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Precise control of PRR gene expression is crucial for maintaining immune homeostasis. Here, we showed that Mediator complex subunit 23 (Med23) is required for the precise production of the innate immune receptor RIG-I in response to RNA virus infection. Med23 deficiency markedly enhances the production of IFN-I, proinflammatory cytokines, and IFN-stimulated genes (ISGs) in both multiple cell lines (MEFs, RAW264.7 cells, and HeLa cells) and mouse primary macrophages (bone marrow-derived macrophages [BMDMs] and peritoneal macrophages [PEMs]) infected with RNA virus VSV or stimulated with poly(I:C). Myeloid-specific Med23 knockout mice were generated to test the critical role of Med23 in host resistance to VSV infection in vivo. Mechanistically, Med23 interacts with the transcription factor forkhead box O3 (Foxo3) to negatively regulate RIG-I, thereby modulating IFN-I signaling. Collectively, these findings elucidate a previously unrecognized role of Med23 as a gatekeeper of the RIG-I-mediated antiviral innate immune response and suggest a potential target for controlling viral infection.<\/jats:p>","DOI":"10.1371\/journal.pbio.3003294","type":"journal-article","created":{"date-parts":[[2025,7,24]],"date-time":"2025-07-24T17:43:20Z","timestamp":1753379000000},"page":"e3003294","update-policy":"https:\/\/doi.org\/10.1371\/journal.pbio.corrections_policy","source":"Crossref","is-referenced-by-count":3,"title":["Mediator complex subunit MED23 dampens antiviral innate immunity by restricting RIG-I 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