Cepharanthine Inhibits Influenza A Virus Infection by Blocking Viral Attachment to Host Cells

Influenza A virus (IAV) is characterized by high transmissibility and pathogenicity, posing a substantial threat to global public health. The rapid mutation of the IAV RNA genome undermines the efficacy of vaccines and prevention strategies, while the emergence of drug-resistant strains has further complicated control efforts-underscoring an urgent need for novel, effective anti-influenza therapeutics. Herein, we demonstrate that cepharanthine (CEP), a secondary metabolite isolated from Stephania spp., potently inhibits infection and replication of multiple IAV subtypes in vitro with its antiviral mechanism being independent of host innate immune response modulation. CEP treatment conferred significant protection to mice infected with a high dose of PR8. Further investigations revealed that CEP treatment during pre-infection and viral adsorption phases significantly suppresses IAV replication, markedly attenuates IAV-induced cytopathic effects, and enhances cell viability. Importantly, we identified for the first time that CEP strongly blocks IAV attachment to host cell membranes. Moreover, CEP administration significantly reduces disease severity in IAV-infected mice. These findings indicate that CEP exhibits broad-spectrum anti-IAV activity, providing a critical foundation for the development of novel anti-influenza pharmaceuticals.