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β-Sitosterol (24-ethyl-5-cholestene-3-ol) is a common phytosterol Chinese medical plants that has been shown to possess antioxidant and anti-inflammatory activity.In this study we investigated the effects of β-sitosterol on influenza virus-induced inflammation and acute lung injury and the molecular mechanisms.We demonstrate that β-sitosterol (150-450 μg/mL) dosedependently suppresses inflammatory response through NF-KB and p38 mitogen-activated protein kinase (MAPK) signaling in influenza A virus (IAV)-infected cells,which was accompanied by decreased induction of interferons (IFNs) (including Type Ⅰ and Ⅲ IFN).Furthermore,we revealed that the anti-inflammatory effect of β-sitosterol resulted from its inhibitory effect on retinoic acidinducible gene Ⅰ (RIG-Ⅰ) signaling,led to decreased STAT1 signaling,thus affecting the transcriptional activity of ISGF3 (interferonstimulated gene factor 3) complexes and resulting in abrogation of the IAV-induced proinflammatory amplification effect in IFN-sensitized cells.Moreover,β-sitosterol treatment attenuated RIG-I-mediated apoptotic injury of alveolar epithelial cells (AEC) via downregulation of pro-apoptotic factors.In a mouse model of influenza,pre-administration of β-sitosterol (50,200 mg·kg-1·d-1,i.g.,for 2 days) dose-dependently ameliorated IAV-mediated recruitment of pathogenic cytotoxic T cells and immune dysregulation.In addition,pre-administration of β-sitosterol protected mice from lethal IAV infection.Our data suggest that β-sitosterol blocks the immune response mediated by RIG-I signaling and deleterious IFN production,providing a potential benefit for the treatment of influenza.