HMGB1–Platelet Interactions: Mechanisms and Targeted Therapy Strategies

Xiyuan Fang; Xianghui Zhou; Xin Zhou; Zhipeng Cheng; Yu Hu

doi:10.1055/a-2622-0074

Thrombosis and Haemostasis, Inhaltsverzeichnis

CC BY 4.0 · Thromb Haemost
DOI: 10.1055/a-2622-0074

Review Article

HMGB1–Platelet Interactions: Mechanisms and Targeted Therapy Strategies

Authors

Xiyuan Fang‡^*

¹Department of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China, Wuhan, People's Republic of China

²Collaborative Innovation Center of Hematology, Huazhong University of Science and Technology, Wuhan, People's Republic of China

³Key Laboratory of Biological Targeted Therapy (Huazhong University of Science and Technology), Ministry of Education, Wuhan, Hubei, People's Republic of China
Xianghui Zhou‡^*

¹Department of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China, Wuhan, People's Republic of China
Xin Zhou

⁴Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China

⁵School of Stomatology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China
Zhipeng Cheng

¹Department of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China, Wuhan, People's Republic of China

³Key Laboratory of Biological Targeted Therapy (Huazhong University of Science and Technology), Ministry of Education, Wuhan, Hubei, People's Republic of China
Yu Hu

¹Department of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China, Wuhan, People's Republic of China

²Collaborative Innovation Center of Hematology, Huazhong University of Science and Technology, Wuhan, People's Republic of China

³Key Laboratory of Biological Targeted Therapy (Huazhong University of Science and Technology), Ministry of Education, Wuhan, Hubei, People's Republic of China

Abstract

Platelets serve not only as crucial hemostatic components but also as pivotal regulators of inflammatory responses, capable of interacting with diverse cell types and secreting abundant extracellular factors. Accumulating evidence demonstrates that high mobility group box 1 (HMGB1), a DNA-binding protein and critical inflammatory mediator, plays multifaceted roles in disease progression, with platelets being one cellular source of circulating HMGB1. Under pathological conditions, platelets release HMGB1 into the extracellular matrix, establishing bidirectional communication between platelets and other immune cells. Moreover, HMGB1 reciprocally activates platelets through Toll-like receptors (TLRs) and receptor for advanced glycation end-products (RAGE), facilitating platelet activation and subsequent release of regulatory factors that drive inflammation-associated pathological thrombosis. In this review, we systematically characterize the HMGB1–platelet axis and elucidate its context-dependent roles in specific disease states. The mechanistic interplay between HMGB1 signaling and platelet pathophysiology is discussed, particularly its implications for disease progression. Furthermore, we critically evaluate therapeutic strategies targeting HMGB1 developed over the past decade, while proposing future directions for dual-target interventions that simultaneously modulate HMGB1 and platelet activity to combat inflammation-driven thrombotic disorders.

Keywords

HMGB1 - platelet activation - proinflammatory - therapy

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Referenzen

References
1 Andrews RK, Berndt MC. Platelet physiology and thrombosis. Thromb Res 2004; 114 (5–6): 447-453
2 Kulkarni S, Dopheide SM, Yap CL. et al. A revised model of platelet aggregation. J Clin Invest 2000; 105 (06) 783-791
3 Mandel J, Casari M, Stepanyan M, Martyanov A, Deppermann C. Beyond hemostasis: platelet innate immune interactions and thromboinflammation. Int J Mol Sci 2022; 23 (07) 3868
4 Storey R, Thomas M. The role of platelets in inflammation. Thromb Haemost 2017; 114 (09) 449-458
5 Hoffman R, Haim N, Brenner B. Cancer and thrombosis revisited. Blood Rev 2001; 15 (02) 61-67
6 Read CM, Cary PD, Crane-Robinson C, Driscoll PC, Norman DG. Solution structure of a DNA-binding domain from HMG1. Nucleic Acids Res 1993; 21 (15) 3427-3436
7 Stott K, Watson M, Howe FS, Grossmann JG, Thomas JO. Tail-mediated collapse of HMGB1 is dynamic and occurs via differential binding of the acidic tail to the A and B domains. J Mol Biol 2010; 403 (05) 706-722
8 Shi Q, Wang Y, Dong W, Song E, Song Y. Polychlorinated biphenyl quinone-induced signaling transition from autophagy to apoptosis is regulated by HMGB1 and p53 in human hepatoma HepG2 cells. Toxicol Lett 2019; 306: 25-34
9 Kang R, Livesey KM, Zeh IIIHJ, Loze MT, Tang D. HMGB1: a novel Beclin 1-binding protein active in autophagy. Autophagy 2014; 6 (08) 1209-1211
10 Bell CW, Jiang W, Reich CF, Pisetsky DS. The extracellular release of HMGB1 during apoptotic cell death. Am J Physiol Cell Physiol 2006; 291 (06) C1318-C1325
11 Scaffidi P, Misteli T, Bianchi ME. Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature 2002; 418 (6894) 191-195
12 Chen G, Ward MF, Sama AE, Wang H. Extracellular HMGB1 as a proinflammatory cytokine. J Interferon Cytokine Res 2004; 24 (06) 329-333
13 Dumitriu IE, Baruah P, Manfredi AA, Bianchi ME, Rovere-Querini P. HMGB1: guiding immunity from within. Trends Immunol 2005; 26 (07) 381-387
14 Fiuza C, Bustin M, Talwar S. et al. Inflammation-promoting activity of HMGB1 on human microvascular endothelial cells. Blood 2003; 101 (07) 2652-2660
15 Lee S-A, Kwak MS, Kim S, Shin J-S. The role of high mobility group box 1 in innate immunity. Yonsei Med J 2014; 55 (05) 1165-1176
16 Venereau E, Schiraldi M, Uguccioni M, Bianchi ME. HMGB1 and leukocyte migration during trauma and sterile inflammation. Mol Immunol 2013; 55 (01) 76-82
17 Sims GP, Rowe DC, Rietdijk ST, Herbst R, Coyle AJ. HMGB1 and RAGE in inflammation and cancer. Annu Rev Immunol 2010; 28 (01) 367-388
18 Maugeri N, Franchini S, Campana L. et al. Circulating platelets as a source of the damage-associated molecular pattern HMGB1 in patients with systemic sclerosis. Autoimmunity 2012; 45 (08) 584-587
19 Feldman C, Anderson R. Platelets and their role in the pathogenesis of cardiovascular events in patients with community-acquired pneumonia. Front Immunol 2020; 11: 577303
20 Lim KH, Staudt LM. Toll-like receptor signaling. Cold Spring Harb Perspect Biol 2013; 5 (01) a011247
21 O'Neill LAJ, Golenbock D, Bowie AG. The history of Toll-like receptors—redefining innate immunity. Nat Rev Immunol 2013; 13 (06) 453-460
22 Bolourani S, Brenner M, Wang P. The interplay of DAMPs, TLR4, and proinflammatory cytokines in pulmonary fibrosis. J Mol Med 2021; 99 (10) 1373-1384
23 Aslam R, Speck ER, Kim M. et al. Platelet Toll-like receptor expression modulates lipopolysaccharide-induced thrombocytopenia and tumor necrosis factor-α production in vivo. Blood 2006; 107 (02) 637-641
24 Zhang Y, Liang X, Bao X, Xiao W, Chen G. Toll-like receptor 4 (TLR4) inhibitors: current research and prospective. Eur J Med Chem 2022; 235: 114291
25 Rouhiainen A, Imai S, Rauvala H, Parkkinen J. Occurrence of amphoterin (HMG1) as an endogenous protein of human platelets that is exported to the cell surface upon platelet activation. Thromb Haemost 2000; 84 (06) 1087-1094
26 Vogel S, Bodenstein R, Chen Q. et al. Platelet-derived HMGB1 is a critical mediator of thrombosis. J Clin Invest 2015; 125 (12) 4638-4654
27 Li Z, Xi X, Gu M. et al. A stimulatory role for cGMP-dependent protein kinase in platelet activation. Cell 2003; 112 (01) 77-86
28 Kierdorf K, Fritz G. RAGE regulation and signaling in inflammation and beyond. J Leukoc Biol 2013; 94 (01) 55-68
29 Lappas M, Permezel M, Rice GE. Advanced glycation endproducts mediate pro-inflammatory actions in human gestational tissues via nuclear factor-κB and extracellular signal-regulated kinase 1/2. J Endocrinol 2007; 193 (02) 269-277
30 Piarulli F, Lapolla A, Ragazzi E. et al. Role of endogenous secretory RAGE (esRAGE) in defending against plaque formation induced by oxidative stress in type 2 diabetic patients. Atherosclerosis 2013; 226 (01) 252-257
31 Basta G. Advanced glycation end products and vascular inflammation: implications for accelerated atherosclerosis in diabetes. Cardiovasc Res 2004; 63 (04) 582-592
32 Gawlowski T, Stratmann B, Ruetter R. et al. Advanced glycation end products strongly activate platelets. Eur J Nutr 2009; 48 (08) 475-481
33 Recabarren-Leiva D, Burgos CF, Hernandez B. et al. Effects of the age/rage axis in the platelet activation. Int J Biol Macromol 2021; 166: 1149-1161
34 Ahrens I, Chen YC, Topcic D. et al. HMGB1 binds to activated platelets via the receptor for advanced glycation end products and is present in platelet rich human coronary artery thrombi. Thromb Haemost 2015; 114 (05) 994-1003
35 Sakaguchi M, Murata HYamamoto K. et al. TIRAP, an adaptor protein for TLR2/4, transduces a signal from RAGE phosphorylated upon ligand binding. PLoS One 2011; 6 (08) e23132
36 van Beijnum JR, Nowak-Sliwinska P, van den Boezem E, Hautvast P, Buurman WA, Griffioen AW. Tumor angiogenesis is enforced by autocrine regulation of high-mobility group box 1. Oncogene 2012; 32 (03) 363-374
37 Kojok K, El-Kadiry AE-H, Merhi Y. Role of NF-κB in platelet function. Int J Mol Sci 2019; 20 (17) 4185
38 Fuentes E, Rojas A, Palomo I. Role of multiligand/RAGE axis in platelet activation. Thromb Res 2014; 133 (03) 308-314
39 Paul M, Kemparaju K, Girish KS. Inhibition of constitutive NF-κB activity induces platelet apoptosis via ER stress. Biochem Biophys Res Commun 2017; 493 (04) 1471-1477
40 Cohn JN. Cardiovascular disease progression: a target for therapy?. Am J Med 2018; 131 (10) 1170-1173
41 Khodadi E. Platelet function in cardiovascular disease: activation of molecules and activation by molecules. Cardiovasc Toxicol 2019; 20 (01) 1-10
42 Thomas MR, Storey RF. The role of platelets in inflammation. Thromb Haemost 2015; 114 (03) 449-458
43 Huo Y, Schober A, Forlow SB. et al. Circulating activated platelets exacerbate atherosclerosis in mice deficient in apolipoprotein E. Nat Med 2002; 9 (01) 61-67
44 Langer H, Gawaz M. Platelet-vessel wall interactions in atherosclerotic disease. Thromb Haemost 2017; 99 (03) 480-486
45 Kalinina N, Agrotis A, Antropova Y. et al. Increased expression of the DNA-binding cytokine HMGB1 in human atherosclerotic lesions. Arterioscler Thromb Vasc Biol 2004; 24 (12) 2320-2325
46 de Souza AWS, Westra J, Limburg PC, Bijl M, Kallenberg CGM. HMGB1 in vascular diseases: its role in vascular inflammation and atherosclerosis. Autoimmun Rev 2012; 11 (12) 909-917
47 Heit JA. Epidemiology of venous thromboembolism. Nat Rev Cardiol 2015; 12 (08) 464-474
48 Mackman N. New insights into the mechanisms of venous thrombosis. J Clin Invest 2012; 122 (07) 2331-2336
49 Stark K, Philippi V, Stockhausen S. et al. Disulfide HMGB1 derived from platelets coordinates venous thrombosis in mice. Blood 2016; 128 (20) 2435-2449
50 Vogel S, Rath D, Borst O. et al. Platelet-derived high-mobility group box 1 promotes recruitment and suppresses apoptosis of monocytes. Biochem Biophys Res Commun 2016; 478 (01) 143-148
51 Brill A, Fuchs TA, Savchenko AS. et al. Neutrophil extracellular traps promote deep vein thrombosis in mice. J Thromb Haemost 2012; 10 (01) 136-144
52 Martinod K, Witsch T, Farley K, Gallant M, Remold-O'Donnell E, Wagner DD. Neutrophil elastase-deficient mice form neutrophil extracellular traps in an experimental model of deep vein thrombosis. J Thromb Haemost 2016; 14 (03) 551-558
53 Martinod K, Wagner DD. Thrombosis: tangled up in NETs. Blood 2014; 123 (18) 2768-2776
54 Carestia A, Kaufman T, Schattner M. Platelets: new bricks in the building of neutrophil extracellular traps. Front Immunol 2016; 7: 271
55 Dyer MR, Chen Q, Haldeman S. et al. Deep vein thrombosis in mice is regulated by platelet HMGB1 through release of neutrophil-extracellular traps and DNA. Sci Rep 2018; 8 (01) 2068
56 Denorme F, Portier I, Rustad JL. et al. Neutrophil extracellular traps regulate ischemic stroke brain injury. J Clin Invest 2022; 132 (10) e154225
57 Singer M, Deutschman CS, Seymour CW. et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA 2016; 315 (08) 801-810
58 Semeraro N, Ammollo CT, Semeraro F, Colucci M. Sepsis, thrombosis and organ dysfunction. Thromb Res 2012; 129 (03) 290-295
59 Kaplan MJ, Radic M. Neutrophil extracellular traps: double-edged swords of innate immunity. J Immunol 2012; 189 (06) 2689-2695
60 Azevedo LCP, Janiszewski M, Pontieri V. et al. Platelet-derived exosomes from septic shock patients induce myocardial dysfunction. Crit Care (Fullerton) 2007; 11 (06) R120
61 Xu J, Feng Y, Jeyaram A, Jay SM, Zou L, Chao W. Circulating plasma extracellular vesicles from septic mice induce inflammation via microRNA- and TLR7-dependent mechanisms. J Immunol 2018; 201 (11) 3392-3400
62 Jiao Y, Li W, Wang W. et al. Platelet-derived exosomes promote neutrophil extracellular trap formation during septic shock. Crit Care (Fullerton) 2020; 24 (01) 380
63 Papayannopoulos V, Metzler KD, Hakkim A, Zychlinsky A. Neutrophil elastase and myeloperoxidase regulate the formation of neutrophil extracellular traps. J Cell Biol 2010; 191 (03) 677-691
64 Maugeri N, De Lorenzo R, Clementi N. et al. Unconventional CD147-dependent platelet activation elicited by SARS-CoV-2 in COVID-19. J Thromb Haemost 2022; 20 (02) 434-448
65 Chen H, Ning Z, Qiu Y. et al. Elevated levels of von Willebrand factor and high mobility group box 1 (HMGB1) are associated with disease severity and clinical outcome of scrub typhus. Int J Infect Dis 2017; 61: 114-120
66 Arnout J, Vermylen J. Current status and implications of autoimmune antiphospholipid antibodies in relation to thrombotic disease. J Thromb Haemost 2003; 1 (05) 931-942
67 Lood C, Eriksson S, Gullstrand B. et al. Increased C1q, C4 and C3 deposition on platelets in patients with systemic lupus erythematosus—a possible link to venous thrombosis?. Lupus 2012; 21 (13) 1423-1432
68 Baroni Pietto MC, Glembotsky AC, Lev PR. et al. Toll-like receptor expression and functional behavior in platelets from patients with systemic lupus erythematosus. Immunobiology 2024; 229 (01) 152782
69 Postlethwaite AE, Chiang TM. Platelet contributions to the pathogenesis of systemic sclerosis. Curr Opin Rheumatol 2007; 19 (06) 574-579
70 Dees C, Akhmetshina A, Zerr P. et al. Platelet-derived serotonin links vascular disease and tissue fibrosis. J Exp Med 2011; 208 (05) 961-972
71 Yoshizaki A, Komura K, Iwata Y. et al. Clinical significance of serum HMGB-1 and sRAGE levels in systemic sclerosis: association with disease severity. J Clin Immunol 2008; 29 (02) 180-189
72 Manganelli V, Truglia S, Capozzi A. et al. Alarmin HMGB1 and soluble RAGE as new tools to evaluate the risk stratification in patients with the antiphospholipid syndrome. Front Immunol 2019; 10: 460
73 Kanne AM, Jülich M, Mahmutovic A. et al. Association of high mobility group box chromosomal protein 1 and receptor for advanced glycation end products serum concentrations with extraglandular involvement and disease activity in Sjögren's syndrome. Arthritis Care Res 2018; 70 (06) 944-948
74 Shafik NM, El-Esawy RO, Mohamed DA, Deghidy EA, El-Deeb OS. Regenerative effects of glycyrrhizin and/or platelet rich plasma on type-II collagen induced arthritis: targeting autophay machinery markers, inflammation and oxidative stress. Arch Biochem Biophys 2019; 675: 108095
75 Habets KLL, Huizinga TWJ, Toes REM. Platelets and autoimmunity. Eur J Clin Invest 2013; 43 (07) 746-757
76 Comings DE. A general theory of carcinogenesis. Proc Natl Acad Sci U S A 1973; 70 (12) 3324-3328
77 Brantley-Sieders DM, Fang WB, Hicks DJ, Zhuang G, Shyr Y, Chen J. Impaired tumor microenvironment in EphA2-deficient mice inhibits tumor angiogenesis and metastatic progression. FASEB J 2005; 19 (13) 1884-1886
78 Jube S, Rivera ZS, Bianchi ME. et al. Cancer cell secretion of the DAMP protein HMGB1 supports progression in malignant mesothelioma. Cancer Res 2012; 72 (13) 3290-3301
79 Kang R, Hou W, Zhang Q. et al. RAGE is essential for oncogenic KRAS-mediated hypoxic signaling in pancreatic cancer. Cell Death Dis 2014; 5 (10) e1480
80 Holmes CE, Levis JE, Ornstein DL. Activated platelets enhance ovarian cancer cell invasion in a cellular model of metastasis. Clin Exp Metastasis 2009; 26 (07) 653-661
81 Gay LJ, Felding-Habermann B. Contribution of platelets to tumour metastasis. Nat Rev Cancer 2011; 11 (02) 123-134
82 Malte AL, Højbjerg JA, Larsen JB. Platelet parameters as biomarkers for thrombosis risk in cancer: a systematic review and meta-analysis. Semin Thromb Hemost 2023; 50 (03) 360-383
83 Sierko E, Wojtukiewicz MZ. Platelets and angiogenesis in malignancy. Semin Thromb Hemost 2004; 30 (01) 95-108
84 Kuznetsov HS, Marsh T, Markens BA. et al. Identification of luminal breast cancers that establish a tumor-supportive macroenvironment defined by proangiogenic platelets and bone marrow–derived cells. Cancer Discov 2012; 2 (12) 1150-1165
85 Janowska-Wieczorek A, Wysoczynski M, Kijowski J. et al. Microvesicles derived from activated platelets induce metastasis and angiogenesis in lung cancer. Int J Cancer 2004; 113 (05) 752-760
86 Nierodzik ML, Karpatkin S. Thrombin induces tumor growth, metastasis, and angiogenesis: evidence for a thrombin-regulated dormant tumor phenotype. Cancer Cell 2006; 10 (05) 355-362
87 Fuentes E, Palomo I, Rojas A. Cross-talk between platelet and tumor microenvironment: role of multiligand/RAGE axis in platelet activation. Blood Rev 2016; 30 (03) 213-221
88 Yu L-X, Yan L, Yang W. et al. Platelets promote tumour metastasis via interaction between TLR4 and tumour cell-released high-mobility group box1 protein. Nat Commun 2014; 5: 5256
89 Yamanaka Y, Sawai Y, Nomura S. Platelet-derived microparticles are an important biomarker in patients with cancer-associated thrombosis. Int J Gen Med 2019; 12: 491-497
90 Nomura S, Fujita S, Ozasa R. et al. The correlation between platelet activation markers and HMGB1 in patients with disseminated intravascular coagulation and hematologic malignancy. Platelets 2011; 22 (05) 396-397
91 Pistoia V, Pezzolo A. Involvement of HMGB1 in resistance to tumor vessel-targeted, monoclonal antibody-based immunotherapy. J Immunol Res 2016; 2016: 1-7
92 Mega JL, Simon T. Pharmacology of antithrombotic drugs: an assessment of oral antiplatelet and anticoagulant treatments. Lancet 2015; 386 (9990) 281-291
93 Guthikonda S, Lev EI, Kleiman NS. Resistance to antiplatelet therapy. Curr Cardiol Rep 2005; 7 (04) 242-248
94 Ekinci D, Sentürk M, Küfrevioğlu Ö. Salicylic acid derivatives: synthesis, features and usage as therapeutic tools. Expert Opin Ther Pat 2011; 21 (12) 1831-1841
95 Vlot AC, Dempsey DMA, Klessig DF. Salicylic acid, a multifaceted hormone to combat disease. Annu Rev Phytopathol 2009; 47 (01) 177-206
96 Choi HW, Tian M, Song F. et al. Aspirin's active metabolite salicylic acid targets high mobility group box 1 to modulate inflammatory responses. Mol Med 2015; 21 (01) 526-535
97 Yang H, Pellegrini L, Napolitano A. et al. Aspirin delays mesothelioma growth by inhibiting HMGB1-mediated tumor progression. Cell Death Dis 2015; 6 (06) e1786
98 Qin S, Wang H, Yuan R. et al. Role of HMGB1 in apoptosis-mediated sepsis lethality. J Exp Med 2006; 203 (07) 1637-1642
99 Levy RM, Mollen KP, Prince JM. et al. Systemic inflammation and remote organ injury following trauma require HMGB1. Am J Physiol Regul Integr Comp Physiol 2007; 293 (04) R1538-R1544
100 Nishibori M, Mori S, Takahashi HK. Anti-HMGB1 monoclonal antibody therapy for a wide range of CNS and PNS diseases. J Pharmacol Sci 2019; 140 (01) 94-101
101 Yang H, Ochani M, Li J. et al. Reversing established sepsis with antagonists of endogenous high-mobility group box 1. Proc Natl Acad Sci U S A 2004; 101 (01) 296-301
102 Yuan H, Jin X, Sun J. et al. Protective effect of HMGB1 a box on organ injury of acute pancreatitis in mice. Pancreas 2009; 38 (02) 143-148
103 Ulloa L, Ochani M, Yang H. et al. Ethyl pyruvate prevents lethality in mice with established lethal sepsis and systemic inflammation. Proc Natl Acad Sci U S A 2002; 99 (19) 12351-12356
104 Pan P, Cardinal J, Dhupar R. et al. Low-dose cisplatin administration in murine cecal ligation and puncture prevents the systemic release of HMGB1 and attenuates lethality. J Leukoc Biol 2009; 86 (03) 625-632
105 Zetterström CK, Jiang W, Wähämaa H. et al. Pivotal advance: inhibition of HMGB1 nuclear translocation as a mechanism for the anti-rheumatic effects of gold sodium thiomalate. J Leukoc Biol 2008; 83 (01) 31-38
106 Hofmann MA, Drury S, Hudson BI. et al. RAGE and arthritis: the G82S polymorphism amplifies the inflammatory response. Genes Immun 2002; 3 (03) 123-135
107 Chen R-C, Yi P-P, Zhou R-R. et al. The role of HMGB1-RAGE axis in migration and invasion of hepatocellular carcinoma cell lines. Mol Cell Biochem 2014; 390 (1–2): 271-280
108 Lutterloh EC, Opal SM, Pittman DD. et al. Inhibition of the RAGE products increases survival in experimental models of severe sepsis and systemic infection. Crit Care (Fullerton) 2007; 11 (06) R122
109 Mollica L, De Marchis F, Spitaleri A. et al. Glycyrrhizin binds to high-mobility group box 1 protein and inhibits its cytokine activities. Chem Biol 2007; 14 (04) 431-441
110 Abeyama K, Stern DM, Ito Y. et al. The N-terminal domain of thrombomodulin sequesters high-mobility group-B1 protein, a novel antiinflammatory mechanism. J Clin Invest 2005; 115 (05) 1267-1274
111 Chorny A, Delgado M. Neuropeptides rescue mice from lethal sepsis by down-regulating secretion of the late-acting inflammatory mediator high mobility group box 1. Am J Pathol 2008; 172 (05) 1297-1302
112 Chorny A, Anderson P, Gonzalez-Rey E, Delgado M. Ghrelin protects against experimental sepsis by inhibiting high-mobility group box 1 release and by killing bacteria. J Immunol 2008; 180 (12) 8369-8377
113 Hagiwara S, Iwasaka H, Hasegawa A, Asai N, Noguchi T. High-dose intravenous immunoglobulin G improves systemic inflammation in a rat model of CLP-induced sepsis. Intensive Care Med 2008; 34 (10) 1812-1819
114 Klint Ea, Grundtman C, Engström M. et al. Intraarticular glucocorticoid treatment reduces inflammation in synovial cell infiltrations more efficiently than in synovial blood vessels. Arthritis Rheum 2005; 52 (12) 3880-3889
115 Dong H, Zhang L, Liu S. Targeting HMGB1: an available therapeutic strategy for breast cancer therapy. Int J Biol Sci 2022; 18 (08) 3421-3434
116 Tanuma S-i, Oyama T, Okazawa M. et al. A dual anti-inflammatory and anti-proliferative 3-styrylchromone derivative synergistically enhances the anti-cancer effects of DNA-damaging agents on colon cancer cells by targeting HMGB1-RAGE-ERK1/2 signaling. Int J Mol Sci 2022; 23 (07) 3426
117 Bedoui Y, Guillot X, Sélambarom J. et al. Methotrexate an old drug with new tricks. Int J Mol Sci 2019; 20 (20) 5023
118 Xie W, Zhou P, Sun Y. et al. Protective effects and target network analysis of ginsenoside Rg1 in cerebral ischemia and reperfusion injury: a comprehensive overview of experimental studies. Cells 2018; 7 (12) 270
119 Zhang Z, Zheng Y, Chen N. et al. San Huang Xiao Yan recipe modulates the HMGB1-mediated abnormal inflammatory microenvironment and ameliorates diabetic foot by activating the AMPK/Nrf2 signalling pathway. Phytomedicine 2023; 118: 154931
120 Zhang Y, Zhang J-X, Xiao L-X. et al. The synergistic effect of Huangqi Gegen decoction on thrombosis relates to the astragalus polysaccharide-improved oral delivery of puerarin. J Ethnopharmacol 2024; 335 (01) 118622
121 Xu D, Young J, Song D, Esko JD. Heparan sulfate is essential for high mobility group protein 1 (HMGB1) signaling by the receptor for advanced glycation end products (RAGE). J Biol Chem 2011; 286 (48) 41736-41744
122 Ebeyer-Masotta M, Eichhorn T, Weiss R. et al. Heparin-functionalized adsorbents eliminate central effectors of immunothrombosis, including platelet factor 4, high-mobility group box 1 protein and histones. Int J Mol Sci 2022; 23 (03) 1823
123 Sloos PH, Maas MAW, Meijers JCM. et al. Anti-high-mobility group box-1 treatment strategies improve trauma-induced coagulopathy in a mouse model of trauma and shock. Br J Anaesth 2023; 130 (06) 687-697
124 Park BS, Son DJ, Choi WS. et al. Antiplatelet activities of newly synthesized derivatives of piperlongumine. Phytother Res 2008; 22 (09) 1195-1199
125 Ku S-K, Kim JA, Bae J-S. Vascular barrier protective effects of piperlonguminine in vitro and in vivo. Inflamm Res 2014; 63 (05) 369-379
126 Francischetti IM, Monteiro RQ, Guimarães JA. Identification of glycyrrhizin as a thrombin inhibitor. Biochem Biophys Res Commun 1997; 235 (01) 259-263
127 Yang H, Antoine DJ, Andersson U, Tracey KJ. The many faces of HMGB1: molecular structure-functional activity in inflammation, apoptosis, and chemotaxis. J Leukoc Biol 2013; 93 (06) 865-873
128 Hudson BI, Lippman ME. Targeting RAGE signaling in inflammatory disease. Annu Rev Med 2018; 69 (01) 349-364
129 Fu Y, Xiang Y, Wang Y. et al. The STAT1/HMGB1/NF-κB pathway in chronic inflammation and kidney injury after cisplatin exposure. Theranostics 2023; 13 (09) 2757-2773
130 Qiao X, Li W, Zheng Z. et al. Inhibition of the HMGB1/RAGE axis protects against cisplatin-induced ototoxicity via suppression of inflammation and oxidative stress. Int J Biol Sci 2024; 20 (02) 784-800
131 Fan J, He K, Zhang Y, Li R, Yi X, Li S. HMGB1: new biomarker and therapeutic target of autoimmune and autoinflammatory skin diseases. Front Immunol 2025; 16: 1569632
132 Wang H, Yu T, An N. et al. Enhancing regulatory T-cell function via inhibition of high mobility group box 1 protein signaling in immune thrombocytopenia. Haematologica 2022; 108 (03) 843-858
133 Zhang Y, Bao S, Zeng J. et al. HMGB1 secretion by resveratrol in NSCLC: a pathway to ferroptosis-mediated platelet activation suppression. Cell Signal 2025; 127: 111607