Журнал «Здоровье ребенка» Том 17, №4, 2022

У цій роботі ми проаналізували дослідження, у яких було визначено залізозалежний регульований тип клітинної загибелі — фероптоз, описали принципові морфологічні й біохімічні відмінності різних варіантів регульованої загибелі клітин, висвітлили сучасні наукові досягнення щодо розуміння властивостей перебігу вищевказаного процесу, описали клінічне значення фероптозу в загальній структурі захворюваності та визначили актуальні питання подальших досліджень. Висновки. Численні дослідження дозволили ідентифікувати фероптоз як форму регульованої клітинної загибелі, ініційовану окиснювальними порушеннями внутрішньоклітинного мікрооточення, що знаходиться під конститутивним контролем глутатіонпероксидази-4 і може бути інгібована хелаторами заліза та ліпофільними антиоксидантами. Фероптоз може бути реалізований двома основними шляхами: зовнішнім (транспортним) та внутрішнім (ферментним). В основі зовнішнього шляху лежать неферментативні реакції, такі як залізозалежна реакція Фентона. Внутрішній шлях відбувається під посередництвом ферментних систем, що включають глутатіонпероксидазу-4 та ліпоксигеназу. Проведення клінічних досліджень дозволить удосконалити не лише розуміння ролі фероптозу в патогенезі перебігу захворювань, але й виявити можливі превентивні стратегії щодо розвитку патологічних процесів.

In this article, we have analysed the studies that determined the iron-dependent regulated type of cell death, ferroptosis, described the fundamental morphological and biochemical differences between various types of regulated cell death, highlighted modern scientific achievements in understanding the features of the above-mentioned process, described the clinical significance of ferroptosis in the general structure of morbidity and identified relevant issues for further research. Conclusions. Numerous studies allowed identifying ferroptosis as a form of regulated cell death, initiated by oxidative disturbances of the intracellular microenvironment, which is under the constitutive control of glutathione peroxidase 4 and can be inhibited by iron chelators and lipophilic antioxidants. Ferroptosis can occur in two main ways: external (transport) and internal (enzymatic). The external pathway is based on non-enzymatic reactions, such as the iron-dependent Fenton reaction. The internal pathway is mediated by enzyme systems, including glutathione peroxidase 4 and lipoxygenase. Conducting clinical research will improve not only the understanding of the role of ferroptosis in the pathogenesis of the course of diseases, but also reveal possible preventive strategies for the development of pathological processes.

фероптоз; клітинна загибель; огляд

ferroptosis; cell death; review

1. Hirschhorn T., Stockwell B. The development of the concept of ferroptosis. Free Radical Biology and Medicine. 2019. 133. 130-143. doi: 10.1016/j.freeradbiomed.2018.09.043.
2. Kuang F., Liu J., Tang D., Kang R. Oxidative damage and antioxidant defense in ferroptosis. Frontiers in Cell and Developmental Biology. 2020. 8. doi: 10.3389/fcell.2020.586578.
3. Lei P., Bai T., Sun Y. Mechanisms of ferroptosis and relations with regulated cell death: a review. Frontiers in Physiology. 2019. 10. doi: 10.3389/fphys.2019.00139.
4. Han C., Liu Y., Dai R., Ismail N., Su W., Li B. Ferroptosis and its potential role in human diseases. Frontiers in Pharmacology. 2020. 11. doi: 10.3389/fphar.2020.00239.
5. Kroemer G., Galluzzi L., Vandenabeele P., Abrams J., Alnemri E., Baehreck E. et al. Classification of cell death: recommendations of the Nomenclature Committee on Cell Death 2009. Cell Death & Differentiation. 2008. 16(1). 3-11. doi: 10.1038/cdd.2008.150.
6. Yagoda N., von Rechenberg M., Zaganjor E., Bauer A., Yang W., Fridman D. et al. RAS-RAF-MEK-dependent oxidative cell death involving voltage-dependent anion channels. Nature. 2007. 447(7146). 865-869. doi: 10.1038/nature05859.
7. Vandenabeele P., Galluzzi L., Vanden Berghe T., Kroemer G. Molecular mechanisms of necroptosis: an ordered cellular explosion. Nature Reviews Molecular Cell Biology. 2010. 11(10). 700-714. doi: 10.1038/nrm2970.
8. Galluzzi L., Vitale I., Abrams J., Alnemri E., Baehrecke E., Blagosklonny M. et al. Molecular definitions of cell death subroutines: recommendations of the Nomenclature Committee on Cell Death 2012. Cell Death & Differentiation. 2011. 19(1). 107-120. doi: 10.1038/cdd.2011.96.
9. Aachoui Y., Leaf I., Hagar J., Fontana M., Campos C., Zak D. et al. Caspase-11 protects against bacteria that escape the vacuole. Science. 2013. 339(6122). 975-978. doi: 10.1126/science.1230751.
10. Kayagaki N., Stowe I., Lee B., O’Rourke K., Anderson K., Warming S. et al. Caspase-11 cleaves gasdermin D for non-canonical inflammasome signalling. Nature. 2015. 526(7575). 666-671. doi: 10.1038/nature15541.
11. Shi J., Zhao Y., Wang K., Shi X., Wang Y., Huang H. et al. Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death. Nature. 2015. 526(7575). 660-665. doi: 10.1038/nature15514.
12. Vande Walle L., Lamkanfi M. Pyroptosis. Current Biology. 2016. 26(13). R568-R572. doi: 10.1016/j.cub.2016.02.019.
13. Wang Y., Gao W., Shi X., Ding J., Liu W., He H. et al. Chemotherapy drugs induce pyroptosis through caspase-3 cleavage of a gasdermin. Nature. 2017. 547(7661). 99-103. doi: 10.1038/nature22393.
14. Galluzzi L., Vitale I., Aaronson S., Abrams J., Adam D., Agostinis P. et al. Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018. Cell Death & Differentiation. 2018. 25(3). 486-541. doi: 10.1038/s41418-017-0012-4.
15. Peng J., Song W., Yao F., Zhang X., Peng J., Luo X., Xia X. Involvement of regulated necrosis in blinding diseases: focus on necroptosis and ferroptosis. Experimental Eye Research. 2020. 191. 107922. doi: 10.1016/j.exer.2020.107922.
16. Nirmala J., Lopus M. Cell death mechanisms in eukaryotes. Cell Biology and Toxicology. 2019. 36(2). 145-164. doi: 10.1007/s10565-019-09496-2.
17. Friedmann Angeli J., Schneider M., Proneth B., Tyurina Y., Tyurin V., Hammond V. et al. Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice. Nature Cell Biology. 2014. 16(12). 1180-1191. doi: 10.1038/ncb3064.
18. Xie Y., Song X., Sun X., Huang J., Zhong M., Lotze M. et al. Identification of baicalein as a ferroptosis inhibitor by natural product library screening. Biochemical and Biophysical Research Communications. 2016. 473(4). 775-780. doi: 10.1016/j.bbrc.2016.03.052.
19. Dixon S., Lemberg K., Lamprecht M., Skouta R., Zaitsev E., Gleaso C. et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell. 2012. 149(5). 1060-1072. doi: 10.1016/j.cell.2012.03.042.
20. Tang D., Kang R., Berghe T., Vandenabeele P., Kroemer G. The molecular machinery of regulated cell death. Cell Research. 2019. 29(5). 347-364. doi: 10.1038/s41422-019-0164-5.
21. Sun Y., Chen P., Zhai B., Zhang M., Xiang Y., Fang J. et al. The emerging role of ferroptosis in inflammation. Biomedicine & Pharmacotherapy. 2020. 127. 110108. doi: 10.1016/j.biopha.2020.110108.
22. Kim E., Wong S., Martinez J. Programmed necrosis and disease: we interrupt your regular programming to bring you necroinflammation. Cell Death & Differentiation. 2018. 26(1). 25-40. doi: 10.1038/s41418-018-0179-3.
23. Proneth B., Conrad M. Ferroptosis and necroinflammation, a yet poorly explored link. Cell Death & Differentiation. 2018. 26(1). 14-24. doi: 10.1038/s41418-018-0173-9.
24. Martin-Sanchez D., Ruiz-Andres O., Poveda J., Carrasco S., Cannata-Ortiz P., Sanchez-Niño M. et al. Ferroptosis, but not necroptosis, is important in nephrotoxic folic acid-induced AKI. Journal of the American Society of Nephrology. 2016. 28(1). 218-229. doi: 10.1681/asn.2015121376.
25. Li Q., Li Q., Jia J., Sun Q., Zhou H., Jin W., Mao X. Baicalein exerts neuroprotective effects in FeCl3-induced posttraumatic epileptic seizures via suppressing ferroptosis. Frontiers in Pharmacology. 2019. 10. doi: 10.3389/fphar.2019.00638.
26. Stockwell B., Friedmann Angeli J., Bayir H., Bush A., Conrad M., Dixon S. et al. 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.
27. Yang W., Kim K., Gaschler M., Patel M., Shchepinov M., Stockwell B. Peroxidation of polyunsaturated fatty acids by lipoxygenases drives ferroptosis. Proceedings of the National Academy of Sciences. 2016. 113(34). doi: 10.1073/pnas.1603244113.
28. Wang H., Liu C., Zhao Y., Gao G. Mitochondria regulation in ferroptosis. European Journal of Cell Biology. 2020. 99(1). 151058. doi: 10.1016/j.ejcb.2019.151058.
29. Maldonado E., Sheldon K., DeHart D., Patnaik J., Manevich Y., Townsend D. et al. Voltage-dependent anion channels modulate mitochondrial metabolism in cancer cells. Journal of Biological Chemistry. 2013. 288(17). 11920-11929. doi: 10.1074/jbc.m112.433847.
30. Friedmann Angeli J., Krysko D., Conrad M. Ferroptosis at the crossroads of cancer-acquired drug resistance and immune evasion. Nature Reviews Cancer. 2019. 19(7). 405-414. doi: 10.1038/s41568-019-0149-1.
31. Wu Y., Zhang S., Gong X., Tam S., Xiao D., Liu S., Tao Y. The epigenetic regulators and metabolic changes in ferroptosis-associated cancer progression. Molecular Cancer. 2020. 19(1). doi: 10.1186/s12943-020-01157-x.
32. Chen X., Yu C., Kang R., Tang D. Iron metabolism in ferroptosis. Frontiers in Cell and Developmental Biology. 2020. 8. doi: 10.3389/fcell.2020.590226.
33. Gao M., Monian P., Pan Q., Zhang W., Xiang J., Jiang X. Ferroptosis is an autophagic cell death process. Cell Research. 2016. 26(9). 1021-1032. doi: 10.1038/cr.2016.95.
34. Hou W., Xie Y., Song X., Sun X., Lotze M., Zeh H. et al. Autophagy promotes ferroptosis by degradation of ferritin. Autophagy. 2016. 12(8). 1425-1428. doi: 10.1080/15548627.2016.1187366.
35. Li Q., Han X., Lan X., Gao Y., Wan J., Durham F. et al. Inhibition of neuronal ferroptosis protects hemorrhagic brain. JCI Insight. 2017. 2(7). doi: 10.1172/jci.insight.90777.
36. Yang W., Huang Z., Wu J., Ding C., Murphy S., Chi J. A TAZ-ANGPTL4-NOX2 axis regulates ferroptotic cell death and chemoresistance in epithelial ovarian cancer. Molecular Cancer Research. 2020. 18(1). 79-90. doi: 10.1158/1541-7786.mcr-19-0691.
37. Kagan V., Mao G., Qu F., Angeli J., Doll S., Croix C. et al. Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis. Nature Chemical Biology. 2016. 13(1). 81-90. doi: 10.1038/nchembio.2238.
38. Zou Y., Li H., Graham E., Deik A., Eaton J., Wang W. et al. Cytochrome P450 oxidoreductase contributes to phospholipid peroxidation in ferroptosis. Nature Chemical Biology. 2020. 16(3). 302-309. doi: 10.1038/s41589-020-0472-6.
39. Gao M., Monian P., Quadri N., Ramasamy R., Jiang X. Glutaminolysis and transferrin regulate ferroptosis. Molecular Cell. 2015. 59(2). 298-308. doi: 10.1016/j.molcel.2015.06.011.
40. Yang W., Stockwell B. Ferroptosis: death by lipid peroxidation. Trends in Cell Biology. 2016. 26(3). 165-176. doi: 10.1016/j.tcb.2015.10.014.
41. Cheng Z., Li Y. What is responsible for the initiating chemistry of iron-mediated lipid peroxidation: an update. Chemical Reviews. 2007. 107(3). 748-766. doi: 10.1021/cr040077w.
42. Kajarabille N., Latunde-Dada G.O. Programmed cell-death by ferroptosis: antioxidants as mitigators. International Journal of Molecular Sciences. 2019. 20(19). 4968. doi: 10.3390/ijms20194968.
43. Dietrich R., Bradley W. Iron accumulation in the basal ganglia following severe ischemic-anoxic insults in children. Radiology. 1988. 168(1). 203-206. doi: 10.1148/radiology.168.1.3380958.
44. Yan H., Zou T., Tuo Q., Xu S., Li H., Belaidi A., Lei P. Ferroptosis: mechanisms and links with diseases. Signal Transduction and Targeted Therapy. 2021. 6(1). doi: 10.1038/s41392-020-00428-9.
45. Anthonymuthu T., Tyurina Y., Sun W., Mikulska-Ruminska K., Shrivastava I., Tyurin V. et al. Resolving the paradox of ferroptotic cell death: ferrostatin-1 binds to 15LOX/PEBP1 complex, suppresses generation of peroxidized ETE-PE, and protects against ferroptosis. Redox Biology. 2021. 38. 101744. doi: 10.1016/j.redox.2020.101744.
46. Amaral E., Costa D., Namasivayam S., Riteau N., Kamenyeva O., Mittereder L. et al. A major role for ferroptosis in Mycobacterium tuberculosis-induced cell death and tissue necrosis. Journal of Experimental Medicine. 2019. 216(3). 556-570. doi: 10.1084/jem.20181776.
47. Lezhenko H., Abaturov O., Pogribna A. Determining the probable role of ferroptosis in the course of inflammatory bacterial diseases of the respiratory organs in young children accompanied by the development of anemia of inflammation. Pathologia. 2021. 18(1). 44-49. doi: 10.14739/2310-1237.2021.1.229019.
48. Pogribna A. Prevention of development of anemia of inflammation in young children with acute inflammatory bacterial diseases (Ph. D.). Zaporizhzhia State Medical University. 2022.