Understudied targets of the ischemia-reperfusion injury pathogenesis in liver transplantation

Background. Liver transplantation is currently the most effective method to treat diseases with end-stage liver failure. Complications are most often associated with the initially severe patient condition, imperfect organ preservation methods, the surgical management per se, and immune system incompetence. The most common complications of transplantation include ischemic reperfusion injury, which occurs to some or another extent in each transplanted organ and worsens the course of the postoperative period. The process is based on complex pathophysiological mechanisms of cell damage due to ischemia and inflammation caused by reperfusion.

Objective. To summarize current data on the mechanisms of the ischemic reperfusion injury development in liver transplantation and to find the ways to reduce adverse effects.

Material and methods. The analysis of data from foreign and homeland experimental and clinical studies on the pathogenesis of ischemic reperfusion injury in liver transplantation has been performed. The search for literature data was carried out in international databases (PubMed/MedLine, ResearchGate, as well as in the scientific electronic library of Russia (eLibrary.RU) for the period from 2020-2024.

Conclusion. The analyzed publications have provided various algorithms for the preservation of donor organs, including those using machine perfusion.

1. Novruzbekov MS, Balkarov AG, Anosova EYu, Dmitriev IV, Anisimov YuA, Zhuravel NS, et al. The importance of oxygenation in machine perfusion of the kidney and liver. Transplantologiya. The Russian Journal of Transplantation. 2023;15(4):529–540. (In Russ.). https://doi.org/10.23873/2074-0506-2023-15-4-529-540

2. Schlegel A, Muller X, Dutkowski P. Machine perfusion strategies in liver transplantation. HepatoBiliary Surg Nutr. 2019;8(5):490–501. PMID: 31673538 https://doi.org/10.21037/hbsn.2019.04.04

3. Dutkowski P, Polak WG, Muiesan P, Schlegel A, Verhoeven CJ, Scalera I, et al. First comparison of hypothermic oxygenated perfusion versus static cold storage of human donation after cardiac death liver transplants: an international-matched case analysis. Ann Surg. 2015;262(5):764–771. PMID: 26583664 https://doi.org/10.1097/SLA.0000000000001473

4. Sarvestani FS, Azarpira N, Al-Abdullah IH, Tamaddon A-M. microRNAs in liver and kidney ischemia reperfusion injury: Insight to improve transplantation outcome. Biomed Pharmacother. 2020;133:110944. PMID: 33227704 https://doi.org/10.1016/j.biopha.2020.110944

5. Yaremin BI, Novruzbekov MS, Lutsyk KN, Olisov OD, Gulyaev VA, Magomedov KM, et al. New factors for predicting the severity of ischemic reperfusion injury of a liver transplant. Russian Journal of Transplantology and Artificial Organs. 2022;24(S):75. Available at: https://journal.transpl.ru/vtio/article/view/1572/1345 [Accessed March 6, 2024] (In Russ.).

6. Serifis N, Matheson R, Cloonan D, Rickert CG, Markmann JF, Coe TM. Machine perfusion of the liver: a review of clinical trials. Front Surg. 2021;8:625394. PMID: 33842530 https://doi.org/10.3389/fsurg.2021.625394

7. Hadjiyannis Y, Thomson AW. Regulatory dendritic cell therapy in organ transplantation. Curr Opin Organ Transplant. 2023;29(0):1–10. https://doi.org/10.1097/MOT.0000000000001127

8. Rampes S, Ma D. Hepatic ischemiareperfusion injury in liver transplant setting: mechanisms and protective strategies. J Biomed Res. 2019;33(4):221– 234. PMID: 32383437 https://doi.org/10.7555/JBR.32.20180087

9. Tsoy DL, Moysyuk YG. Prevention and treatment of ischemia-reperfusion injury in liver transplantation-possible way to expand the donor pool. Russian Journal of Transplantology and Artificial Organs. 2013;15(3):102–114. (In Russ.). https://doi.org/10.15825/1995-1191-2013-3-102114

10. Tran LM, Macedo C, Zahorchak AF, Gu X, Elinoff B, Singhi A, et al. Donorderived regulatory dendritic cell infusion modulates effector CD8+ T cell and NK cell responses after liver transplantation. Sci Transl Med. 2023;15(717):eadf4287. PMID: 37820009 https://doi.org/10.1126/scitranslmed.adf4287

11. Malyarevskaya OV, Namitokov AM, Rusinova SV, Kosmacheva ED. PCSK9 inhibitors: their role in reducing cardiovascular morbidity. The South Russian Journal of Therapeutic Practice. 2022;3(2):32–40. (In Russ.). https://doi.org/10.21886/2712-8156-2022-3-2-32-40

12. Zhang Y, Wang Z, Jia C, Yu W, Li X, Xia N, et al. Blockade of hepatocyte PCSK9 ameliorates hepatic ischemiareperfusion injury by promoting pink1parkin-mediated mitophagy. Cell Mol Gastroenterol Hepatol. 2024;17(1):149–169. PMID: 37717824 https://doi.org/10.1016/j.jcmgh.2023.09.004

13. Mirzaei R, Karampoor S, Korotkova NL. The emerging role of miRNA122 in infectious diseases: Mechanisms and potential biomarkers. Pathol Res Pract. 2023;249:154725. PMID: 37544130 https://doi.org/10.1016/j.prp.2023.154725

14. Singh SP, Maurya V, Kumar K, Singh D, Verma P, Samanta D, et al. Serum expression level of microRNA-122 and its significance in different stages of hepatitis B virus infection. Cell Mol Biol (Noisy-le-grand). 2023;69(6):36– 40. PMID: 37605594 https://doi.org/10.14715/cmb/2023.69.6.6

15. Ju C, Wang M, Tak E, Kim B, Emontzpohl C, Yang Y, et al. Hypoxia-inducible factor–1α–dependent induction of miR122 enhances hepatic ischemia tolerance. J Clin Invest. 2021;131(7):e140300. PMID: 33792566 https://doi.org/10.1172/JCI140300

16. Huang Z, Mou T, Luo Y, Pu X, Pu J, Wan L, et al. Inhibition of miR-450b-5p ameliorates hepatic ischemia/reperfusion injury via targeting CRYAB. Cell Death Dis. 2020;11(6):455. PMID: 32532961 https://doi.org/10.1038/s41419-0202648-0

17. Wu K, Tao G, Xu T, An Y, Yu X, Wang Y, et al. Downregulation of miR497-5p prevents liver ischemia-reperfusion injury in association with MED1/ TIMP-2 axis and the NF-κB pathway. FASEB J. 2021;35(4):e21180. PMID: 33715222 https://doi.org/10.1096/fj.202001029R

18. Li S, Zhu Z, Xue M, Pan X, Tong G, Yi X, et al. The protective effects of fibroblast growth factor 10 against hepatic ischemia-reperfusion injury in mice. Redox Biol. 2021;40:101859. PMID: 33445067 https://doi.org/10.1016/j.redox.2021.101859

19. Kojima H, Kadono K, Hirao H, Dery KJ, Kupiec-Weglinski JW. CD4+ T cell NRF2 signaling improves liver transplantation outcomes by modulating T cell activation and differentiation. Antioxid Redox Signal. 2023;38(7– 9):670–683. PMID: 36070449 https://doi.org/10.1089/ars.2022.0094

20. Becker PD, Ratnasothy K, Sen M, Peng Q, Romano M, Bazoer J, et al. B lymphocytes contribute to indirect pathway T cell sensitization via acquisition of extracellular vesicles. Am J Transplant. 2021;21(4):1415–1426. PMID: 32483894 https://doi.org/10.1111/ajt.16088

21. Brandl K, Schnabl B. Intestinal microbiota and nonalcoholic steatohepatitis. Curr Opin Gastroenterol. 2017;33(3):128– 133. PMID: 28257306 https://doi.org/10.1097/MOG.0000000000000349

22. Ahmed O, Xu M, Zhou F, Wein AN, Upadhya GA, Ye L, et al. NRF2 assessment in discarded liver allografts: a role in allograft function and salvage. Am J Transplant. 2022;22(1):58–70. PMID: 34379880 https://doi.org/10.1111/ajt.16789

23. Zhou M, Hui J, Gao L, Liang J, Wang C, Xu J. Extracellular vesicles from bone marrow mesenchymal stem cells alleviate acute rejection injury after liver transplantation by carrying MiR-22-3p and inducing M2 polarization of Kupffer cells. J Gene Med. 2023;25(7):e3497. PMID: 36890611 https://doi.org/10.1002/jgm.3497

24. Cui B, Sun J, Li SP, Zhou GP, Chen XJ, Sun LY, et al. CD80+ dendritic cell derived exosomes inhibit CD8+ T cells through down-regulating NLRP3 expression after liver transplantation. Int Immunopharmacol. 2022;109:108787. PMID: 35490667 https://doi.org/10.1016/j.intimp.2022.108787

25. Malhi H. Emerging role of extracellular vesicles in liver diseases. Am J Physiol Gastrointest Liver Physiol. 2019;317(5):G739–G749. PMID: 31545919 https://doi.org/10.1152/ajpgi.00183.2019

26. Zhang L, Song Y, Chen L, Li D, Feng H, Lu Z, et al. MiR-20a-containing exosomes from umbilical cord mesenchymal stem cells alleviates liver ischemia/reperfusion injury. J Cell Physiol. 2020;235(4):3698–3710. PMID: 31566731 https://doi.org/10.1002/jcp.29264

27. Ichinohe N, Ishii M, Tanimizu N, Mizuguchi T, Yoshioka Y, Ochiya T, et al. Extracellular vesicles containing MiR146a-5p secreted by bone marrow mesenchymal cells activate hepatocytic progenitors in regenerating rat livers. Stem Cell Res Ther. 2021;12(1):312. PMID: 34051870 https://doi.org/10.1186/s13287-021-02387-6

28. Eltzschig HK, Eckle T. Ischemia and reperfusion--from mechanism to translation. Nature Medicine. 2011;17(11):1391– 1401. PMID: 22064429 https://doi.org/10.1038/nm.2507

29. Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell. 2012;149(5):1060–1072. PMID: 22632970 https://doi.org/10.1016/j.cell.2012.03.042

30. Stockwell BR, Friedmann Angeli JP, Bayir H, Bush AI, Conrad M, Dixon SJ, et al. Ferroptosis: a regulated cell death nexus linking metabolism, redox biology, and disease. Cell. 2017;171(2):273– 285. PMID: 28985560 https://doi.org/10.1016/j.cell.2017.09.021

31. ten Hove M, Lygate CA, Fischer A, Schneider JE, Sang AE, Hulbert K, et al. Reduced inotropic reserve and increased susceptibility to cardiac ischemia/ reperfusion injury in phosphocreatinedeficient guanidinoacetate-N-methyltransferase-knockout mice. Circulation. 2005;111(19):2477–2485. PMID: 15883212 https://doi.org/10.1161/01.CIR.0000165147.99592.01

32. Hanson LR, Roeytenberg A, Martinez PM, Coppes VG, Sweet DC, Rao RJ, et al. Intranasal deferoxamine provides increased brain exposure and significant protection in rat ischemic stroke. J Pharmacol Exp Ther. 2009;330(3):679–686. PMID: 19509317 https://doi.org/10.1124/jpet.108.149807

33. Liang C, Zhang X, Yang M, Dong X. Recent progress in ferroptosis inducers for cancer therapy. Adv Mater. 2019;31(51):e1904197. PMID: 31595562 https://doi.org/10.1002/adma.201904197

34. Friedmann Angeli JP, Schneider M, Proneth B, Tyurina YY, Tyurin VA, Hammond VJ, et al. Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice. Nat Cell Biol. 2014;16(12):1180–1191. PMID: 25402683 https://doi.org/10.1038/ncb3064

35. Montalvo-Jave EE, Escalante-Tattersfield T, Ortega-Salgado JA, Piña E, Geller DA. Factors in the pathophysiology of the liver ischemia-reperfusion injury. J Surg Res. 2008;147(1):153– 159. PMID: 17707862 https://doi.org/10.1016/j.jss.2007.06.015

36. Yagoda N, von Rechenberg M, Zaganjor E, Bauer AJ, Yang WS, Fridman DJ, et al. RAS-RAF-MEK-dependent oxidative cell death involving voltage-dependent anion channels. Nature. 2007;447(7146):864–868. PMID: 17568748 https://doi.org/10.1038/nature05859

37. Yang WS, Stockwell BR. Synthetic lethal screening identifies compounds activating iron-dependent, nonapoptotic cell death in oncogenic-RAS-harboring cancer cells. Chem Biol. 2008;15(3):234– 245. PMID: 18355723 https://doi.org/10.1016/j.chembiol.2008.02.010

38. Fatokun V, Dawson L, Dawson TM. Parthanatos: mitochondrial-linked mechanisms and therapeutic opportunities. Br J Pharmacol. 2014;171(8):2000– 2016. PMID: 24684389 https://doi.org/10.1111/bph.12416

39. Wu J, Tuo QZ, Lei P. Ferroptosis, a recent defined form of critical cell death in neurological disorders. J Molr Neurosci. 2018;66(2):197–206. PMID: 30145632 https://doi.org/10.1007/s12031-0181155-6

40. Bochkov V, Oskolkova O, Birukov K, Levonen AL, Binder CJ, Stöckl J. Generation and biological activities of oxidized phospholipids. Antioxid Redox Signal. 2010;12(8):1009–1059. PMID: 19686040 https://doi.org/10.1089/ars.2009.2597

41. Yang WS, SriRamaratnam R, We lsch ME, Shimada K, Skouta R, Viswanathan VS, et al. Regulation of ferroptotic cancer cell death by GPX4. Cell. 2014;156(1–2):317–331. PMID: 24439385 https://doi.org/10.1016/j.cell.2013.12.010

42. Dixon SJ, Patel DN, Welsch M, Skouta R, Lee ED, Hayano M, et al. Pharmacological inhibition of cystineglutamate exchange induces endoplasmic reticulum stress and ferroptosis. ELife. 2014;3:e02523. PMID: 24844246 https://doi.org/10.7554/eLife.02523

43. Bröer S, Wagner CA. Structure-function relationships of heterodimeric amino acid transporters. Cell Biochem Biophys. 2002;36(2-3):155–168. PMID: 12139401 https://doi.org/10.1385/CBB:36:2-3:155

44. Conrad M, Sato H. The oxidative stress-inducible cystine/glutamate antiporter, system: cystine supplier and beyond. Amino Acids. 2012;42(1):231– 246. PMID: 21409388 https://doi.org/10.1007/s00726-011-0867-5

45. Bridges R, Natale NR, Patel SA. System Xc- cystine/glutamate antiporter: an update on molecular pharmacology and roles within the CNS. Br J Pharmacol. 2012;165(1):20–34. PMID: 21564084 https://doi.org/10.1111/j.1476-5381.2011.01480.x

46. Dixon SJ, Winter GE, Musavi LS, Lee ED, Snijder B, Rebsamen M, et al. Human haploid cell genetics reveals roles for lipid metabolism genes in nonapoptotic cell death. ACS Chemical Biology. 2015;10(7):1604–1609. PMID: 25965523 https://doi.org/10.1021/acschembio.5b00245

47. Cardoso BR, Hare DJ, Bush AI, Roberts BR. Glutathione peroxidase 4: a new player in neurodegeneration? Mol Psychiatry. 2017;22(3):328–335. PMID: 27777421 https://doi.org/10.1038/mp.2016.196

48. Ingold I, Berndt C, Schmitt S, Doll S, Poschmann G, Buday K, et al. Selenium utilization by GPX4 is required to prevent hydroperoxide-induced ferroptosis. Cell. 2018;172(3):409–422. PMID: 29290465 https://doi.org/10.1016/j.cell.2017.11.048

49. Yang WS, Kim KJ, Gaschler M, Patel MS, Shchepinov MS, Stockwell BR. Peroxidation of polyunsaturated fatty acids by lipoxygenases drives ferroptosis. Proc Natl Acad Sci USA. 2016;113(34):E4966–E4975. PMID: 27506793 https://doi.org/10.1073/pnas.1603244113

50. Meister A, Anderson ME. Glutathione. Ann Rev Biochem. 1983;52(1):711–760. PMID: 6137189 https://doi.org/10.1146/annurev.bi.52.070183.003431

51. Maiorino M, Conrad M, Ursini F. GPx4, lipid peroxidation, and cell death: discoveries, rediscoveries, and open issues. Antioxid Redox Signal. 2018;29(1):61–74. PMID: 28462584 https://doi.org/10.1089/ars.2017.7115

52. Dolma S, Lessnick S, Hahn W, Stockwell BR. Identification of genotype-selective antitumor agents using synthetic lethal chemical screening in engineered human tumor cells. Cancer Cell. 2003;3(3):285–296. PMID: 12676586 https://doi.org/10.1016/s1535-6108(03)00050-3

53. Ke B, Tian M, Li J, Liu B, He G. Targeting programmed cell death using small-molecule compounds to improve potential cancer therapy. Med Res Rev. 2016;36(6):983–1035. PMID: 27357603 https://doi.org/10.1002/med.21398

54. Li W, Li W, Leng Y, Xiong Y, Xia Z. Ferroptosis is involved in diabetes myocardial ischemia/reperfusion injury through endoplasmic reticulum stress. DNA Cell Biol. 2020;39(2):210–225. PMID: 31809190 https://doi.org/10.1089/dna.2019.5097

55. Bersuker K, Hendricks JM, Li Z, Magtanong L, Ford B, Tang PH, et al. The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis. Nature. 2019;575(7784):688–692. PMID: 31634900 https://doi.org/10.1038/s41586-019-1705-2

56. Doll S, Freitas FP, Shah R, Aldrovandi M, da Silva MC, Ingold I, et al. FSP1 is a glutathione-independent ferroptosis suppressor. Nature. 2019;575(7784):693– 698. PMID: 31634899 https://doi.org/10.1038/s41586-019-1707-0

57. Shimada K, Skouta R, Kaplan A, Yang WS, Hayano M, Dixon SJ, et al. Global survey of cell death mechanisms reveals metabolic regulation of ferroptosis. Nat Chem Biol. 2016;12(7):497–503. PMID: 27159577 https://doi.org/10.1038/nchembio.2079