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ISSN 2522-9028 (Print)
ISSN 2522-9036 (Online)

Fiziologichnyi Zhurnal

is a scientific journal issued by the

Bogomoletz Institute of Physiology
National Academy of Sciences of Ukraine

Editor-in-chief: V.F. Sagach

The journal was founded in 1955 as
1955 – 1977 "Fiziolohichnyi zhurnal" (ISSN 0015 – 3311)
1978 – 1993 "Fiziologicheskii zhurnal" (ISSN 0201 – 8489)
1994 – 2016 "Fiziolohichnyi zhurnal" (ISSN 0201 – 8489)
2017 – "Fiziolohichnyi zhurnal" (ISSN 2522-9028)

Fiziol. Zh. 2023; 69(6): 120-132


O.A. Kondratska, N.G. Grushka, V.V. Veshko, S.I. Pavlovych, R.I. Yanchii

    Bogomoletz Institute of Physiology of the National Academy of Sciences of Ukraine, Kyiv, Ukraine


The review summarizes generalizing modern scientific data on the main functions of the protein HMGB1, and its physiological and pathological roles. Amphoterin is involved in key processes that ensure the functioning of DNA in the cell nucleus and plays an important role outside it. HMGB1 has been implicated in many human inflammatory diseases such as sepsis, ischemic reperfusion injury, neurological conditions, cardiovascular disease, autoimmune disease, and others. This manuscript describes the structure and main functions of HMGB1, discusses the significance of this alarmin as damage-associated molecular patterns, and analyzes its role in the development of inflammation and cell death. Special attention is focused on the role of HMGB1 in the development of endotoxemia, as well as data on the signaling pathways involved in its pathogenesis. Information on the results of studies of the possibility of modulating the activity of this protein using inhibitors is also considered, since understanding this may be useful for developing new therapeutic strategies aimed at treating inflammatory conditions of various origins.

Keywords: amphoterin; endotoxemia; therapeutic strategies; inflammatory conditions.


  1. Raucci A, Di Maggio S, Scavello F, D'Ambrosio A, Bianchi ME, Capogrossi MC. The Janus face of HMGB1 in heart disease: a necessary update. Cell Mol Life Sci. 2019;76(2):211-29. CrossRef PubMed PubMedCentral
  2. Andersson U, Yang H, Harris H. High-mobility group box 1 protein (HMGB1) operates as an alarmin outside as well as inside cells. Semin Immunol. 2018;38:40-8. CrossRef PubMed
  3. Gonelevue S, Bandyopadhyay A, Bhagat S, Alam MI, Khan GA. Sterile inflammatory role of high mobility group box 1 protein: biological functions and involvement in disease. J Vascul Res. 2018;55(4):244-54. CrossRef PubMed
  4. Singh H, Agrawal DK. Therapeutic potential of targeting the HMGB1/RAGE axis in inflammatory diseases. Molecules. 2022;27(21):7311. CrossRef PubMed PubMedCentral
  5. Vijayakumar EC, Bhatt LK, Prabhavalkar KS. High mobility group box-1 (HMGB1): a potential target in therapeutics. Curr Drug Targets. 2019;20(14):1474-85. CrossRef PubMed
  6. Vitali R, Mancuso AB, Palone F, Pioli C, Cesi V, Negroni A, Cucchiara S, Oliva S, Carissimi C, Laudadio I, Stronati L. PARP1 activation induces HMGB1 secretion promoting intestinal inflammation in mice and human intestinal organoids. Int J Mol Sci. 2023;24(8):7096. CrossRef PubMed PubMedCentral
  7. Watanabe H, Son M. The immune tolerance role of the HMGB1-RAGE axis. Cells. 2021;10(3):564. CrossRef PubMed PubMedCentral
  8. Chen R, Kang R, Tang D. The mechanism of HMGB1 secretion and release. Exp Mol Med. 2022;54(2):91-102. CrossRef PubMed PubMedCentral
  9. Kang R, Chen R, Zhang Q, Hou W, Wu S, Cao L, Huang J, Yu Y, Fan XG, Yan Z, Sun X, Wang H, Wang Q, Tsung A, Billiar TR, Zeh HJ 3rd, Lotze MT, Tang D. HMGB1 in health and disease. Mol Aspect Med. 2014;40:1-116. CrossRef PubMed PubMedCentral
  10. Magna M, Pisetsky DS. The alarmin properties of DNA and DNA-associated nuclear proteins. Clin Ther. 2016;38(5):1029-41. CrossRef PubMed
  11. Wang Y, Wang L, Hu F, Zou M, Luo R, Sun Y, Wang T, Guo Q, Peng X. Extracellular HMGB1 as inflammatory mediator in the progression of mycoplasma gallisepticum infection. Cells. 2022;11(18):2817. CrossRef PubMed PubMedCentral
  12. Liu F, Yang X, Xing J, Han K, Sun Y. Glycyrrhizin potentially suppresses the inflammatory response in preeclampsia rat model. Pregnan Hypertens. 2021;23:34-40. CrossRef PubMed
  13. Sun X, Tang D. HMGB1-dependent and-independent autophagy. Autophagy. 2014;10(10):1873-6. CrossRef PubMed PubMedCentral
  14. Chen R, Zou J, Kang R, Tang D. The redox protein HMGB1 in cell death and cancer. Antioxid Redox Signal. 2023 Feb 2. Epub ahead of print. CrossRef PubMed
  15. Paudel YN, Angelopoulou E, Piperi C, Othman I, Aamir K, Shaikh MF. Impact of HMGB1, RAGE, and TLR4 in Alzheimer's disease (AD): from risk factors to therapeutic targeting. Cells. 2020;9(2):383. CrossRef PubMed PubMedCentral
  16. Zhao F, Fang Y, Deng S, Li X, Zhou Y, Gong Y, Zhu H, Wang W. Glycyrrhizin protects rats from sepsis by blocking HMGB1 signaling. Biomed Res Int. 2017;2017:9719647. CrossRef PubMed PubMedCentral
  17. Zhou M, Zhang Y, Tang R, Liu H, Du M, Gao Z, Ji Z, Fang H. HMGB1/TLR4 signaling affects regulatory T cells in acute lung injury. J Inflamm Res. 2021;14:1551-61. CrossRef PubMed PubMedCentral
  18. D'Agostino G, Artinger M, Locati M, Perez L, Legler DF, Bianchi ME, Rüegg C, Thelen M, Marchese A, Rocchi MBL, Cecchinato V, Uguccioni M. β-Arrestin1 and β-Arrestin2 are required to support the activity of the CXCL12/HMGB1 heterocomplex on CXCR4. Front Immunol. 2020;11:550824. CrossRef PubMed PubMedCentral
  19. Haque N, Fareez IM, Fong LF, Mandal C, Abu Kasim NH, Kacharaju KR, Soesilawati P. Role of the CXCR4- SDF1-HMGB1 pathway in the directional migration of cells and regeneration of affected organs. World J Stem Cells. 2020;12(9):938-51. CrossRef PubMed PubMedCentral
  20. Cazzato G, Colagrande A, Cimmino A, Cicco G, Scarcella VS, Tarantino P, Lospalluti L, Romita P, Foti C, Demarco A, Sablone S, Candance PMV, Cicco S, Lettini T, Ingravallo G, Resta L. HMGB1-TIM3-HO1: A new pathway of inflammation in skin of SARS-CoV-2 patients? A retrospective pilot study. Biomolecules. 2021;11(8):1219. CrossRef PubMed PubMedCentral
  21. Huang S, Liu D, Sun J, Zhang H, Zhang J, Wang Q, Gan L, Qu G, Qiu J, Deng J, Jiang J, Zeng L. Tim-3 regulates sepsis-induced immunosuppression by inhibiting the NF-κB signaling pathway in CD4 T cells. Mol Ther. 2022;30(3):1227-38. CrossRef PubMed PubMedCentral
  22. El Mezayen R, El Gazzar M, Seeds MC, McCall CE, Dreskin SC, Nicolls MR. Endogenous signals released from necrotic cells augment inflammatory responses to bacterial endotoxin. Immunol Lett. 2007;111(1):36-44. CrossRef PubMed PubMedCentral
  23. De Leo F, Quilici G, Tirone M, De Marchis F, Mannella V, Zucchelli C, Preti A, Gori A, Casalgrandi M, Mezzapelle R, Bianchi ME, Musco G. Diflunisal targets the HMGB1/ CXCL12 heterocomplex and blocks immune cell recruitment. EMBO Rep. 2019;20(10):e47788. CrossRef PubMed PubMedCentral
  24. Ferguson TA, Choi J, Green DR. Armed response: how dying cells influence T-cell functions. Immunol Rev. 2011;241(1):77-88. CrossRef PubMed PubMedCentral
  25. Kaczmarek A, Vandenabeele P, Krysko DV. Necroptosis: the release of damage-associated molecular patterns and its physiological relevance. Immunity. 2013;38(2):209-23. CrossRef PubMed
  26. Anderton H, Wicks IP, Silke J. Cell death in chronic inflammation: breaking the cycle to treat rheumatic disease. Nat Rev Rheumatol. 2020;16(9):496-513. CrossRef PubMed
  27. Tao Z, Helms MN, Leach BCB, Wu X. Molecular insights into the multifaceted functions and therapeutic targeting of high mobility group box 1 in metabolic diseases. J Cell Mol Med. 2022;26(14):3809-15. CrossRef PubMed PubMedCentral
  28. Yu T, Xiaojuan F, Jinxi L, Xinyan M, Jie X, Yuexin T, Qingjuan L, Wei Z, Cunyang G, Jie H, Lunbi W, Hang Z, Shuxia L, Huifang G. Extracellular HMGB1 induced glomerular endothelial cell injury via TLR4/MyD88 signaling pathway in lupus nephritis. Mediat Inflamm. 2021;2021:9993971. CrossRef PubMed PubMedCentral
  29. Meng L, Li L, Lu S, Li K, Su Z, Wang Y, Fan X, Li X, Zhao G. The protective effect of dexmedetomidine on LPS-induced acute lung injury through the HMGB1- mediated TLR4/NF-κB and PI3K/Akt/mTOR pathways. Mol Immunol. 2018;94:7-17. CrossRef PubMed
  30. Shen CH, Ma ZY, Li JH, Li RD, Tao YF, Zhang QB, Wang ZX. Glycyrrhizin improves inflammation and apoptosis via suppressing HMGB1 and PI3K/mTOR pathway in lipopolysaccharide-induced acute liver injury. Eur Rev Med Pharmacol Sci. 2020;24(12):7122-30.
  31. Gu J, Ran X, Deng J, Zhang A, Peng G, Du J, Wen D, Jiang B, Xia F. Glycyrrhizin alleviates sepsis-induced acute respiratory distress syndrome via suppressing of HMGB1/ TLR9 pathways and neutrophils extracellular traps formation. Int Immunopharmacol. 2022;108:108730. CrossRef PubMed
  32. Olcum M, Tufekci KU, Durur DY, Tastan B, Gokbayrak IN, Genc K, Genc S. Ethyl pyruvate attenuates microglial NLRP3 inflammasome activation via inhibition of HMGB1/NF-κB/miR-223 signaling. Antioxidants (Basel). 2021;10(5):745. CrossRef PubMed PubMedCentral
  33. Xue J, Suarez JS, Minaai M, Li S, Gaudino G, Pass HI, Carbone M, Yang H. HMGB1 as a therapeutic target in disease. J Cell Physiol. 2021;236(5):3406-19. CrossRef PubMed PubMedCentral
  34. Gajić D, Despotović S, Koprivica I, Miljković Đ, Saksida T. Ethyl pyruvate ameliorates experimental autoimmune myocarditis. Biomolecules. 2021;11(12):1768. CrossRef PubMed PubMedCentral
  35. Jung SM, Lee J, Baek SY, Lee J, Jang SG, Hong SM, Park JS, Cho ML, Park SH, Kwok SK. Ethyl pyruvate ameliorates inflammatory arthritis in mice. Int Immunopharmacol. 2017;52:333-41. CrossRef PubMed
  36. Ding HS, Yang J, Yang J, Guo X, Tang YH, Huang Y, Chen Z, Fan ZX, Huang CX. Fluvastatin attenuated ischemia/reperfusion-induced autophagy and apoptosis in cardiomyocytes through down-regulation HMGB1/TLR4 signaling pathway. Mol Biol Rep. 2021;48(5):3893-901. CrossRef PubMed
  37. Zhu JR, Lu HD, Guo C, Fang WR, Zhao HD, Zhou JS, Wang F, Zhao YL, Li YM, Zhang YD, Yang CQ, Sun JG. Berberine attenuates ischemia-reperfusion injury through inhibiting HMGB1 release and NF-κB nuclear translocation. Acta Pharmacol Sin. 2018;39(11):1706-15. CrossRef PubMed PubMedCentral
  38. Li W, Deng M, Loughran PA, Yang M, Lin M, Yang C, Gao W, Jin S, Li S, Cai J, Lu B, Billiar TR, Scott MJ. LPS induces active HMGB1 release from hepatocytes into exosomes through the coordinated activities of TLR4 and caspase-11/GSDMD signaling. Front Immunol. 2020;11:229. CrossRef PubMed PubMedCentral
  39. Grushka NG, Pavlovych SI, Kondratska OA, Pilkevcih NO, Yanchii RI. The protective effect of germanium citrate on functional state of immune cells and neutrophil activity under the condition of lipolysaccharide induced inflammation. Fiziol Zh. 2019;65(6):43-50. CrossRef
  40. Wang X, Shi J, Li Z, Li L, Zhang R, Bai Y, Li J, Liang F, Tang Y. An 8-hydroxy-quinoline derivative protects against lipopolysaccharide-induced lethality in endotoxemia by inhibiting HMGB1-mediated caspase-11 signaling. Front Pharmacol. 2021;12:673818. CrossRef PubMed PubMedCentral
  41. Yang R, Zhang X. A potential new pathway for heparin treatment of sepsis-induced lung injury: inhibition of pulmonary endothelial cell pyroptosis by blocking hMGB1-LPS-induced caspase-11 activation. Front Cell Infect Microbiol. 2022;12:984835. CrossRef PubMed PubMedCentral
  42. Kondratska OA, Grushka NG, Pavlovych SI, Stovbun YuR, Plyska OI, Yanchii RI. Ammonium glycyrrhizinate has a protective effect on oogenesis and reduces genotoxic stress and death of immune cell in lipopolysaccharideinduced endotoxemia. ECPB. 2020, 91(3): 5-11. CrossRef

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