome. Nature 458(7239):719-724. DOI: https://doi.org/10.1038/nature07943.
  106. Greaves M, Maley CC 2012. Clonal evolution in cancer. Nature 481(7381):306-313. DOI: https://doi.org/10.1038/nature10762
  107. Rothenberg SM, Concannon K, Cullen S, Boulay G, Turke AB, Faber AC, Lockerman EL, Rivera MN, Engelman JA, Maheswaran S, Haber DA 2015. Inhibition of mutant EGFR in lung cancer cells triggers SOX2-FOXO6-dependent survival pathways. Elife 4. DOI: https://doi.org/10.7554/eLife.06132
  108. Swanton C 2012. Intratumor heterogeneity: evolution through space and time. Cancer Res 72(19):4875-4882. DOI: https://doi.org/10.1158/0008-5472.CAN-12-2217
  109. Wilting RH, Dannenberg JH 2012. Epigenetic mechanisms in tumorigenesis, tumor cell heterogeneity and drug resistance. Drug Resist Updat 15(1-2):21-38. DOI: https://doi.org/10.1016/j.drup.2012.01.008
  110. Blakely CM, Watkins TBK, Wu W, Gini B, Chabon JJ, McCoach CE, McGranahan N, Wilson GA, Birkbak NJ, Olivas VR, Rotow J, Maynard A, Wang V, Gubens MA, Banks KC, Lanman RB, Caulin AF, St John J, Cordero AR, Giannikopoulos P, Simmons AD, Mack PC, Gandara DR, Husain H, Doebele RC, Riess JW, Diehn M, Swanton C, Bivona TG 2017. Evolution and clinical impact of co-occurring genetic alterations in advanced-stage EGFR-mutant lung cancers. Nat Genet 49(12):1693-1704. DOI: https://doi.org/10.1038/ng.3990
  111. Jamal-Hanjani M, Wilson GA, McGranahan N, Birkbak NJ, Watkins TBK, Veeriah S, Shafi S, Johnson DH, Mitter R, Rosenthal R, Salm M, Horswell S, Escudero M, Matthews N, Rowan A, Chambers T, Moore DA, Turajlic S, Xu H, Lee SM, Forster MD, Ahmad T, Hiley CT, Abbosh C, Falzon M, Borg E, Marafioti T, Lawrence D, Hayward M, Kolvekar S, Panagiotopoulos N, Janes SM, Thakrar R, Ahmed A, Blackhall F, Summers Y, Shah R, Joseph L, Quinn AM, Crosbie PA, Naidu B, Middleton G, Langman G, Trotter S, Nicolson M, R
  112. Torti SV, Torti FM 2013. Iron and cancer: more ore to be mined. Nature reviews Cancer 13(5):342-355. DOI: https://doi.org/10.1038/nrc3495
  113. Kwon S, Ko H, You DG, Kataoka K, Park JH 2019. Nanomedicines for Reactive Oxygen Species Mediated Approach: An Emerging Paradigm for Cancer Treatment. Acc Chem Res 52(7):1771-1782. DOI: https://doi.org/10.1021/acs.accounts.9b00136
  114. Cui Q, Wang JQ, Assaraf YG, Ren L, Gupta P, Wei L, Ashby CR, Jr., Yang DH, Chen ZS 2018. Modulating ROS to overcome multidrug resistance in cancer. Drug Resist Updat 41:1-25. DOI: https://doi.org/10.1016/j.drup.2018.11.001
  115. Elgendy SM, Alyammahi SK, Alhamad DW, Abdin SM, Omar HA 2020. Ferroptosis: An emerging approach for targeting cancer stem cells and drug resistance. Crit Rev Oncol Hematol 155:103095. DOI: https://doi.org/10.1016/j.critrevonc.2020.103095
  116. Xu G, Wang H, Li X, Huang R, Luo L 2021. Recent progress on targeting ferroptosis for cancer therapy. Biochem Pharmacol 190:114584. DOI: https://doi.org/10.1016/j.bcp.2021.114584
  117. Zhang C, Liu X, Jin S, Chen Y, Guo R 2022. Ferroptosis in cancer therapy: a novel approach to reversing drug resistance. Mol Cancer 21(1):47. DOI: https://doi.org/10.1186/s12943-022-01530-y
  118. Ni H, Ruan G, Sun C, Yang X, Miao Z, Li J, Chen Y, Qin H, Liu Y, Zheng L, Xing Y, Xi T, Li X 2022. Tanshinone IIA inhibits gastric cancer cell stemness through inducing ferroptosis. Environ Toxicol 37(2):192-200. DOI: https://doi.org/10.1002/tox.23388
  119. Tang D, Chen X, Kang R, Kroemer G 2021. Ferroptosis: molecular mechanisms and health implications. Cell Res 31(2):107-125. DOI: https://doi.org/10.1038/s41422-020-00441-1
  120. Zhu S, Zhang Q, Sun X, Zeh HJ, 3rd, Lotze MT, Kang R, Tang D 2017. HSPA5 Regulates Ferroptotic Cell Death in Cancer Cells. Cancer Res 77(8):2064-2077. DOI: https://doi.org/10.1158/0008-5472.CAN-16-1979
  121. Sun X, Ou Z, Chen R, Niu X, Chen D, Kang R, Tang D 2016. Activation of the p62-Keap1-NRF2 pathway protects against ferroptosis in hepatocellular carcinoma cells. Hepatology 63(1):173-184. DOI: https://doi.org/10.1002/hep.28251
  122. Poursaitidis I, Wang X, Crighton T, Labuschagne C, Mason D, Cramer SL, Triplett K, Roy R, Pardo OE, Seckl MJ, Rowlinson SW, Stone E, Lamb RF 2017. Oncogene-Selective Sensitivity to Synchronous Cell Death following Modulation of the Amino Acid Nutrient Cystine. Cell Rep 18(11):2547-2556. DOI: https://doi.org/10.1016/j.celrep.2017.02.054
  123. Du J, Wang X, Li Y, Ren X, Zhou Y, Hu W, Zhou C, Jing Q, Yang C, Wang L, Li H, Fang L, Zhou Y, Tong X, Wang Y 2021. DHA exhibits synergistic therapeutic efficacy with cisplatin to induce ferroptosis in pancreatic ductal adenocarcinoma via modulation of iron metabolism. Cell Death Dis 12(7):705. DOI: https://doi.org/10.1038/s41419-021-03996-y
  124. Chen TC, Chuang JY, Ko CY, Kao TJ, Yang PY, Yu CH, Liu MS, Hu SL, Tsai YT, Chan H, Chang WC, Hsu TI 2020. AR ubiquitination induced by the curcumin analog suppresses growth of temozolomide-resistant glioblastoma through disrupting GPX4-Mediated redox homeostasis. Redox Biol 30:101413. DOI: https://doi.org/10.1016/j.redox.2019.101413
  125. Ye Z, Hu Q, Zhuo Q, Zhu Y, Fan G, Liu M, Sun Q, Zhang Z, Liu W, Xu W, Ji S, Yu X, Xu X, Qin Y 2020. Abrogation of ARF6 promotes RSL3-induced ferroptosis and mitigates gemcitabine resistance in pancreatic cancer cells. Am J Cancer Res 10(4):1182-1193.
  126. Liu X, Qiu Z, Zhang X, Su Z, Yi R, Zou D, Xie C, Jin N, Long W, Liu X 2023. Generalized machine learning based on multi-omics data to profile the effect of ferroptosis pathway on prognosis and immunotherapy response in patients with bladder cancer. Environ Toxicol. DOI: https://doi.org/10.1002/tox.239490.1002