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PRV has developed several immune evasion mechanisms to antagonize the host\u2019s antiviral immune response. However, the precise role of PRV-encoded proteins in regulating the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon (IFN) gene (STING) signal for immune evasion remains unclear. In this study, we demonstrate that the PRV UL42 protein (pUL42) inhibited cGAS-mediated antiviral signaling by modulating cGAS recognition of dsDNA. Mechanistically, pUL42 interacts with the DNA-binding domain of cGAS, thereby inhibiting its recognition of double-stranded DNA, leading to the inhibition of its dimerization and oligomerization activation. Furthermore, knocking down the expression of the\n                      <jats:italic toggle=\"yes\">Ul42<\/jats:italic>\n                      gene in the PRV genome diminishes the antagonistic effect on type I IFN production and inhibits PRV replication. Ultimately, we have established that pUL42 targets cGAS-mediated signaling, thereby inhibiting the production of type I IFN and facilitating viral replication. Overall, our findings suggest that PRV pUL42 functions as an antagonist to evade the host\u2019s antiviral response by targeting the cGAS-STING axis.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>IMPORTANCE<\/jats:title>\n                    <jats:p>Cyclic GMP-AMP synthase (cGAS)-stimulator of interferon gene (STING) axis is essential for host resistance to DNA virus infections by regulating type I interferon production. However, whether pseudorabies virus (PRV) antagonizes the cGAS-STING signaling pathway to immune evasion is not fully investigated. In this study, we clearly demonstrated that the PRV pUL42 protein inhibits the recognition of double-stranded DNA of cGAS, leading to inhibiting the oligomerization and activation of cGAS, thereby suppressing the cGAS-mediated host antiviral immune responses. Taken together, our results reveal a novel strategy employed by PRV to evade host defenses, which will provide theoretical support for the development of anti-PRV drugs for the prevention and control of PRV.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/jvi.01218-25","type":"journal-article","created":{"date-parts":[[2025,9,30]],"date-time":"2025-09-30T13:01:10Z","timestamp":1759237270000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":2,"title":["Pseudorabies virus DNA polymerase processivity factor pUL42 inhibits type I IFN production by negatively regulating cGAS-STING signaling pathway"],"prefix":"10.1128","volume":"99","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1747-1063","authenticated-orcid":false,"given":"Guangqiang","family":"Ye","sequence":"first","affiliation":[{"name":"Division of Fundamental Immunology, National African Swine Fever Para-reference Laboratory, State Key Laboratory for 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