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Arctigenin (ACT) is a novel anti‐inflammatory lignan extracted from Arctium lappa L, a herb commonly used in traditional Chinese herbal medicine. In this study, we investigated the molecular mechanism whereby ACT inhibits PCV2 infection‐induced proinflammatory cytokine production in vitro and in vivo. We observed that in PCV2 infection+ACT treated PK‐15 cells, proinflammatory cytokine production was significantly reduced, compared to the PCV2‐infected cells. The transfection and luciferase reporter assay confirmed that ACT suppressed NF‐κB signalling pathway activation following PCV2 infection in PK‐15 cells. Furthermore, western blotting demonstrated that ACT suppressed the NF‐κB signal pathway in PCV2 infection‐stimulated PK‐15 cells by inhibiting the translocation of p65 from the cytoplasm to the nucleus and IκBα phosphorylation. BALB/c mice were used as a model to evaluate the anti‐inflammatory effect of ACT in vivo. We found that the BALB/c mice inoculated with PCV2 infection + ACT treated showed a significant reduction of proinflammatory cytokine production in serum, lung and spleen tissue, compared to the PCV2‐infected mice. Western blotting confirmed that ACT suppressed the NF‐κB signal pathway in PCV2‐infected mice by inhibiting the translocation of p65 from the cytoplasm to the nucleus and IκBα phosphorylation in lung tissue. Our studies first demonstrate that ACT inhibits PCV2 infection‐induced proinflammatory cytokine production by suppressing the phosphorylation and nuclear translocation of NF‐κB in vitro and in vivo. These results will help further develop ACT as a Traditional Chinese herbal medicine remedy in the treatment of porcine circovirus‐associated diseases. This study investigates the molecular mechanism of ACT inhibits PCV2 infection‐induced proinflammatory cytokine production in vitro and in vivo. The results demonstrate that ACT could inhibit PCV2 infection‐induced proinflammatory cytokine production by suppressing the phosphorylation and nuclear translocation of NF‐κB. This study will help further develop ACT as a Traditional Chinese herbal medicine remedy in the treatment of PCVADs. [ABSTRACT FROM AUTHOR]