Herbacetin Alleviates Influenza Virus-Induced Lung Injury and Fibrosis by Targeting the Neuraminidase Protein

Background: Influenza A virus (IAV) is a major human pathogen, contributing to substantial morbidity and mortality during seasonal outbreaks and pandemics. Human infection with IAV can lead to pneumonia and acute respiratory distress syndrome (ARDS), and numerous clinical and basic research studies have established an association between IAV and pulmonary fibrosis (PF). However, the treatment of IAV-induced PF fibrosis has not been studied and discussed. Methods: An IAV-induced PF mouse model was established. Herbacetin (HBT) was identified as the most effective compound in the in vitro study of seven components of Rhodiola rosea L. (R. rosea L.). The effect of HBT on IAV-induced lung injury and PF was evaluated in vivo and in vitro. The binding between HBT and neuraminidase (NA) protein was investigated by biological layer interferometry (BLI) and cell thermal shift assay (CETSA). Results: Following IAV infection, the TGF-β/Smad3 pathway is activated, leading to the upregulation of fibrosis-related proteins that promote fibrosis. HBT exhibited a significant ability to reduce influenza virus-induced lung injury and fibrosis both in vitro and in vivo. Mechanistically, HBT binds to the NA protein of the influenza virus, reducing viral infection and the activation of the TGF-β/Smad3 pathway, thereby mitigating the formation of lung injury and PF. Conclusions: HBT represents a promising therapeutic agent for modulating influenza virus-induced lung injury and PF, marking a significant step toward the development of effective treatments for influenza-induced PF.