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Precise regulation of this response is critical to avoid pathological inflammation and autoimmunity, but the molecular mechanisms that restrain IFN signaling remain incompletely defined. Here, we performed a human whole-genome cDNA library screen and identified ZC3H10 as a negative regulator of the type I IFN response. Overexpression of ZC3H10 suppressed ISG expression following IFN\u03b2 stimulation and increased susceptibility to infection by Newcastle disease virus, human rhinovirus 16, Enterovirus A71, and SARS-CoV-2, whereas genetic deletion of ZC3H10 enhanced ISG expression and antiviral resistance. Mechanistically, ZC3H10 required nuclear localization, a functional nucleic acid-binding domain, and its coiled-coil domain to exert its inhibitory function. Furthermore, chromatin immunoprecipitation assays revealed that ZC3H10 directly binds to the TTTC motif within ISG promoters, thereby preventing their activation. Together, these findings establish ZC3H10 as a critical negative regulator of IFN signaling that functions to balance antiviral immunity.<\/jats:p>","DOI":"10.1371\/journal.pbio.3003881","type":"journal-article","created":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T17:27:49Z","timestamp":1784222869000},"page":"e3003881","update-policy":"https:\/\/doi.org\/10.1371\/journal.pbio.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["The zinc-finger protein ZC3H10 suppresses type I interferon responses during viral infection by repressing interferon-stimulated gene 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