Porcine epidemic diarrhea (PED) is an acute and highly contagious enteric disease caused by porcine epidemic diarrhea virus (PEDV). The disease poses a significant threat to global swine production, underscoring the urgent need for effective antiviral therapeutics. In this study, we investigated the antiviral activity and underlying mechanism of febrifugine dihydrochloride (FFG), a quinazolinone alkaloid derived from Dichroa febrifuga. Although traditionally recognized for its antimalarial properties, the antiviral potential of FFG has remained largely unexplored. Our findings demonstrated that FFG exhibited strong and dose-dependent antiviral activity against PEDV, with its action targeting viral replication. Moreover, FFG displayed broad-spectrum antiviral activity against multiple viruses. Network pharmacology analysis combined with experimental validation identified IGF1R as a key host target of FFG. Mechanistically, FFG completely blocked the activation of the PI3K/AKT pathway induced by various viruses, establishing the host signaling axis as a critical node for its antiviral activity. We subsequently demonstrated that FFG inhibited PEDV replication by inducing apoptosis through the downstream cascades of the PI3K/AKT pathway. Notably, FFG's antiviral mechanism was effective against multiple viruses, highlighting its role in targeting conserved host antiviral mechanisms. Collectively, these findings identify FFG as a promising host-directed antiviral candidate. By targeting the IGF1R-PI3K/AKT-apoptosis axis, FFG modulates critical host signaling pathways to restrict viral replication, providing valuable mechanistic insight and new therapeutic targets for the development of antiviral agents.IMPORTANCEPorcine epidemic diarrhea virus (PEDV) remains one of the most devastating pathogens threatening the global swine industry, yet effective antiviral treatments are still lacking. In this study, we identified FFG as a promising broad-spectrum antiviral agent with dramatic effects on PEDV. The PI3K/AKT signaling pathway is a central phosphorylation cascade involved in the regulation of diverse cellular processes and frequently exploited by viruses to facilitate infection. Our results demonstrated that FFG suppressed PEDV replication through PI3K/AKT-dependent modulation of apoptosis, and the regulatory effect was mediated by targeting host receptor IGF1R. Collectively, these findings provide insight into host-virus interactions and highlight the IGF1R-PI3K/AKT-apoptosis axis as a promising target for antiviral therapy.
Yan et al. (Wed,) studied this question.