Manganese Ion Inhibits Influenza A Virus Replication by Targeting the PA Endonuclease

Influenza A virus remains a major global health threat, with rapid mutation and emerging drug resistance underscoring the urgent need for novel antivirals. Manganese ions (Mn ²⁺ ) are known to enhance host antiviral immunity, but their direct effects on influenza virus replication remain elusive. Here, we demonstrate that manganese chloride (MnCl ₂ ) potently inhibits the replication of both H1N1 and H3N2 subtypes in cultured cells at micromolar concentrations, with antiviral activity not shared by other divalent cations (Ca ²⁺ , Cu ²⁺ , Zn ²⁺ , Mg ²⁺ ). Mechanistically, MnCl ₂ acts predominantly at post-entry stages, suppresses viral mRNA synthesis, and directly inhibits the RNA cleavage activity of the PA endonuclease. Pharmacological antagonism with the PA inhibitor baloxavir further supports PA as a key target. In a mouse model, intranasal MnCl ₂ administration alleviated body weight loss, reduced mortality, and decreased pulmonary viral RNA loads. Collectively, these findings identify Mn ²⁺ as a direct inhibitor of influenza virus replication that acts, at least in part, by targeting the PA endonuclease, providing a conceptual framework for metal ion-based antiviral strategies.