Isoliquiritigenin Elicits Potent Antiviral Activity Against Pseudorabies Virus Through Modulating the cGAS/STING and JAK/STAT Signaling Cascades.

Pseudorabies virus (PRV), a member of the Alphaherpesvirinae subfamily, poses a significant economic threat to the global swine industry and has raised growing public health concerns due to its cross-species transmission potential. Given emerging variants and the fact that current vaccines are restricted to pigs, novel antiviral agents are urgently needed. The present study assessed the anti-PRV activity of isoliquiritigenin, as well as its modulatory role in innate immune pathways, using cell-based assays and a PRV-infected mouse model. The results showed that isoliquiritigenin exhibited a half-maximal inhibitory concentration (IC50) of 35.47 μM and a selective index of 3.34 in PK-15 cells, with efficacy sustained at high infectious dose. Mechanistically, it counteracted PRV-induced suppression of type I interferon responses, correlating with core genes in the cGAS/STING pathway and enhancing IRF3 phosphorylation, while also activating the JAK/STAT axis and increasing STAT1 phosphorylation. In vivo, treatment with isoliquiritigenin decreased mortality by 40 percentage points (from 70% to 30%), substantially suppressed viral burden in various tissues, and concomitantly activated type I interferon signaling. Collectively, these findings suggest that isoliquiritigenin potentiates host innate immunity, potentially through the cGAS/STING and JAK/STAT cascades, offering a novel flavonoid-based lead for anti-herpesvirus drug development.