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The dual function of cGAS-STING signaling axis in liver diseases

Acta Pharmacologica Sinica (2024)Cite this article

Abstract

Numerous liver diseases, such as nonalcoholic fatty liver disease, hepatitis, hepatocellular carcinoma, and hepatic ischemia-reperfusion injury, have been increasingly prevalent, posing significant threats to global health. In recent decades, there has been increasing evidence linking the dysregulation of cyclic-GMP-AMP synthase (cGAS)-stimulator of interferon gene (STING)-related immune signaling to liver disorders. Both hyperactivation and deletion of STING can disrupt the immune microenvironment dysfunction, exacerbating liver disorders. Consequently, there has been a surge in research investigating medical agents or mediators targeting cGAS-STING signaling. Interestingly, therapeutic manipulation of the cGAS-STING pathway has yielded inconsistent and even contradictory effects on different liver diseases due to the distinct physiological characteristics of intrahepatic cells that express and respond to STING. In this review, we comprehensively summarize recent advancements in understanding the dual roles of the STING pathway, highlighting that the benefits of targeting STING signaling depend on the specific types of target cells and stages of liver injury. Additionally, we offer a novel perspective on the suitability of STING agonists and antagonists for clinical assessment. In conclusion, STING signaling remains a highly promising therapeutic target, and the development of STING pathway modulators holds great potential for the treatment of liver diseases.

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Fig. 1: Activation of the cGAS-STING pathway in the intrahepatic and immune cells.
Fig. 2: Activation of cGAS-STING signaling contributes to the progression of several chronic liver disorders.
Fig. 3: Activation of cGAS-STING signaling inhibits the progression of several liver diseases.
Fig. 4: The dual function of cGAS-STING signaling in liver diseases.

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References

  1. Li X, Sun R, Liu R. Natural products in licorice for the therapy of liver diseases: Progress and future opportunities. Pharmacol Res. 2019;144:210–26.

    Article  CAS  PubMed  Google Scholar 

  2. Bram Y, Nguyen DT, Gupta V, Park J, Richardson C, Chandar V, et al. Cell and tissue therapy for the treatment of chronic liver disease. Annu Rev Biomed Eng. 2021;23:517–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Li X, Ge J, Li Y, Cai Y, Zheng Q, Huang N, et al. Integrative lipidomic and transcriptomic study unravels the therapeutic effects of saikosaponins A and D on non-alcoholic fatty liver disease. Acta Pharm Sin B. 2021;11:3527–41.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Choudhary NS, Duseja A. Genetic and epigenetic disease modifiers: non-alcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD). Transl Gastroenterol Hepatol. 2021;6:2.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Voss JD, Dhurandhar NV. Viral infections and obesity. Curr Obes Rep. 2017;6:28–37.

    Article  PubMed  Google Scholar 

  6. Chen H, Lu D, Yang X, Hu Z, He C, Li H, et al. One shoot, two birds: alleviating inflammation caused by ischemia/reperfusion injury to reduce the recurrence of hepatocellular carcinoma. Front Immunol. 2022;13:879552.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Mukai K, Konno H, Akiba T, Uemura T, Waguri S, Kobayashi T, et al. Activation of STING requires palmitoylation at the Golgi. Nat Commun. 2016;7:11932.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Yum S, Li M, Fang Y, Chen ZJ. TBK1 recruitment to STING activates both IRF3 and NF-κB that mediate immune defense against tumors and viral infections. Proc Natl Acad Sci USA. 2021;118:e2100225118.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Luo X, Li H, Ma L, Zhou J, Guo X, Woo SL, et al. Expression of STING is increased in liver tissues from patients with NAFLD and promotes macrophage-mediated hepatic inflammation and fibrosis in mice. Gastroenterology. 2018;155:1971–84.e4.

    Article  CAS  PubMed  Google Scholar 

  10. Ishikawa H, Barber GN. STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling. Nature. 2008;455:674–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Decout A, Katz JD, Venkatraman S, Ablasser A. The cGAS-STING pathway as a therapeutic target in inflammatory diseases. Nat Rev Immunol. 2021;21:548–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Zhang X, Bai XC, Chen ZJ. Structures and mechanisms in the cGAS-STING innate immunity pathway. Immunity. 2020;53:43–53.

    Article  CAS  PubMed  Google Scholar 

  13. Woodward JJ, Iavarone AT, Portnoy DA. c-di-AMP secreted by intracellular Listeria monocytogenes activates a host-type I interferon response. Science. 2010;328:1703–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Burdette DL, Monroe KM, Sotelo-Troha K, Iwig JS, Eckert B, Hyodo M, et al. STING is a direct innate immune sensor of cyclic di-GMP. Nature. 2011;478:515–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Sun L, Wu J, Du F, Chen X, Chen ZJ. Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway. Science. 2013;339:786–91.

    Article  CAS  PubMed  Google Scholar 

  16. Jeltema D, Abbott K, Yan N. STING trafficking as a new dimension of immune signaling. J Exp Med. 2023;220:e20220990.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Zhang C, Shang G, Gui X, Zhang X, Bai XC, Chen ZJ. Structural basis of STING binding with and phosphorylation by TBK1. Nature. 2019;567:394–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Liu S, Cai X, Wu J, Cong Q, Chen X, Li T, et al. Phosphorylation of innate immune adaptor proteins MAVS, STING, and TRIF induces IRF3 activation. Science. 2015;347:aaa2630.

    Article  PubMed  Google Scholar 

  19. Domizio JD, Gulen MF, Saidoune F, Thacker VV, Yatim A, Sharma K, et al. The cGAS-STING pathway drives type I IFN immunopathology in COVID-19. Nature. 2022;603:145–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Oduro PK, Zheng X, Wei J, Yang Y, Wang Y, Zhang H, et al. The cGAS-STING signaling in cardiovascular and metabolic diseases: Future novel target option for pharmacotherapy. Acta Pharm Sin B. 2022;12:50–75.

    Article  CAS  PubMed  Google Scholar 

  21. Chen Q, Sun L, Chen ZJ. Regulation and function of the cGAS-STING pathway of cytosolic DNA sensing. Nat Immunol. 2016;17:1142–9.

    Article  CAS  PubMed  Google Scholar 

  22. Murthy AMV, Robinson N, Kumar S. Crosstalk between cGAS–STING signaling and cell death. Cell Death Differ. 2020;27:2989–3003.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Gui X, Yang H, Li T, Tan X, Shi P, Li M, et al. Autophagy induction via STING trafficking is a primordial function of the cGAS pathway. Nature. 2019;567:262–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Cai Y, Xu B, Zhou F, Wu J, Li S, Zheng Q, et al. Si-Ni-San ameliorates chronic colitis by modulating type I interferons-mediated inflammation. Phytomedicine. 2021;84:153495.

    Article  CAS  PubMed  Google Scholar 

  25. Wu NN, Wang L, Wang L, Xu X, Lopaschuk GD, Zhang Y, et al. Site-specific ubiquitination of VDAC1 restricts its oligomerization and mitochondrial DNA release in liver fibrosis. Exp Mol Med. 2023;55:269–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Huang X, Yao Y, Hou X, Wei L, Rao Y, Su Y, et al. Macrophage SCAP contributes to metaflammation and lean NAFLD by activating STING-NF-kappaB signaling pathway. Cell Mol Gastroenterol Hepatol. 2022;14:1–26.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Li Y, He M, Wang Z, Duan Z, Guo Z, Wang Z, et al. STING signaling activation inhibits HBV replication and attenuates the severity of liver injury and HBV-induced fibrosis. Cell Mol Immunol. 2022;19:92–107.

    Article  PubMed  Google Scholar 

  28. Maher JJ. Macrophages steal STING from the infectious disease playbook to promote nonalcoholic fatty liver disease. Gastroenterology. 2018;155:1687–88.

    Article  PubMed  Google Scholar 

  29. Barreby E, Chen P, Aouadi M. Macrophage functional diversity in NAFLD - more than inflammation. Nat Rev Endocrinol. 2022;18:461–72.

    Article  CAS  PubMed  Google Scholar 

  30. Li Y, Liu R, Wu J, Li X. Self-eating: friend or foe? The emerging role of autophagy in fibrotic diseases. Theranostics. 2020;10:7993–8017.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Li X, Zu Y, Li G, Xiang D, Zhang C, Liu D. Molecular mechanisms of transporter regulation and their impairment in intrahepatic cholestasis. Acta Mater Med. 2022;1:381–91.

    Google Scholar 

  32. Zhang Q, Chen Q, Yan C, Niu C, Zhou J, Liu J, et al. The absence of STING ameliorates non-alcoholic fatty liver disease and reforms gut bacterial community. Front Immunol. 2022;13:931176.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Liu Y, Zhang Y, Zhu H, Shen W, Chen Z, Bai J, et al. Aucubin administration suppresses STING signaling and mitigated high-fat diet-induced atherosclerosis and steatohepatosis in LDL receptor deficient mice. Food Chem Toxicol. 2022;169:113422.

    Article  CAS  PubMed  Google Scholar 

  34. Wang Q, Bu Q, Liu M, Zhang R, Gu J, Li L, et al. XBP1-mediated activation of the STING signalling pathway in macrophages contributes to liver fibrosis progression. JHEP Rep. 2022;4:100555.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Li X, Liu R, Wang Y, Zhu W, Zhao D, Wang X, et al. Cholangiocyte-derived exosomal lncRNA H19 promotes macrophage activation and hepatic inflammation under cholestatic conditions. Cells. 2020;9:190.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Yu Y, Liu Y, An W, Song J, Zhang Y, Zhao X. STING-mediated inflammation in Kupffer cells contributes to progression of nonalcoholic steatohepatitis. J Clin Invest. 2019;129:546–55.

    Article  PubMed  Google Scholar 

  37. Wang XA, Zhang R, She ZG, Zhang XF, Jiang DS, Wang T, et al. Interferon regulatory factor 3 constrains IKKβ/NF-κB signaling to alleviate hepatic steatosis and insulin resistance. Hepatology. 2014;59:870–85.

    Article  CAS  PubMed  Google Scholar 

  38. Cao L, Xu E, Zheng R, Zhangchen Z, Zhong R, Huang F, et al. Traditional Chinese medicine Lingguizhugan decoction ameliorate HFD-induced hepatic-lipid deposition in mice by inhibiting STING-mediated inflammation in macrophages. Chin Med. 2022;17:7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Wang X, Rao H, Zhao J, Wee A, Li X, Fei R, et al. STING expression in monocyte-derived macrophages is associated with the progression of liver inflammation and fibrosis in patients with nonalcoholic fatty liver disease. Lab Invest. 2020;100:542–52.

    Article  CAS  PubMed  Google Scholar 

  40. Qiao JT, Cui C, Qing L, Wang LS, He TY, Yan F, et al. Activation of the STING-IRF3 pathway promotes hepatocyte inflammation, apoptosis and induces metabolic disorders in nonalcoholic fatty liver disease. Metabolism. 2018;81:13–24.

    Article  CAS  PubMed  Google Scholar 

  41. Donne R, Saroul-Ainama M, Cordier P, Hammoutene A, Kabore C, Stadler M, et al. Replication stress triggered by nucleotide pool imbalance drives DNA damage and cGAS-STING pathway activation in NAFLD. Dev Cell. 2022;57:1728–41. e6

    Article  CAS  PubMed  Google Scholar 

  42. Li YN, Su Y. Remdesivir attenuates high fat diet (HFD)-induced NAFLD by regulating hepatocyte dyslipidemia and inflammation via the suppression of STING. Biochem Biophys Res Commun. 2020;526:381–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Cho CS, Park HW, Ho A, Semple IA, Kim B, Jang I, et al. Lipotoxicity induces hepatic protein inclusions through TANK binding kinase 1-mediated p62/sequestosome 1 phosphorylation. Hepatology. 2018;68:1331–46.

    Article  CAS  PubMed  Google Scholar 

  44. Mao Y, Luo W, Zhang L, Wu W, Yuan L, Xu H, et al. STING-IRF3 triggers endothelial inflammation in response to free fatty acid-induced mitochondrial damage in diet-induced obesity. Arterioscler Thromb Vasc Biol. 2017;37:920–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Miyao M, Kotani H, Ishida T, Kawai C, Manabe S, Abiru H, et al. Pivotal role of liver sinusoidal endothelial cells in NAFLD/NASH progression. Lab Invest. 2015;95:1130–44.

    Article  CAS  PubMed  Google Scholar 

  46. Mihm S. Danger-Associated Molecular Patterns (DAMPs): Molecular triggers for sterile inflammation in the liver. Int J Mol Sci. 2018;19:3104.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Petrasek J, Iracheta-Vellve A, Csak T, Satishchandran A, Kodys K, Kurt-Jones EA, et al. STING-IRF3 pathway links endoplasmic reticulum stress with hepatocyte apoptosis in early alcoholic liver disease. Proc Natl Acad Sci USA. 2013;110:16544–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Ma X, Chen A, Melo L, Clemente-Sanchez A, Chao X, Ahmadi AR, et al. Loss of hepatic DRP1 exacerbates alcoholic hepatitis by inducing megamitochondria and mitochondrial maladaptation. Hepatology. 2023;77:159–75.

    Article  PubMed  Google Scholar 

  49. Wang L, You HM, Meng HW, Pan XY, Chen X, Bi YH, et al. STING-mediated inflammation contributes to Gao binge ethanol feeding model. J Cell Physiol. 2022;237:1471–85.

    Article  CAS  PubMed  Google Scholar 

  50. Lin CL, Kao JH. Review article: the prevention of hepatitis B-related hepatocellular carcinoma. Aliment Pharmacol Ther. 2018;48:5–14.

    Article  PubMed  Google Scholar 

  51. Lee SY, Choi YM, Oh SJ, Yang SB, Lee J, Choe WH, et al. rt269I Type of Hepatitis B Virus (HBV) leads to HBV e antigen negative infections and liver disease progression via mitochondrial stress mediated type i interferon production in chronic patients with genotype C infections. Front Immunol. 2019;10:1735.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. He J, Hao R, Liu D, Liu X, Wu S, Guo S, et al. Inhibition of hepatitis B virus replication by activation of the cGAS-STING pathway. J Gen Virol. 2016;97:3368–78.

    Article  CAS  PubMed  Google Scholar 

  53. Verrier ER, Yim SA, Heydmann L, El Saghire H, Bach C, Turon-Lagot V, et al. Hepatitis B virus evasion from cyclic guanosine monophosphate-adenosine monophosphate synthase sensing in human hepatocytes. Hepatology. 2018;68:1695–709.

    Article  CAS  PubMed  Google Scholar 

  54. Chen H, Jiang L, Chen S, Hu Q, Huang Y, Wu Y, et al. HBx inhibits DNA sensing signaling pathway via ubiquitination and autophagy of cGAS. Virol J. 2022;19:55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Wong GLH, Gane E, Lok ASF. How to achieve functional cure of HBV: Stopping NUCs, adding interferon or new drug development? J Hepatol. 2022;76:1249–62.

    Article  CAS  PubMed  Google Scholar 

  56. Tegtmeyer PK, Spanier J, Borst K, Becker J, Riedl A, Hirche C, et al. STING induces early IFN-β in the liver and constrains myeloid cell-mediated dissemination of murine cytomegalovirus. Nat Commun. 2019;10:2830.

    Article  PubMed  PubMed Central  Google Scholar 

  57. Choi YM, Kim H, Lee SA, Lee SY, Kim BJ. A telomerase-derived peptide exerts an anti-hepatitis B virus effect via mitochondrial DNA stress-dependent type I interferon production. Front Immunol. 2020;11:652.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Staff C, Mozaffari F, Frodin JE, Mellstedt H, Liljefors M. Telomerase (GV1001) vaccination together with gemcitabine in advanced pancreatic cancer patients. Int J Oncol. 2014;45:1293–303.

    Article  CAS  PubMed  Google Scholar 

  59. Pimkova Polidarova M, Vanekova L, Brehova P, Dejmek M, Vavrina Z, Birkus G, et al. Synthetic stimulator of interferon genes (STING) agonists induce a cytokine-mediated anti-hepatitis B virus response in nonparenchymal liver cells. ACS Infect Dis. 2023;9:23–32.

    Article  CAS  PubMed  Google Scholar 

  60. Papatheodoridis GV, Lekakis V, Voulgaris T, Lampertico P, Berg T, Chan HLY, et al. Hepatitis B virus reactivation associated with new classes of immunosuppressants and immunomodulators: A systematic review, meta-analysis, and expert opinion. J Hepatol. 2022;77:1670–89.

    Article  CAS  PubMed  Google Scholar 

  61. Lin M, Guo R, Ma C, Zeng D, Su Z. Manganese breaks the immune tolerance of HBs-Ag. Open Forum Infect Dis. 2021;8:ofab028.

    Article  PubMed  PubMed Central  Google Scholar 

  62. Rodriguez-Garcia E, Zabaleta N, Gil-Farina I, Gonzalez-Aparicio M, Echeverz M, Bähre H, et al. AdrA as a potential immunomodulatory candidate for STING-mediated antiviral therapy that required both type I IFN and TNF-α production. J Immunol. 2021;206:376–85.

    Article  CAS  PubMed  Google Scholar 

  63. Lu T, Hu F, Yue H, Yang T, Ma G. The incorporation of cationic property and immunopotentiator in poly (lactic acid) microparticles promoted the immune response against chronic hepatitis B. J Control Rel. 2020;321:576–88.

    Article  CAS  Google Scholar 

  64. Landi A, Law J, Hockman D, Logan M, Crawford K, Chen C, et al. Superior immunogenicity of HCV envelope glycoproteins when adjuvanted with cyclic-di-AMP, a STING activator or archaeosomes. Vaccine. 2017;35:6949–56.

    Article  CAS  PubMed  Google Scholar 

  65. Zhang CH, Cheng Y, Zhang S, Fan J, Gao Q. Changing epidemiology of hepatocellular carcinoma in Asia. Liver Int. 2022;42:2029–41.

    Article  PubMed  Google Scholar 

  66. Pu Z, Liu J, Liu Z, Peng F, Zhu Y, Wang X, et al. STING pathway contributes to the prognosis of hepatocellular carcinoma and identification of prognostic gene signatures correlated to tumor microenvironment. Cancer Cell Int. 2022;22:314.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Chen D, Ren H, Zhao N, Hao J. Expression and prognostic value of DNA sensors in hepatocellular carcinoma. J Leukoc Biol. 2023;114:68–78.

    Article  PubMed  Google Scholar 

  68. Zhang L, Yang Z, Huang W, Wu J. H19 potentiates let-7 family expression through reducing PTBP1 binding to their precursors in cholestasis. Cell Death Dis. 2019;10:168.

    Article  PubMed  PubMed Central  Google Scholar 

  69. Li T, Chen ZJ. The cGAS-cGAMP-STING pathway connects DNA damage to inflammation, senescence, and cancer. J Exp Med. 2018;215:1287–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Li YJ, Zhang C, Martincuks A, Herrmann A, Yu H. STAT proteins in cancer: orchestration of metabolism. Nat Rev Cancer. 2023;23:115–34.

    Article  PubMed  Google Scholar 

  71. Thomsen MK, Skouboe MK, Boularan C, Vernejoul F, Lioux T, Leknes SL, et al. The cGAS-STING pathway is a therapeutic target in a preclinical model of hepatocellular carcinoma. Oncogene. 2020;39:1652–64.

    Article  CAS  PubMed  Google Scholar 

  72. Zhao Q, Wang Y, Zhao B, Chen H, Cai Z, Zheng Y, et al. Neoantigen immunotherapeutic-gel combined with TIM-3 blockade effectively restrains orthotopic hepatocellular carcinoma progression. Nano Lett. 2022;22:2048–58.

    Article  CAS  PubMed  Google Scholar 

  73. Chen X, Tang Q, Wang J, Zhou Y, Li F, Xie Y, et al. A DNA/DMXAA/Metal-organic framework activator of innate immunity for boosting anticancer immunity. Adv Mater. 2023;35:e2210440.

    Article  PubMed  Google Scholar 

  74. Zhan M, Yu X, Zhao W, Peng Y, Peng S, Li J, et al. Extracellular matrix-degrading STING nanoagonists for mild NIR-II photothermal-augmented chemodynamic-immunotherapy. J Nanobiotechnol. 2022;20:23.

    Article  CAS  Google Scholar 

  75. Wang X, Hu R, Song Z, Zhao H, Pan Z, Feng Y, et al. Sorafenib combined with STAT3 knockdown triggers ER stress-induced HCC apoptosis and cGAS-STING-mediated anti-tumor immunity. Cancer Lett. 2022;547:215880.

    Article  CAS  PubMed  Google Scholar 

  76. Wang S, Wu Q, Chen T, Su R, Pan C, Qian J, et al. Blocking CD47 promotes antitumour immunity through CD103+ dendritic cell-NK cell axis in murine hepatocellular carcinoma model. J Hepatol. 2022;77:467–78.

    Article  CAS  PubMed  Google Scholar 

  77. Zhang Y, Zhai Q, Feng X, Chen D, Lu Y, Hu J, et al. Cancer cell-intrinsic STING is associated with CD8+ T-cell infiltration and might serve as a potential immunotherapeutic target in hepatocellular carcinoma. Clin Transl Oncol. 2021;23:1314–24.

    Article  CAS  PubMed  Google Scholar 

  78. Sheng H, Huang Y, Xiao Y, Zhu Z, Shen M, Zhou P, et al. ATR inhibitor AZD6738 enhances the antitumor activity of radiotherapy and immune checkpoint inhibitors by potentiating the tumor immune microenvironment in hepatocellular carcinoma. J Immunother Cancer. 2020;8:e000340.

    Article  PubMed  PubMed Central  Google Scholar 

  79. Lasarte-Cia A, Lozano T, Cano D, Martín-Otal C, Navarro F, Gorraiz M, et al. Intratumoral STING agonist injection combined with irreversible electroporation delays tumor growth in a model of Hepatocarcinoma. Biomed Res Int. 2021;2021:8852233.

    Article  PubMed  PubMed Central  Google Scholar 

  80. Li Q, Chen Q, Yang X, Zhang Y, Lv L, Zhang Z, et al. Cocktail strategy based on a dual function nanoparticle and immune activator for effective tumor suppressive. J Nanobiotechnol. 2022;20:84.

    Article  CAS  Google Scholar 

  81. Yum S, Li M, Chen ZJ. Old dogs, new trick: classic cancer therapies activate cGAS. Cell Res. 2020;30:639–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Li K, Gong Y, Qiu D, Tang H, Zhang J, Yuan Z, et al. Hyperbaric oxygen facilitates teniposide-induced cGAS-STING activation to enhance the antitumor efficacy of PD-1 antibody in HCC. J Immunother Cancer. 2022;10:e004006.

    Article  PubMed  PubMed Central  Google Scholar 

  83. Huang Y, Sheng H, Xiao Y, Hu W, Zhang Z, Chen Y, et al. Wnt/β-catenin inhibitor ICG-001 enhances the antitumor efficacy of radiotherapy by increasing radiation-induced DNA damage and improving tumor immune microenvironment in hepatocellular carcinoma. Radiother Oncol. 2021;162:34–44.

    Article  CAS  PubMed  Google Scholar 

  84. Du SS, Chen GW, Yang P, Chen YX, Hu Y, Zhao QQ, et al. Radiation therapy promotes hepatocellular carcinoma immune cloaking via PD-L1 upregulation induced by cGAS-STING activation. Int J Radiat Oncol Biol Phys. 2022;112:1243–55.

    Article  PubMed  Google Scholar 

  85. Xu C, Cheng S, Chen K, Song Q, Liu C, Fan C, et al. Sex differences in genomic features of Hepatitis B-associated hepatocellular carcinoma with distinct antitumor immunity. Cell Mol Gastroenterol Hepatol. 2023;15:327–54.

    Article  CAS  PubMed  Google Scholar 

  86. Salem R, Lewandowski RJ, Mulcahy MF, Riaz A, Ryu RK, Ibrahim S, et al. Radioembolization for hepatocellular carcinoma using Yttrium-90 microspheres: a comprehensive report of long-term outcomes. Gastroenterology. 2010;138:52–64.

    Article  CAS  PubMed  Google Scholar 

  87. Li Z, Zhang Y, Hong W, Wang B, Chen Y, Yang P, et al. Gut microbiota modulate radiotherapy-associated antitumor immune responses against hepatocellular carcinoma Via STING signaling. Gut Microbes. 2022;14:2119055.

    Article  PubMed  PubMed Central  Google Scholar 

  88. Du S, Chen G, Yuan B, Hu Y, Yang P, Chen Y, et al. DNA sensing and associated type 1 interferon signaling contributes to progression of radiation-induced liver injury. Cell Mol Immunol. 2021;18:1718–28.

    Article  CAS  PubMed  Google Scholar 

  89. Ma H, Kang Z, Foo TK, Shen Z, Xia B. Disrupted BRCA1-PALB2 interaction induces tumor immunosuppression and T-lymphocyte infiltration in HCC through cGAS-STING pathway. Hepatology. 2022;77:33–47.

    Article  PubMed  Google Scholar 

  90. Coppé JP, Patil CK, Rodier F, Sun Y, Muñoz DP, Goldstein J, et al. Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol. 2008;6:2853–68.

    Article  PubMed  Google Scholar 

  91. Takahashi A, Loo TM, Okada R, Kamachi F, Watanabe Y, Wakita M, et al. Downregulation of cytoplasmic DNases is implicated in cytoplasmic DNA accumulation and SASP in senescent cells. Nat Commun. 2018;9:1249.

    Article  PubMed  PubMed Central  Google Scholar 

  92. Chan CY, Chiu DK, Yuen VW, Law CT, Wong BP, Thu KL, et al. CFI-402257, a TTK inhibitor, effectively suppresses hepatocellular carcinoma. Proc Natl Acad Sci USA. 2022;119:e2119514119.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Garrido A, Djouder N. Cirrhosis: A questioned risk factor for hepatocellular carcinoma. Trends Cancer. 2021;7:29–36.

    Article  CAS  PubMed  Google Scholar 

  94. Yagi S, Hirata M, Miyachi Y, Uemoto S. Liver regeneration after hepatectomy and partial liver transplantation. Int J Mol Sci. 2020;21:8414.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Michalopoulos GK, Bhushan B. Liver regeneration: biological and pathological mechanisms and implications. Nat Rev Gastroenterol Hepatol. 2021;18:40–55.

    Article  PubMed  Google Scholar 

  96. Schulze S, Stoss C, Lu M, Wang B, Laschinger M, Steiger K, et al. Cytosolic nucleic acid sensors of the innate immune system promote liver regeneration after partial hepatectomy. Sci Rep. 2018;8:12271.

    Article  PubMed  PubMed Central  Google Scholar 

  97. Jiao J, Jiang Y, Qian Y, Liu G, Xu M, Wang F, et al. Expression of STING is increased in monocyte-derived macrophages and contributes to liver inflammation in hepatic ischemia-reperfusion injury. Am J Pathol. 2022;192:1745–62.

    Article  CAS  PubMed  Google Scholar 

  98. Shen A, Zheng D, Luo Y, Mou T, Chen Q, Huang Z, et al. MicroRNA-24-3p alleviates hepatic ischemia and reperfusion injury in mice through the repression of STING signaling. Biochem Biophys Res Commun. 2020;522:47–52.

    Article  CAS  PubMed  Google Scholar 

  99. Wu XY, Chen YJ, Liu CA, Gong JH, Xu XS. STING induces liver ischemia-reperfusion injury by promoting calcium-dependent caspase 1-GSDMD processing in macrophages. Oxid Med Cell Longev. 2022;2022:8123157.

    PubMed  PubMed Central  Google Scholar 

  100. Zhan Y, Xu D, Tian Y, Qu X, Sheng M, Lin Y, et al. Novel role of macrophage TXNIP-mediated CYLD-NRF2-OASL1 axis in stress-induced liver inflammation and cell death. JHEP Rep. 2022;4:100532.

    Article  PubMed  PubMed Central  Google Scholar 

  101. Xu J, Wu D, Zhou S, Hu H, Li F, Guan Z, et al. MLKL deficiency attenuated hepatocyte oxidative DNA damage by activating mitophagy to suppress macrophage cGAS-STING signaling during liver ischemia and reperfusion injury. Cell Death Discov. 2023;9:58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Hu H, Cheng X, Li F, Guan Z, Xu J, Wu D, et al. Defective efferocytosis by aged macrophages promotes STING signaling mediated inflammatory liver injury. Cell Death Discov. 2023;9:236.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Lei Z, Deng M, Yi Z, Sun Q, Shapiro RA, Xu H, et al. cGAS-mediated autophagy protects the liver from ischemia-reperfusion injury independently of STING. Am J Physiol Gastrointest Liver Physiol. 2018;314:G655–g67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Liang L, Shen Y, Hu Y, Liu H, Cao J. cGAS exacerbates Schistosoma japonicum infection in a STING-type I IFN-dependent and independent manner. PLoS Pathog. 2022;18:e1010233.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Souza C, Sanches RCO, Assis NRG, Marinho FV, Mambelli FS, Morais SB, et al. The role of the adaptor molecule STING during Schistosoma mansoni infection. Sci Rep. 2020;10:7901.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Zhang Q, Wei J, Liu Z, Huang X, Sun M, Lai W, et al. STING signaling sensing of DRP1-dependent mtDNA release in kupffer cells contributes to lipopolysaccharide-induced liver injury in mice. Redox Biol. 2022;54:102367.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Wu Y, Hao C, Han G, Liu X, Xu C, Zou Z, et al. SS-31 ameliorates hepatic injury in rats subjected to severe burns plus delayed resuscitation via inhibiting the mtDNA/STING pathway in Kupffer cells. Biochem Biophys Res Commun. 2021;546:138–44.

    Article  CAS  PubMed  Google Scholar 

  108. Li Y, Yu P, Fu W, Wang S, Zhao W, Ma Y, et al. Ginsenoside Rd inhibited ferroptosis to alleviate CCl4-induced acute liver injury in mice via cGAS/STING pathway. Am J Chin Med. 2023;51:91–105.

    Article  CAS  PubMed  Google Scholar 

  109. Li XJ, Jiang ZZ, Zhang LY. Triptolide: progress on research in pharmacodynamics and toxicology. J Ethnopharmacol. 2014;155:67–79.

    Article  CAS  PubMed  Google Scholar 

  110. Chen X, Yu Z, Nong C, Xue R, Zhang M, Zhang Y, et al. Activation of cDCs and iNKT cells contributes to triptolide-induced hepatotoxicity via STING signaling pathway and endoplasmic reticulum stress. Cell Biol Toxicol. 2022;39:1753–72.

    Article  PubMed  Google Scholar 

  111. Shen P, Han L, Chen G, Cheng Z, Liu Q. Emodin attenuates acetaminophen-induced hepatotoxicity via the cGAS-STING pathway. Inflammation. 2022;45:74–87.

    Article  CAS  PubMed  Google Scholar 

  112. Dong K, Zhang M, Liu Y, Gao X, Wu X, Shi D, et al. Pterostilbene-loaded Soluplus/Poloxamer 188 mixed micelles for protection against acetaminophen-induced acute liver injury. Mol Pharmacol. 2023;20:1189–201.

    Article  CAS  Google Scholar 

  113. Ishikawa T, Tamura E, Kasahara M, Uchida H, Higuchi M, Kobayashi H, et al. Severe liver disorder following liver transplantation in STING-associated vasculopathy with onset in infancy. J Clin Immunol. 2021;41:967–74.

    Article  CAS  PubMed  Google Scholar 

  114. Llovet JM, Kelley RK, Villanueva A, Singal AG, Pikarsky E, Roayaie S, et al. Hepatocellular carcinoma. Nat Rev Dis Prim. 2021;7:6.

    Article  PubMed  Google Scholar 

  115. Ablasser A, Schmid-Burgk JL, Hemmerling I, Horvath GL, Schmidt T, Latz E, et al. Cell intrinsic immunity spreads to bystander cells via the intercellular transfer of cGAMP. Nature. 2013;503:530–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Chen Q, Boire A, Jin X, Valiente M, Er EE, Lopez-Soto A, et al. Carcinoma-astrocyte gap junctions promote brain metastasis by cGAMP transfer. Nature. 2016;533:493–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Schadt L, Sparano C, Schweiger NA, Silina K, Cecconi V, Lucchiari G, et al. Cancer-cell-intrinsic cGAS expression mediates tumor immunogenicity. Cell Rep. 2019;29:1236–48.e7.

    Article  CAS  PubMed  Google Scholar 

  118. Zhang H, You QD, Xu XL. Targeting Stimulator of Interferon Genes (STING): A medicinal chemistry perspective. J Med Chem. 2020;63:3785–816.

    Article  CAS  PubMed  Google Scholar 

  119. Meric-Bernstam F, Sweis RF, Hodi FS, Messersmith WA, Andtbacka RHI, Ingham M, et al. Phase I dose-escalation trial of MIW815 (ADU-S100), an intratumoral STING agonist, in patients with advanced/metastatic solid tumors or lymphomas. Clin Cancer Res. 2022;28:677–88.

    Article  CAS  PubMed  Google Scholar 

  120. Mullard A. Biotechs step on cGAS for autoimmune diseases. Nat Rev Drug Discov. 2023;22:939–41.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by the Beijing Nova Program of Science & Technology (Grant No. Z211100002121167 to RPL); the Fundamental Research Funds for the Central Universities to XJYL; the Fundamental Research Funds for the Central Universities (Grant No. 2023-JYB-XJSJJ009 to JRQ); the Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine (Grant No. ZYYCXTD-C-202006 to XJYL); Beijing Municipal Science & Technology Commission (Grant No. 7212174 to XL); National Natural Science Foundation of China (Grant No. 82004045 and 82274186 to XJYL); National Key Research and Development Program on Modernization of Traditional Chinese Medicine (No. 613 2022YFC3502100 to XJYL) and the National High-Level Talents Special Support Program to XJYL. Thanks to Li Han for providing partial information for this article.

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  1. These authors contributed equally: Xiao-jiao-yang Li, Jiao-rong Qu

Authors and Affiliations

  1. School of Life Sciences, Beijing University of Chinese Medicine, 11 Bei San Huan Dong Lu, Beijing, 100029, China

    Xiao-jiao-yang Li, Jiao-rong Qu & Yin-hao Zhang

  2. School of Chinese Materia Medica, Beijing University of Chinese Medicine, 11 Bei San Huan Dong Lu, Beijing, 100029, China

    Run-ping Liu

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XJYL: Resources, Supervision, Writing- Review & Editing. JRQ: Investigation, Formal analysis, Writing- Original Draft. YHZ: Visualization. RPL: Resources, Supervision, Writing- Review & Editing.

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Correspondence to Xiao-jiao-yang Li or Run-ping Liu.

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Li, Xjy., Qu, Jr., Zhang, Yh. et al. The dual function of cGAS-STING signaling axis in liver diseases. Acta Pharmacol Sin (2024). https://doi.org/10.1038/s41401-023-01220-5

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