{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T17:13:59Z","timestamp":1790356439196,"version":"4.1.0"},"reference-count":50,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,8,21]],"date-time":"2025-08-21T00:00:00Z","timestamp":1755734400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Infect. Microbiol."],"abstract":"<jats:p>The innate immune system serves as the first line of defense against viral infections. Type I interferon (IFN-I) signaling, in particular, plays a crucial role in mediating antiviral immunity. Here, we identify Betrixaban (BT), a novel small-molecule compound that activates innate immune responses, leading to broad-spectrum antiviral effects. BT induces IFN-\u03b2 production and upregulates interferon-stimulated genes (ISGs), effectively suppressing the replication of multiple viruses, including vesicular stomatitis virus (VSV), herpes simplex virus type 1 (HSV-1), murine hepatitis virus strain A59 (MHV-A59), encephalomyocarditis virus (EMCV), and influenza A virus (IAV). BT\u2019s antiviral activity relies on innate immune activation, with IRF3 playing a key role. The antiviral effect was significantly reduced upon loss of ISGs induction, including Mx1 and Mx2. <jats:italic>In vivo<\/jats:italic>, BT treatment markedly induced IFNB1 expression across multiple mouse tissues and significantly inhibited viral replication in VSV-infected wild-type mice, confirming the essential role of innate antiviral immune activation. These findings establish BT as a potent stimulator of the innate immune system, demonstrating broad-spectrum antiviral potential and highlighting its promise as a therapeutic agent.<\/jats:p>","DOI":"10.3389\/fcimb.2025.1603530","type":"journal-article","created":{"date-parts":[[2025,8,21]],"date-time":"2025-08-21T05:28:41Z","timestamp":1755754121000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Betrixaban is a broad anti-virus inhibitor by activating innate immunity"],"prefix":"10.3389","volume":"15","author":[{"given":"Shiyu","family":"Hu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xingyu","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haocheng","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjun","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rong","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenxi","family":"Niu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuefei","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fuping","family":"You","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,8,21]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1038\/s41590-019-0556-1","article-title":"Regulation of cGAS- and RLR-mediated immunity to nucleic acids","volume":"21","author":"Ablasser","year":"2020","journal-title":"Nat. Immunol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"1153","DOI":"10.1016\/S1473-3099(22)00228-6","article-title":"Clinical features and management of human monkeypox: a retrospective observational study in the UK","volume":"22","author":"Adler","year":"2022","journal-title":"Lancet Infect. Dis."},{"key":"B3","doi-asserted-by":"publisher","first-page":"525","DOI":"10.1007\/s40256-020-00438-6","article-title":"Potential therapeutic roles for direct factor xa inhibitors in coronavirus infections","volume":"20","author":"Al-Horani","year":"2020","journal-title":"Am. J. Cardiovasc. Drug"},{"key":"B4","doi-asserted-by":"publisher","first-page":"3601","DOI":"10.1021\/acs.jcim.3c00282","article-title":"Targeting SARS-coV-2 main protease: A successful story guided by an drug repurposing approach","volume":"63","author":"Ambrosio","year":"2023","journal-title":"J. Chem. Inf Model."},{"key":"B5","doi-asserted-by":"publisher","first-page":"1574","DOI":"10.1038\/s41590-019-0466-2","article-title":"Interferon target-gene expression and epigenomic signatures in health and disease","volume":"20","author":"Barrat","year":"2019","journal-title":"Nat. Immunol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"427","DOI":"10.1016\/j.chom.2022.03.022","article-title":"Interferons in coronavirus pathogenesis: The good, the bad, and the ugly","volume":"30","author":"Channappanavar","year":"2022","journal-title":"Cell Host Microbe"},{"key":"B7","doi-asserted-by":"publisher","first-page":"387","DOI":"10.1038\/ni.2239","article-title":"NLRP4 negatively regulates type I interferon signaling by targeting the kinase TBK1 for degradation via the ubiquitin ligase DTX4","volume":"13","author":"Cui","year":"2012","journal-title":"Nat. Immunol."},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.15252\/embj.2022112907","article-title":"Viral recognition and the antiviral interferon response","volume":"42","author":"Dalskov","year":"2023","journal-title":"EMBO J."},{"key":"B9","doi-asserted-by":"publisher","first-page":"1323","DOI":"10.1055\/s-0040-1713889","article-title":"Apixaban for stroke prevention in atrial fibrillation: why are event rates higher in clinical practice than in randomized trials?-A systematic review","volume":"120","author":"de Vries","year":"2020","journal-title":"Thromb. Haemostasis"},{"key":"B10","doi-asserted-by":"publisher","first-page":"174","DOI":"10.1016\/j.bbrc.2007.05.092","article-title":"Cleavage of spike protein of SARS coronavirus by protease factor Xa is associated with viral infectivity","volume":"359","author":"Du","year":"2007","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"B11","doi-asserted-by":"publisher","first-page":"187","DOI":"10.1007\/s00018-022-04220-6","article-title":"Hematopoietic responses to SARS-CoV-2 infection","volume":"79","author":"Elahi","year":"2022","journal-title":"Cell Mol. Life Sci."},{"key":"B12","doi-asserted-by":"publisher","first-page":"1249","DOI":"10.1016\/j.ijbiomac.2021.10.172","article-title":"SARS-COV-2, infection, transmission, transcription, translation, proteins, and treatment: A review","volume":"193","author":"Emrani","year":"2021","journal-title":"Int. J. Biol. Macromol"},{"key":"B13","doi-asserted-by":"publisher","first-page":"793","DOI":"10.1016\/j.jid.2021.11.031","article-title":"Type I interferons in autoimmunity","volume":"142","author":"Fernandez-Ruiz","year":"2022","journal-title":"J. Invest. Dermatol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"e288","DOI":"10.1055\/s-0040-1718415","article-title":"The potential role of coagulation factor xa in the pathophysiology of COVID-19: A role for anticoagulants as multimodal therapeutic agents","volume":"4","author":"Frydman","year":"2020","journal-title":"TH Open"},{"key":"B15","doi-asserted-by":"publisher","first-page":"175","DOI":"10.1016\/j.cytogfr.2015.01.001","article-title":"New perspectives on type I IFNs in cancer","volume":"26","author":"Gajewski","year":"2015","journal-title":"Cytokine Growth F R"},{"key":"B16","doi-asserted-by":"publisher","first-page":"453","DOI":"10.1042\/BST0360453","article-title":"Targeting IRFs by ubiquitination: regulating antiviral responses","volume":"36","author":"Higgs","year":"2008","journal-title":"Biochem. Soc. Trans."},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.3390\/cells11050804","article-title":"Virus-host cell interactions","volume":"11","author":"Hoenen","year":"2022","journal-title":"Cells-Basel"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.adg2339","article-title":"VANGL2 inhibits antiviral IFN-I signaling by targeting TBK1 for autophagic degradation","volume":"9","author":"Hu","year":"2023","journal-title":"Sci. Adv."},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01853-17","article-title":"Activities of thrombin and factor xa are essential for replication of hepatitis E virus and are possibly implicated in ORF1 polyprotein processing","volume":"92","author":"Kanade","year":"2018","journal-title":"J. Virol."},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.77444.sa2","article-title":"Coagulation factors directly cleave SARS-CoV-2 spike and enhance viral entry","volume":"11","author":"Kastenhuber","year":"2022","journal-title":"Elife"},{"key":"B21","doi-asserted-by":"publisher","first-page":"257","DOI":"10.1186\/s12967-020-02430-9","article-title":"Advanced bioinformatics rapidly identifies existing therapeutics for patients with coronavirus disease-2019 (COVID-19)","volume":"18","author":"Kim","year":"2020","journal-title":"J. Transl. Med."},{"key":"B22","doi-asserted-by":"publisher","first-page":"907","DOI":"10.1016\/j.immuni.2019.03.025","article-title":"Shared and distinct functions of type I and type III interferons","volume":"50","author":"Lazear","year":"2019","journal-title":"Immunity"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2020.108631","article-title":"The mitochondrial protein ERAL1 suppresses RNA virus infection by facilitating RIG-I-like receptor signaling","volume":"34","author":"Li","year":"2021","journal-title":"Cell Rep."},{"key":"B24","doi-asserted-by":"publisher","first-page":"369","DOI":"10.1016\/j.cytogfr.2014.07.015","article-title":"Interferons: Success in anti-viral immunotherapy","volume":"25","author":"Lin","year":"2014","journal-title":"Cytokine Growth F R"},{"key":"B25","doi-asserted-by":"publisher","first-page":"295","DOI":"10.1007\/978-3-540-71329-6_14","article-title":"Viral regulation and evasion of the host response","volume":"316","author":"Loo","year":"2007","journal-title":"Curr. Top. Microbiol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"1113","DOI":"10.1016\/j.chembiol.2022.05.009","article-title":"Identifying enhancers of innate immune signaling as broad-spectrum antivirals active against emerging viruses","volume":"29","author":"Maarifi","year":"2022","journal-title":"Cell Chem. Biol."},{"key":"B27","doi-asserted-by":"publisher","first-page":"842","DOI":"10.1016\/j.it.2019.07.005","article-title":"Interferon control of neurotropic viral infections","volume":"40","author":"Milora","year":"2019","journal-title":"Trends Immunol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"214","DOI":"10.1038\/nrrheum.2018.31","article-title":"Type I interferon in rheumatic diseases","volume":"14","author":"Muskardin","year":"2018","journal-title":"Nat. Rev. Rheumatol."},{"key":"B29","doi-asserted-by":"publisher","first-page":"671","DOI":"10.1016\/j.ejmech.2016.05.039","article-title":"Contemporary developments in the discovery of selective factor Xa inhibitors: A review","volume":"121","author":"Patel","year":"2016","journal-title":"Eur. J. Med. Chem."},{"key":"B30","doi-asserted-by":"publisher","first-page":"370","DOI":"10.1016\/j.immuni.2007.08.012","article-title":"Innate recognition of viruses","volume":"27","author":"Pichlmair","year":"2007","journal-title":"Immunity"},{"key":"B31","doi-asserted-by":"publisher","first-page":"774","DOI":"10.1002\/rth2.12406","article-title":"Antiviral anticoagulation","volume":"4","author":"Pryzdial","year":"2020","journal-title":"Res. Pract. Thromb. Hae"},{"key":"B32","doi-asserted-by":"publisher","first-page":"3133","DOI":"10.1016\/j.csbj.2021.05.037","article-title":"Prediction of repurposed drugs for Coronaviruses using artificial intelligence and machine learning","volume":"19","author":"Rajput","year":"2021","journal-title":"Comput. Struct. Biotec"},{"key":"B33","doi-asserted-by":"publisher","first-page":"2527","DOI":"10.1084\/jem.20161596","article-title":"Type I interferon-mediated monogenic autoinflammation: The type I interferonopathies, a conceptual overview","volume":"213","author":"Rodero","year":"2016","journal-title":"J. Exp. Med."},{"key":"B34","doi-asserted-by":"publisher","first-page":"597","DOI":"10.1097\/JS9.0000000000000190","article-title":"Marburg virus disease outbreak amid COVID-19 pandemic: an emerging concern in Ghana, West Africa","volume":"109","author":"Roy","year":"2023","journal-title":"Int. J. Surg."},{"key":"B35","doi-asserted-by":"publisher","first-page":"559","DOI":"10.1038\/nri2314","article-title":"Interferon-inducible antiviral effectors","volume":"8","author":"Sadler","year":"2008","journal-title":"Nat. Rev. Immunol."},{"key":"B36","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1016\/S2222-1808(14)60322-4","article-title":"Hepatitis B and hepatitis C viruses: a review of viral genomes, viral induced host immune responses, genotypic distributions and worldwide epidemiology","volume":"4","author":"Saeed","year":"2014","journal-title":"Asian Pac. J. Trop. Dis."},{"key":"B37","doi-asserted-by":"publisher","first-page":"509","DOI":"10.1038\/nri.2016.69","article-title":"Immune responses and immunopathology in acute and chronic viral hepatitis","volume":"16","author":"Shin","year":"2016","journal-title":"Nat. Rev. Immunol."},{"key":"B38","doi-asserted-by":"publisher","first-page":"373","DOI":"10.1016\/j.immuni.2006.08.007","article-title":"Type I interferons in host defense","volume":"25","author":"Stetson","year":"2006","journal-title":"Immunity"},{"key":"B39","doi-asserted-by":"publisher","first-page":"482","DOI":"10.1111\/jth.14389","article-title":"Virus envelope tissue factor promotes infection in mice","volume":"17","author":"Sutherland","year":"2019","journal-title":"J. Thromb. Haemost."},{"key":"B40","doi-asserted-by":"publisher","first-page":"947","DOI":"10.1160\/TH04-04-0242","article-title":"Herpes simplex virus type 1-encoded glycoprotein C enhances coagulation factor VIIa activity on the virus","volume":"92","author":"Sutherland","year":"2004","journal-title":"Thromb. Haemost."},{"key":"B41","doi-asserted-by":"publisher","first-page":"109801","DOI":"10.1016\/j.celrep.2021.109801","article-title":"Dengue virus is sensitive to inhibition prior to productive replication","volume":"37","author":"Talemi","year":"2021","journal-title":"Cell Rep."},{"key":"B42","doi-asserted-by":"publisher","first-page":"155","DOI":"10.1038\/s41579-020-00468-6","article-title":"Coronavirus biology and replication: implications for SARS-CoV-2","volume":"19","author":"V\u2019kovski","year":"2021","journal-title":"Nat. Rev. Microbiol."},{"key":"B43","doi-asserted-by":"publisher","first-page":"395","DOI":"10.1146\/annurev-med-050715-105122","article-title":"Zika, chikungunya, and other emerging vector-borne viral diseases","volume":"69","author":"Weaver","year":"2018","journal-title":"Annu. Rev. Med."},{"key":"B44","doi-asserted-by":"publisher","first-page":"930","DOI":"10.1016\/j.jhep.2016.12.008","article-title":"Type I interferon signaling in systemic immune cells from patients with alcoholic cirrhosis and its association with outcome","volume":"66","author":"Weiss","year":"2017","journal-title":"J. Hepatol."},{"key":"B45","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1111\/imm.12622","article-title":"Strategies for designing synthetic immune agonists","volume":"148","author":"Wu","year":"2016","journal-title":"Immunology"},{"key":"B46","doi-asserted-by":"publisher","first-page":"766","DOI":"10.1016\/j.apsb.2020.02.008","article-title":"Analysis of therapeutic targets for SARS-CoV-2 and discovery of potential drugs by computational methods","volume":"10","author":"Wu","year":"2020","journal-title":"Acta Pharm. Sin. B"},{"key":"B47","doi-asserted-by":"publisher","first-page":"4005","DOI":"10.1007\/s00253-021-11319-6","article-title":"Potential role of IFN-\u03b1 in COVID-19 patients and its underlying treatment options","volume":"105","author":"Yang","year":"2021","journal-title":"Appl. Microbiol. Biotechnol."},{"key":"B48","doi-asserted-by":"publisher","first-page":"191","DOI":"10.1007\/s00018-022-04219-z","article-title":"Type I interferon-mediated tumor immunity and its role in immunotherapy","volume":"79","author":"Yu","year":"2022","journal-title":"Cell Mol. Life Sci."},{"key":"B49","doi-asserted-by":"publisher","first-page":"194","DOI":"10.1016\/j.it.2016.12.004","article-title":"Crosstalk between cytoplasmic RIG-I and STING sensing pathways","volume":"38","author":"Zevini","year":"2017","journal-title":"Trends Immunol."},{"key":"B50","doi-asserted-by":"publisher","first-page":"2179","DOI":"10.1016\/j.bmcl.2009.02.111","article-title":"Discovery of betrixaban (PRT054021), -(5-chloropyridin-2-yl)-2-(4-(,-dimethylcarbamimidoyl)benzamido)-5-methoxybenzamide, a highly potent, selective, and orally efficacious factor Xa inhibitor","volume":"19","author":"Zhang","year":"2009","journal-title":"Bioorg Med. Chem. Lett."}],"container-title":["Frontiers in Cellular and Infection Microbiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcimb.2025.1603530\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,8,21]],"date-time":"2025-08-21T05:28:42Z","timestamp":1755754122000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcimb.2025.1603530\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,21]]},"references-count":50,"alternative-id":["10.3389\/fcimb.2025.1603530"],"URL":"https:\/\/doi.org\/10.3389\/fcimb.2025.1603530","relation":{},"ISSN":["2235-2988"],"issn-type":[{"value":"2235-2988","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,21]]},"article-number":"1603530"}}