PRRSV suppresses FTO-dependent m6A demethylation to reprogram STAT signaling and innate immunity

RNA viruses have evolved diverse strategies to evade host interferon (IFN)-stimulated gene (ISG) defenses; however, how they exploit host epitranscriptomic regulation remains poorly understood. Here, we identify an immune-evasion mechanism in which porcine reproductive and respiratory syndrome virus (PRRSV) targets the m6A 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 m6A 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 in vivo 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 m6A regulation as a potential target for antiviral intervention.