Peroxiredoxin-6 (PRDX6) is an antioxidant enzyme with both the activities of peroxidase and phospholipase A2 (PLA2),which is involved in regulation of many cellular reactions.However,the function of PRDX6 during virus infection remains unknown.In this study,we found that the abundance of PRDX6 protein was dramatically decreased in foot-and-mouth disease virus (FMDV) infected cells.Overexpression of PRDX6 inhibited FMDV replication.In contrast,knockdown of PRDX6 expression promoted FMDV replication,suggesting an antiviral role of PRDX6.To explore whether the activity of peroxidase and PLA2 was associated with PRDX6-mediated antiviral function,a specific inhibitor of PLA2 (MJ33) and a specific inhibitor of peroxidase activity (mercaptosuccinate) were used to treat the cells before FMDV infection.The results showed that incubation of MJ33 but not mercaptosuccinate promoted FMDV replication.Meanwhile,overex-pression of PRDX6 slightly enhanced type I interferon signaling.We further determined that the viral 3Cpro was responsible for degradation of PRDX6,and 3Cpro-induced reduction of PRDX6 was independent of the proteasome,lysosome,and caspase pathways.The protease activity of 3Cpro was required for induction of PRDX6 reduction.Besides,PRDX6 suppressed the replication of another porcine picornavirus Senecavirus A (SVA),and the 3Cpro of SVA induced the reduction of PRDX6 through its proteolytic activity as well.Together,our results suggested that PRDX6 plays an important antiviral role during porcine picornavirus infection,and the viral 3Cpro induces the degradation of PRDX6 to overcome PRDX6-mediated antiviral function.