Oroxylin A regulates cGAS DNA hypermethylation induced by methionine metabolism to promote HSC senescence. (January 2023)

• Record Type: Journal Article
• Authors: Zhao, Danli; Gao, Yuanyuan; Su, Ying; Zhou, Yuanyuan; Yang, Ting; Li, Yang; Wang, Yingqian; Sun, Ying; Chen, Li; Zhang, Feng; Zhang, Zili; Wang, Feixia; Shao, Jiangjuan; Zheng, Shizhong
• Is Part Of: Pharmacological research. Volume 187(2023)
• Publication Date: 2023-01
• Subjects: Hepatic fibrosis -- Cell senescence -- cGAS-STING -- DNA methylation -- Methionine cyclic metabolism -- Oroxylin A; cGAS cyclic guanosine monophosphate-adenosine monophosphate synthase -- STING stimulator of interferon genes -- p-TBK1 phospho-TANK Binding Kinase 1 -- p-IRF3 phospho-Interferon regulatory Factor 3 -- cGAMP Cyclic GMP-AMP -- IFN-β Interferon-β -- cxcl9 Chemokine(C-X-C Motif) Ligand 9 -- cxcl10 Chemokine (C-X-C Motif) Ligand10 -- cxcl11 Chemokine (C-X-C Motif) Ligand 11 -- ISG15 Interferon stimulated gene 15 -- IL-6 Interleukin-6 -- IL-8 Interleukin-8 -- IL-1β Interleukin-1β -- TERT Telomerase reverse transcriptase -- TRF1 Telomeric repeat-binding factor 1 -- TRF2 Telomeric repeat-binding factor 2 -- dsDNA double-stranded DNA -- poly I:C Polyinosinic acid-polycytidylic acid -- 5-aza Decitabine -- DNMT3A DNA methyltransferase 3A -- MAT2A Methionine adenosyl transferase II Alpha -- SAM S-adenosyl methionine -- SAH S-adenosyl homocysteine -- TBK1 TANK Binding Kinase 1 -- IRF3 Interferon regulatory Factor 3; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2022.106590
• Languages: English
• ISSNs: 1043-6618

Abstract

Abstract: Relevant studies have recognized the important role of hepatic stellate cell (HSC) senescence in anti-liver fibrosis. Cellular senescence is believed to be regulated by the cGAS-STING signaling pathway. However, underlying exact mechanisms of cGAS-STING pathway in hepatic stellate cell senescence are still unclear. Here, we found that Oroxylin A could promote senescence in HSC by activating the cGAS-STING pathway. Moreover, activation of the cGAS-STING pathway was dependent on DNMT3A downregulation, which suppressed cGAS gene DNA methylation. Interestingly, the attenuation of DNMT activity relied on the reduction of methyl donor SAM level. Noteworthy, the downregulation of SAM levels implied the imbalance of methionine cycle metabolism, and MAT2A was considered to be an important regulatory enzyme in metabolic processes. In vivo experiments also indicated that Oroxylin A induced senescence of HSCs in mice with liver fibrosis, and DNMT3A overexpression partly offset this effect. In conclusion, we discovered that Oroxylin A prevented the methylation of the cGAS gene by preventing the production of methionine metabolites, which promoted the senescence of HSCs. This finding offers a fresh hypothesis for further research into the anti-liver fibrosis mechanism of natural medicines. Graphical Abstract: ga1