Bidirectionally Regulating Viral and Cellular Ferroptosis with Metastable Iron Sulfide Against Influenza Virus

Influenza virus with numerous subtypes and frequent variation limits the development of high‐efficacy and broad‐spectrum antiviral strategy. Here, a novel multi‐antiviral metastable iron sulfides (mFeS) against various influenza A/B subtype viruses is developed. This work finds that mFeS induces high levels of lipid peroxidation and •OH free radicals in the conservative viral envelope, which depends on Fe2+. This phenomenon, termed as a viral ferroptosis, results in the loss of viral infectibility and pathogenicity in vitro and in vivo, respectively. Furthermore, the decoction of mFeS (Dc(mFeS)) inhibits cellular ferroptosis‐dependent intracellular viral replication by correcting the virus‐induced reprogrammed sulfur metabolism, a conserved cellular metabolism. Notably, personal protective equipment (PPE) that is loaded with mFeS provides good antiviral protection. Aerosol administration of mFeS combined with the decoction (mFeS&Dc) has a potential therapeutic effect against H1N1 lethal infection in mice. Collectively, mFeS represents an antiviral alternative with broad‐spectrum activity against intracellular and extracellular influenza virus. mFeS induces the viral ferroptosis by enhancing the lipid peroxidation level, which results in a failed viral infection. In addition, Dc(mFeS) suppresses the cellular ferroptosis‐dependent intracellular replication of influenza virus via restoring influenza virus‐induced imbalance of sulfur metabolism, and the supply of intracellular S0. Comprehensively, mFeS&Dc through aerosol administration shows a potential preventive therapy against H1N1 virus infection in mice.