Selective bromodomain and extra-terminal bromodomain inhibitor inactivates macrophages and hepatic stellate cells to inhibit liver inflammation and fibrosis

References

• Bai P, Ye H, Xie M, et al. A synthetic biology-based device prevents liver injury in mice. J Hepatol. 2016;65:84–94.
   PubMed Web of Science ®Google Scholar
• Macpherson AJ, Heikenwalder M, Ganal-Vonarburg SC. The liver at the nexus of host-microbial interactions. Cell Host Microbe. 2016;20:561–571.
   PubMed Web of Science ®Google Scholar
• Robinson MW, Harmon C, O’Farrelly C. Liver immunology and its role in inflammation and homeostasis. Cell Mol Immunol. 2016;13:267–276.
   PubMed Web of Science ®Google Scholar
• Duarte S, Baber J, Fujii T, et al. Matrix metalloproteinases in liver injury, repair and fibrosis. Matrix Biol. 2015;44-46:147–156.
   PubMed Web of Science ®Google Scholar
• Pellicoro A, Ramachandran P, Iredale JP, et al. Liver fibrosis and repair: immune regulation of wound healing in a solid organ. Nat Rev Immunol. 2014;14:181–194.
   PubMed Web of Science ®Google Scholar
• Kisseleva T, Brenner D. Molecular and cellular mechanisms of liver fibrosis and its regression. Nat Rev Gastroenterol Hepatol. 2021;18:151–166.
   PubMed Web of Science ®Google Scholar
• Tsuchida T, Friedman SL. Mechanisms of hepatic stellate cell activation. Nat Rev Gastroenterol Hepatol. 2017;14:397–411.
   PubMed Web of Science ®Google Scholar
• Cordero-Espinoza L, Huch M. The balancing act of the liver: tissue regeneration versus fibrosis. J Clin Invest. 2018;128:85–96.
   PubMed Web of Science ®Google Scholar
• Ruart M, Chavarria L, Campreciós G, et al. Impaired endothelial autophagy promotes liver fibrosis by aggravating the oxidative stress response during acute liver injury. J Hepatol. 2019;70:458–469.
   PubMed Web of Science ®Google Scholar
• Schuppan D, Kim YO. Evolving therapies for liver fibrosis. J Clin Invest. 2013;123:1887–1901.
   PubMed Web of Science ®Google Scholar
• Tacke F, Zimmermann HW. Macrophage heterogeneity in liver injury and fibrosis. J Hepatol. 2014;60:1090–1096.
   PubMed Web of Science ®Google Scholar
• Hernandez-Gea V, Friedman SL. Pathogenesis of liver fibrosis. Annu Rev Pathol. 2011;6:425–456.
   PubMed Web of Science ®Google Scholar
• Tough DF, Tak PP, Tarakhovsky A, et al. Epigenetic drug discovery: breaking through the immune barrier. Nat Rev Drug Discov. 2016;15:835–853.
   PubMed Web of Science ®Google Scholar
• Cochran AG, Conery AR, Sims RJ. Bromodomains: a new target class for drug development. Nat Rev Drug Discov. 2019;18:609–628. 3rd.
   PubMed Web of Science ®Google Scholar
• Petretich M, Demont EH, Grandi P. Domain-selective targeting of BET proteins in cancer and immunological diseases. Curr Opin Chem Biol. 2020;57:184–193.
   PubMed Web of Science ®Google Scholar
• Medzhitov R, Horng T. Transcriptional control of the inflammatory response. Nat Rev Immunol. 2009;9(10):692–703.
   PubMed Web of Science ®Google Scholar
• Wells AD. New insights into the molecular basis of T cell anergy: anergy factors, avoidance sensors, and epigenetic imprinting. J Immunol. 2009;182:7331–7341.
   PubMed Web of Science ®Google Scholar
• Filippakopoulos P, Picaud S, Mangos M, et al. Histone recognition and large-scale structural analysis of the human bromodomain family. Cell. 2012;149:214–231.
   PubMed Web of Science ®Google Scholar
• Jang MK, Mochizuki K, Zhou M, et al. The bromodomain protein Brd4 is a positive regulatory component of P-TEFb and stimulates RNA polymerase II-dependent transcription. Mol Cell. 2005;19:523–534.
   PubMed Web of Science ®Google Scholar
• Shi J, Vakoc CR. The mechanisms behind the therapeutic activity of BET bromodomain inhibition. Mol Cell. 2014;54:728–736.
   PubMed Web of Science ®Google Scholar
• Kulikowski E, Rakai BD, Wong NCW. Inhibitors of bromodomain and extra-terminal proteins for treating multiple human diseases. Med Res Rev. 2021;41:223–245.
   PubMed Web of Science ®Google Scholar
• Yin M, Guo Y, Hu R, et al. Potent BRD4 inhibitor suppresses cancer cell-macrophage interaction. Nat Commun. 2020;11(1):1833.
   PubMed Web of Science ®Google Scholar
• Duan Q, McMahon S, Anand P, et al. BET bromodomain inhibition suppresses innate inflammatory and profibrotic transcriptional networks in heart failure. Sci Transl Med. 2017;9. DOI:10.1126/scitranslmed.aah5084.
   PubMed Web of Science ®Google Scholar
• Gilan O, Rioja I, Knezevic K, et al. Selective targeting of BD1 and BD2 of the BET proteins in cancer and immunoinflammation. Science. 2020;368:387–394.
   PubMed Web of Science ®Google Scholar
• Stratton MS, Bagchi RA, Felisbino MB, et al. dynamic chromatin targeting of brd4 stimulates cardiac fibroblast activation. Circ Res. 2019;125:662–677.
   PubMed Web of Science ®Google Scholar
• Ding N, Hah N, Yu RT, et al. BRD4 is a novel therapeutic target for liver fibrosis. Proc Natl Acad Sci U S A. 2015;112:15713–15718.
   PubMed Web of Science ®Google Scholar
• Duan Q, Wu P, Liu Z, et al. BET bromodomain inhibition suppresses adipogenesis in mice. Endocrine. 2020;67:264–267.
   PubMed Web of Science ®Google Scholar
• Wilflingseder J, Willi M, Lee HK, et al. Enhancer and super-enhancer dynamics in repair after ischemic acute kidney injury. Nat Commun. 2020;11:3383.
   PubMed Web of Science ®Google Scholar
• Borck PC, Guo L-W, Plutzky J. BET epigenetic reader proteins in cardiovascular transcriptional programs. Circ Res. 2020;126:1190–1208.
   PubMed Web of Science ®Google Scholar
• Kim SY, Zhang X, Schiattarella GG, et al. Epigenetic reader BRD4 (bromodomain-containing protein 4) governs nucleus-encoded mitochondrial transcriptome to regulate cardiac function. Circulation. 2020;142:2356–2370.
   PubMed Web of Science ®Google Scholar
• Shi C, Ye Z, Han J, et al. BRD4 as a therapeutic target for non functioning and growth hormone pituitary adenoma. Neuro Oncol. 2020;22:1114–1125.
   PubMed Web of Science ®Google Scholar
• Latif A-L, Newcombe A, Li S, et al. BRD4-mediated repression of p53 is a target for combination therapy in AML. Nat Commun. 2021;12:241.
   PubMed Web of Science ®Google Scholar
• Shu S, Lin CY, He HH, et al. Response and resistance to BET bromodomain inhibitors in triple-negative breast cancer. Nature. 2016;529:413–417.
   PubMed Web of Science ®Google Scholar
• S-Y W, Lee C-F, Lai H-T, et al. Opposing Functions of BRD4 Isoforms in Breast Cancer. Mol Cell. 2020;78(6):1114–1132.
   PubMed Web of Science ®Google Scholar
• Yan Y, Ma J, Wang D, et al. The novel BET-CBP/p300 dual inhibitor NEO2734 is active in SPOP mutant and wild-type prostate cancer. EMBO Mol Med. 2019;11:e10659.
   PubMed Web of Science ®Google Scholar
• Li Z, Xiao S, Yang Y, et al. Discovery of 8-Methyl-pyrrolo[1,2-]pyrazin-1(2)-one derivatives as highly potent and selective bromodomain and extra-terminal (BET) bromodomain inhibitors. J Med Chem. 2020;63:3956–3975.
   PubMed Web of Science ®Google Scholar
• Turnbull AP, Ioannidis S, Krajewski WW, et al. Molecular basis of USP7 inhibition by selective small-molecule inhibitors. Nature. 2017;550(7677):481–486.
   PubMed Web of Science ®Google Scholar
• Peng J, Li J, Huang J, et al. p300/CBP inhibitor A-485 alleviates acute liver injury by regulating macrophage activation and polarization. Theranost-ics. 2019;9:8344–8361.
   PubMed Web of Science ®Google Scholar
• Lan T, Li C, Yang G, et al. Sphingosine kinase 1 promotes liver fibrosis by preventing miR-19b-3p-mediated inhibition of CCR2. Hepatology. 2018;68:1070–1086.
   PubMed Web of Science ®Google Scholar
• Sakaida I, Terai S, Yamamoto N, et al. Transplantation of bone marrow cells reduces CCl4-induced liver fibrosis in mice. Hepatology. 2004;40:1304–1311.
   PubMed Web of Science ®Google Scholar
• Dobin A, Davis CA, Schlesinger F, et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics. 2013;29:15–21.
   PubMed Web of Science ®Google Scholar
• Liao Y, Smyth GK, Shi W. featureCounts: an efficient general purpose program for assigning sequence reads to genomic features. Bioinformatics. 2014;30:923–930.
   PubMed Web of Science ®Google Scholar
• Robinson MD, McCarthy DJ, Smyth GK. edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics. 2010;26:139–140.
   PubMed Web of Science ®Google Scholar
• Yu G, Wang LG, Han Y, et al. clusterProfiler: an R package for comparing biological themes among gene clusters. Omics. 2012;16:284–287.
   PubMed Web of Science ®Google Scholar
• Subramanian A, Tamayo P, Mootha VK, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A. 2005;102:15545–15550.
   PubMed Web of Science ®Google Scholar
• Szklarczyk D, Gable AL, Lyon D, et al. STRING v11: protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. Nucleic Acids Res. 2019;47:D607–d13.
   PubMed Web of Science ®Google Scholar
• Shannon P, Markiel A, Ozier O, et al. Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res. 2003;13:2498–2504.
   PubMed Web of Science ®Google Scholar
• Luedde T, Schwabe RF. NF-κB in the liver–linking injury, fibrosis and hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol. 2011;8:108–118.
   PubMed Web of Science ®Google Scholar
• Movita D, Kreefft K, Biesta P, et al. Kupffer cells express a unique combination of phenotypic and functional characteristics compared with splenic and peritoneal macrophages. J Leukoc Biol. 2012;92:723–733.
   PubMed Web of Science ®Google Scholar
• Kawai T, Akira S. The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat Immunol. 2010;11:373–384.
   PubMed Web of Science ®Google Scholar
• Tacke F. Targeting hepatic macrophages to treat liver diseases. J Hepatol. 2017;66:1300–1312.
   PubMed Web of Science ®Google Scholar
• Han CY, Koo JH, Kim SH, et al. Hepcidin inhibits Smad3 phosphorylation in hepatic stellate cells by impeding ferroportin-mediated regulation of Akt. Nat Commun. 2016;7:13817.
   PubMed Web of Science ®Google Scholar
• Jia Y, Wang F, Guo Q, et al. Curcumol induces RIPK1/RIPK3 complex-dependent necroptosis via JNK1/2-ROS signaling in hepatic stellate cells. Redox Biol. 2018;19:375–387.
   PubMed Web of Science ®Google Scholar
• Tomasek JJ, Gabbiani G, Hinz B, et al. Myofibroblasts and mechano-regulation of connective tissue remodelling. Nat Rev Mol Cell Biol. 2002;3:349–363.
   PubMed Web of Science ®Google Scholar
• Parola M, Pinzani M. Liver fibrosis: pathophysiology, pathogenetic targets and clinical issues. Mol Aspects Med. 2019;65:37–55.
   PubMed Web of Science ®Google Scholar
• Gehrke N, Hövelmeyer N, Waisman A, et al. Hepatocyte-specific deletion of IL1-RI attenuates liver injury by blocking IL-1 driven autoinflammation. J Hepatol. 2018;68:986–995.
   PubMed Web of Science ®Google Scholar
• Krenkel O, Tacke F. Liver macrophages in tissue homeostasis and disease. Nat Rev Immunol. 2017;17:306–321.
   PubMed Web of Science ®Google Scholar
• Marra F, Tacke F. Roles for chemokines in liver disease. Gastroenterology. 2014;147(3):577–594.
   PubMed Web of Science ®Google Scholar
• Dawson MA, Prinjha RK, Dittmann A, et al. Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. Nature. 2011;478:529–533.
   PubMed Web of Science ®Google Scholar
• Feng L, Wang G, Chen Y, et al. Dual-target inhibitors of bromodomain and extra-terminal proteins in cancer: A review from medicinal chemistry perspectives. Med Res Rev. 2021;42(2): 710–743.
   PubMed Web of Science ®Google Scholar
• Kleppe M, Koche R, Zou L, et al. Dual Targeting of Oncogenic Activation and Inflammatory Signaling Increases Therapeutic Efficacy in Myeloproliferative Neoplasms. Cancer Cell. 2018;33(1):29–43.
   PubMed Web of Science ®Google Scholar
• Segatto M, Szokoll R, Fittipaldi R, et al. BETs inhibition attenuates oxidative stress and preserves muscle integrity in Duchenne muscular dystrophy. Nat Commun. 2020;11:6108.
   PubMed Web of Science ®Google Scholar
• Segura MF, Fontanals-Cirera B, Gaziel-Sovran A, et al. BRD4 sustains melanoma proliferation and represents a new target for epigenetic therapy. Cancer Res. 2013;73:6264–6276.
   PubMed Web of Science ®Google Scholar
• Tian B, Liu Z, Litvinov J, et al. Efficacy of novel highly specific bromodomain-containing protein 4 inhibitors in innate inflammation-driven airway remodeling. Am J Respir Cell Mol Biol. 2019;60:68–83.
   PubMed Web of Science ®Google Scholar
• Schuppan D, Ashfaq-Khan M, Yang AT, et al. Liver fibrosis: direct antifibrotic agents and targeted therapies. Matrix Biol. 2018;68-69:435–451.
   PubMed Web of Science ®Google Scholar
• Schuppan D, Ruehl M, Somasundaram R, et al. Matrix as a modulator of hepatic fibrogenesis. Semin Liver Dis. 2001;21:351–372.
   PubMed Web of Science ®Google Scholar
• Schuppan D, Surabattula R, Wang XY. Determinants of fibrosis progression and regression in NASH. J Hepatol. 2018;68:238–250.
   PubMed Web of Science ®Google Scholar
• Yan Y, Zeng J, Xing L, et al. Extra- and Tntra-Cellular Mechanisms of Hepatic Stellate Cell Activation. Biomedicines. 2021;9(8): 1014.
   PubMed Web of Science ®Google Scholar