Suppressing FXR promotes antiviral effects of bile acids via enhancing the interferon transcription  

作　　者：Xue Liang Kunpeng Liu Xin Jia Cuiqin Cheng Meiqi Zhang Lingdong Kong Qiqi Li Zhe Liu Min Li Junliang Li Yao Wang Anlong Xu 

机构地区：[1]School of Life Sciences,Beijing University of Chinese Medicine,Beijing 100029,China [2]Guangxi Key Laboratory of Special Biomedicine,School of Medicine,Guangxi University,Nanning 530004,China [3]Beijing Academy of Traditional Chinese Medicine,Beijing University of Chinese Medicine,Beijing 100029,China [4]Beijing Research Institute of Chinese Medicine,Beijing University of Chinese Medicine,Beijing 100029,China

出　　处：《Acta Pharmaceutica Sinica B》2024年第8期3513-3527,共15页药学学报（英文版）

基　　金：supported by the National Natural Science Foundation(NNSF)of China(Nos.82371774 and 81901613);Beijing Nova Program(20230484342,China);Natural Science Foundation of Guangdong Province(2020A1515011299,China).

摘　　要：Bile acids(BAs)are natural metabolites in mammals and have the potential to function as drugs against viral infection.However,the limited understanding of chenodeoxycholic acid(CDCA)receptors and downstream signaling,along with its lower suppression efficiency in inhibiting virus infection limits its clinical application.In this study,we demonstrate that farnesoid X receptor(FXR),the receptor of CDCA,negatively regulates interferon signaling,thereby contributing to the reduced effectiveness of CDCA against virus replication.FXR deficiency or pharmacological inhibition enhances interferon signaling activation to suppress virus infection.Mechanistically,FXR impairs the DNA binding and transcriptional abilities of activated interferon regulatory factor 3(IRF3)through interaction.Reduced IRF3 transcriptional activity by FXReIRF3 interaction significantly undermines the expression of Interferon Beta 1(IFNB1)and the antiviral response of cells,especially upon the CDCA treatment.In FXR-deficient cells,or when combined with Z-guggulsterone(GUGG)treatment,CDCA exhibits a more potent ability to restrict virus infection.Thus,these findings suggest that FXR serves as a limiting factor for CDCA in inhibiting virus replication,which can be attributed to the“signaling-brake”roles of FXR in interferon signaling.Targeting FXR inhibition represents a promising pharmaceutical strategy for the clinical application of BAs metabolites as antiviral drugs.

关 键 词：Bile acids FXR IRF3 Interferon transcription RNA virus Z-guggulsterone Broad-spectrum antiviral activity Synergistic inhibitory effect 

分 类 号：R730.3[医药卫生—肿瘤]