The dual functions of a nor-sesquiterpene-triazole derivative against influenza A viruses through the activation of the Nrf2/HO-1 signaling pathway and interaction with hemagglutinin.

Influenza viruses are the main causative agents of seasonal influenza epidemics in humans. The emergence of drug-resistant strains has significantly limited the effectiveness of existing antiviral therapies, highlighting the urgent need for new antiviral agents. In this study, we screened a series of synthesized nor-sesquiterpene-1,2,3-triazole compounds and identified one, SF-4, that demonstrated potent anti-influenza A virus (IAV) activity with minimal cytotoxicity. Mechanistic investigations revealed that SF-4 targets the HA2 subunit of hemagglutinin (HA), thereby inhibiting viral entry by blocking membrane fusion between the virus and host cells. Additionally, SF-4 attenuated influenza virus infection by suppressing NF-κB activation and stimulating the Nrf2/HO-1 signaling pathway, which resulted in reduced expression of pro-inflammatory cytokines such as TNF-α, IL-6, and IL-1β. Collectively, these findings suggest that SF-4 is a promising lead compound for the development of novel anti-influenza therapeutics.