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Here, we identify an immune-evasion mechanism in which porcine reproductive and respiratory syndrome virus (PRRSV) targets the\n                      <jats:italic toggle=\"yes\">m6A<\/jats:italic>\n                      demethylase fat mass and obesity-associated protein (FTO) to suppress antiviral signaling. Mechanistically, the viral endoribonuclease nsp11 inhibits STAT5-dependent transcription through the key residues Q96 and S104, thereby reducing FTO expression. Loss of FTO increases\n                      <jats:italic toggle=\"yes\">m6A<\/jats:italic>\n                      modification of STAT2 and STAT3 transcripts, impairing their translation and phosphorylation, thereby attenuating ISG responses. Reduced STAT3 activity further dampens STAT5 signaling, establishing a feed-forward circuit that amplifies suppression of antiviral immunity. Functionally, disruption of this regulatory region (Q96A and S104A) attenuates viral pathogenicity\n                      <jats:italic toggle=\"yes\">in vivo<\/jats:italic>\n                      and restores ISG induction. These mutations also reduce infection-associated inflammatory responses and the accumulation of reactive oxygen species. Together, these findings define a nsp11-STAT5-FTO-STAT2\/3 axis that enables PRRSV to reprogram host epitranscriptomic control of innate immunity. Our work reveals a mechanism of epitranscriptomic hijacking and identifies FTO as a key host factor exploited by RNA viruses, highlighting\n                      <jats:italic toggle=\"yes\">m6A<\/jats:italic>\n                      regulation as a potential target for antiviral intervention.\n                    <\/jats:p>\n                    <jats:sec>\n                      <jats:title>IMPORTANCE<\/jats:title>\n                      <jats:p>\n                        Viruses must overcome host innate immune defenses to establish infection; however, the mechanisms by which they manipulate host RNA regulation remain incompletely understood. In this study, we show that porcine reproductive and respiratory syndrome virus (PRRSV) suppresses interferon responses by targeting the host\n                        <jats:italic toggle=\"yes\">m6A<\/jats:italic>\n                        demethylase FTO through its endoribonuclease nsp11. This process involves the inhibition of STAT5 phosphorylation, which reduces FTO expression and increases\n                        <jats:italic toggle=\"yes\">m6A<\/jats:italic>\n                        modification of key immune regulators, including STAT2 and STAT3, thereby impairing their activation. Disruption of this pathway attenuates viral pathogenicity\n                        <jats:italic toggle=\"yes\">in vivo<\/jats:italic>\n                        and restores antiviral signaling. These results demonstrate that PRRSV can reprogram host epitranscriptomic regulation to modulate innate immunity and suggest that\n                        <jats:italic toggle=\"yes\">m6A<\/jats:italic>\n                        -related pathways may be potential targets for antiviral intervention.\n                      <\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/mbio.00843-26","type":"journal-article","created":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T13:00:17Z","timestamp":1786626017000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["PRRSV suppresses FTO-dependent\n                    <i>m6A<\/i>\n                    demethylation to reprogram STAT signaling and innate immunity"],"prefix":"10.1128","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-5468-1215","authenticated-orcid":false,"given":"Yipeng","family":"Pang","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/051hvcm98","id-type":"ROR","asserted-by":"publisher"}],"name":"School of Life Science, Institute of Cellular and Molecular Biology, Jiangsu Normal University","place":["Xuzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3436-4553","authenticated-orcid":true,"given":"Fructueux Modeste","family":"Amona","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/051hvcm98","id-type":"ROR","asserted-by":"publisher"}],"name":"School of Life Science, Institute of Cellular and Molecular Biology, Jiangsu Normal University","place":["Xuzhou, 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