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Here, we demonstrated that JMJD6 was upregulated during pseudorabies virus (PRV) infection and critically enhanced viral replication by promoting virion release. Mechanistically, JMJD6 suppressed PRV-induced histone H4K16 acetylation, a modification associated with chromatin relaxation and DNA damage response activation. This epigenetic modulation attenuated the cGAS\u2013STING-mediated innate immune signaling pathway, leading to reduced interferon production and enhanced viral propagation. Furthermore, we identified METTL23 as a nuclear interactor of JMJD6 upon viral infection, revealing a cooperative role between these proteins in facilitating immune evasion. Importantly, administration of the JMJD6-specific inhibitor JMJD6-IN-1 potently activated innate immunity and restricted PRV replication in mice. Our findings unveil a novel epigenetic strategy employed by PRV to evade host antiviral responses and highlight JMJD6 as a potential therapeutic target for combating herpesvirus infections.<\/jats:p>\n                    <jats:sec>\n                      <jats:title>IMPORTANCE<\/jats:title>\n                      <jats:p>The ongoing conflict between viruses and host antiviral defenses is central to viral pathogenesis. Pseudorabies virus (PRV), a highly contagious alphaherpesvirus, causes severe economic losses in the global swine industry and poses an emerging zoonotic threat to humans. This study identifies the epigenetic modulator, the JMJD6, as a critical host factor exploited by PRV to evade antiviral immunity. Our work uncovers a previously unrecognized epigenetic strategy employed by herpesviruses and establishes JMJD6 as a promising target for developing broad-spectrum antivirals against PRV and related pathogenic herpesviruses.<\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/jvi.00028-26","type":"journal-article","created":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T13:01:29Z","timestamp":1777467689000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":1,"title":["JMJD6-mediated epigenetic silencing of innate immunity promotes pseudorabies virus replication"],"prefix":"10.1128","volume":"100","author":[{"given":"Sheng-Li","family":"Ming","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04eq83d71","id-type":"ROR","asserted-by":"publisher"}],"name":"College of Veterinary Medicine, Henan Agricultural University","place":["Zhengzhou, China"]},{"name":"Key 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