LPS/D-gal诱导急性肝衰竭小鼠肝组织cGAS-STING通路蛋白表达及其肝素保护作用研究

doi:10.3969/j.issn.1672-5069.2026.05.003

Abstract

Abstract: Objective This experiment aimed to investigate the effects of extracellular histones and heparin intervention on cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway in mice with lipopolysaccharide (LPS)/D-galactosamine(D-gal)-induced acute liver failure (ALF). Methods Forty mice were randomly divided into control, model, extracellular histones -intervened and extracellular histones/ heparin-intervened groups , with 10 mice in each. ALF model was established in mice by using LPS/D-gal intraperitoneal injection. Hepatic protein expression of cGAS and STING were detected by Western blotting, and hepatic homogenate tumor necrosis factor-α(TNF-α),interleukin ( IL)-1β and IL-18 levers were measured by using ELISA. Results Histopathological examination of liver tissue confirmed the successful establishment of ALF model in mice, liver tissue damage in the extracellular histones-intervened group was similar to that in the model group, whereas it was significantly milder in the extracellular histones/heparin-intervened group; serum ALT and AST levels in the model group and extracellular histones group were significantly higher than those in the control group (P<0.05), while they decreased greatly in the extracellular histones/heparin-intervened group (P<0.05); hepatic cGAS and STING expression, and liver tissue homogenate TNF-α, IL-1β and IL-18 levels in the model group and extracellular histones group were significantly intensified and elevated as compared to in the control group (P<0.05), however,the expression or levels of these molecules in the extracellular histones/heparin group were significantly weaken or reduced compared to both in the model group or in the extracellular histones group (P<0.05). Conclusion Extracellular histones could induce ALF, probably by activating the cGAS-STING pathway,while heparin might inhibit extracellular histone expression and block the cGAS-STING pathway and thereby exerting a protective effect.

Key words: Acute liver failure, Extracellular histone, Heparin, cyclic GMP-AMP synthase- stimulator of interferon genes, Mice

Luo Ke, Zhang Danmei, Guo Jin, et al. Hepatic tissue of cGAS-STING pathway proteins and heparin’s protective roles in LPS/D-gal-induced acute liver failure in mice[J]. Journal of Practical Hepatology, 2026, 29(5): 649-652.

References

[1] Shingina A, Mukhtar N, Wakim-Fleming J, et al. Acute liver failure guidelines. Am J Gastroenterol,2023,118(7):1128-1153.
[2] Murao A, Aziz M, Wang H C, et al. Release mechanisms of major DAMPs. Apoptosis,2021,26(3-4):152-162.
[3] Richards C M, McRae S A, Ranger A L, et al. Extracellular histones as damage-associated molecular patterns in neuroinflammatory responses. Rev Neurosci,2023,34(5):533-558.
[4] Onishi A, St Ange K, Dordick J S, et al. Heparin and anticoagulation. Front Bioscience-Landmark,2016,21:1372-1392.
[5] Mulloy B, Hogwood J, Gray E, et al. Pharmacology of heparin and related drugs. Pharmacol Rev,2016,68(1):76-141.
[6] Hogwood J, Mulloy B, Lever R, et al. Pharmacology of heparin and related drugs: An Update. Pharmacol Rev,2023,75(2):328-379.
[7] Zhang Y L, Zhao Z M, Guan L, et al. N-acetyl-heparin attenuates acute lung injury caused by acid aspiration mainly by antagonizing histones in mice. PLoS One,2014,9(5):e97074.
[8] Nagano F, Mizuno T, Mizumoto S, et al. Chondroitin sulfate protects vascular endothelial cells from toxicities of extracellular histones. Eur J Pharmacol,2018,826:48-55.
[9] Zhang Z Y, Zhang C G. Regulation of cGAS-STING signalling and its diversity of cellular outcomes. Nat Rev Immunol,2025,25(6):425-444.
[10] Decout A, Katz J D, Venkatraman S, et al. The cGAS-STING pathway as a therapeutic target in inflammatory diseases. Nat Rev Immunol,2021,21(9):548-569.
[11] Maiwall R, Kulkarni A, Arab J P, et al. Acute liver failure. Lancet,2024,404(10454):789-802.
[12] Shvedunova M, Akhtar A. Modulation of cellular processes by histone and non-histone protein acetylation. Nat Rev Mol Cell Biol,2022,23(5):329-349.
[13] Sabari B R, Zhang D, Allis C D, et al. Metabolic regulation of gene expression through histone acylations. Nat Rev Mol Cell Biol,2017,18(2):90-101.
[14] Tayal A, Sankar J. Extracellular histones-friend or foe?. Indian J Pediatr,2022,89(10):966-967.
[15] Silk E, Zhao H L, Weng H, et al. The role of extracellular histone in organ injury. Cell Death Dis,2017,8(5):e2812.
[16] Zhang D M, Guo J, Wang Y K, et al. Extracellular histone H3 induces macrophage inflammation in acute liver failure via HDAC2 activation and PKM2 subcellular relocalization. Cell Signal,2025,135:112003.
[17] Dinarvand P, Hassanian S M, Qureshi S H, et al. Polyphosphate amplifies proinflammatory responses of nuclear proteins through interaction with receptor for advanced glycation end products and P2Y1 purinergic receptor. Blood,2014,123(6):935-945.
[18] Thålin C, Hisada Y, LundstrÏm S, et al. Neutrophil extracellular traps villains and targets in arterial, venous, and cancer-associated thrombosis. Arterioscl Throm Vas Biol,2019,39(9):1724-1738.
[19] Mizuno T, Yoshioka K, Mizuno M, et al. Complement component 5 promotes lethal thrombosis. Sci Rep,2017,7:42714.
[20] Liu R X, Huang H, Hou D Y, et al. Unfractionated heparin enhances sepsis prognosis through inhibiting Drp1-mediated mitochondrial quality imbalance. Adv Sci,2024,11(46):e2407705.
[21] Wang A M, Ren J, Wang C P, et al. Heparin prevents intracellular hyaluronan synthesis and autophagy responses in hyperglycemic dividing mesangial cells and activates synthesis of an extensive extracellular monocyte-adhesive hyaluronan matrix after completing cell division. J Biol Chem,2014,289(13):9418-9429.
[22] Chen C, Xu P L. Cellular functions of cGAS-STING signaling. Trends Cell Biol,2023,33(8):630-648.
[23] Zhang X Q, He B, Lu J, et al. The crucial roles and research advances of cGAS-STING pathway in liver diseases. Ann Med,2024,56(1):2394588.
[24] Chen B J, Rao X Y, Wang X Y, et al. cGAS-STING signaling pathway and liver disease: From basic research to clinical practice. Front Pharmacol,2021,12:719644.
[25] Zhang Z M, Yang J R, Zhou Q L, et al. The role and mechanism of the cGAS-STING pathway-mediated ROS in apoptosis and ferroptosis induced by manganese exposure. Redox Biol,2025,85:103761.
[26] Xu Y F, Chen C, Liao Z Y, et al. cGAS-STING signaling in cell death: Mechanisms of action and implications in pathologies. Eur J Immunol,2023,53(9):e2350386.

Hepatic tissue of cGAS-STING pathway proteins and heparin’s protective roles in LPS/D-gal-induced acute liver failure in mice

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