{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T19:17:31Z","timestamp":1777663051108,"version":"3.51.4"},"reference-count":40,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T00:00:00Z","timestamp":1777420800000},"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. Pharmacol."],"abstract":"<jats:p>Probenecid is a host-directed drug that inhibits virus replication. Studies exploring how probenecid affects viral replication have demonstrated that it inhibits mitogen-activated protein kinase (MAPK) signaling pathways, which are important for the virus\u2019s replication and inflammation, and disrupt the formation of the activator protein-1 (AP-1) transcription complex, which regulates gene expression and inflammation. The modulation of MAPK signaling and suppression of the inflammasome response yields a dual anti-inflammatory and antiviral effect. The anti-inflammatory effects of probenecid, achieved through modulation of MAPK signaling and suppression of inflammasome activation, can decrease viral replication and reduces an excessive immune response. This dual mechanism could be advantageous for treating viruses where hyperinflammation plays a significant role in severe disease symptoms. This review suggests that probenecid\u2019s anti-inflammatory activity, mediated by inhibition of MAPK pathways, suppression of NLRP3 inflammasome activation, and reduction of proinflammatory cytokines (such as IL-6, TNF-\u03b1, and IL-1\u03b2), may help manage viral infections by limiting immune-mediated tissue damage and enhancing clinical outcomes, in addition to its antiviral effects.<\/jats:p>","DOI":"10.3389\/fphar.2026.1765763","type":"journal-article","created":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T07:31:14Z","timestamp":1777447874000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Probenecid is a dual-acting antiviral\/anti-inflammatory therapy for diverse respiratory viruses"],"prefix":"10.3389","volume":"17","author":[{"given":"Ralph A.","family":"Tripp","sequence":"first","affiliation":[{"name":"Department of Infectious Diseases, University of Georgia","place":["Athens, GA, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Les P.","family":"Jones","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, University of Georgia","place":["Athens, GA, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David E.","family":"Martin","sequence":"additional","affiliation":[{"name":"TrippBio","place":["Jacksonville, FL, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,4,29]]},"reference":[{"key":"B36","doi-asserted-by":"publisher","first-page":"678627","DOI":"10.1155\/2013\/678627","article-title":"The NLRP3 Inflammasome as a novel player of the intercellular crosstalk in metabolic disorders","author":"Benetti","year":"2013","journal-title":"Mediators Inflamm."},{"key":"B1","doi-asserted-by":"publisher","first-page":"1087","DOI":"10.3390\/v16071087","article-title":"Probenecid inhibits human metapneumovirus (HMPV) replication in vitro and in BALB\/c mice","volume":"16","author":"Bergeron","year":"2024","journal-title":"Viruses"},{"key":"B40","first-page":"258","article-title":"Benemid: an anticatabolite; its pharmacological properties","volume":"9","author":"Beyer","year":"1950","journal-title":"Federation Proceedings"},{"key":"B2","doi-asserted-by":"publisher","first-page":"335","DOI":"10.1186\/s12964-023-01356-1","article-title":"P2X7 receptor activation leads to NLRP3-independent IL-1beta release by human macrophages","volume":"21","author":"Bockstiegel","year":"2023","journal-title":"Cell Commun. 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