LAUSR

Uncontrolled inflammation and excessive M1 macrophage polarization are key drivers of acute lung injury (ALI). Scutellarin (SCU), a natural flavonoid compound, possesses anti‐inflammatory activity, but its precise mechanism remains unclear. This study aimed to investigate whether SCU alleviates ALI by targeting guanine nucleotide‐binding protein 2 (GBP2) and regulating alveolar macrophage polarization. A lipopolysaccharide (LPS)‐induced ALI mouse model was used to evaluate the therapeutic effects of SCU. Macrophage polarization and lung injury severity were assessed histologically and by cytokine analysis. Transcriptomic profiling (RNA‐seq) identified GBP2 as a candidate target. GBP2 was knocked down or overexpressed in MH‐S cells to evaluate its role in LPS‐induced polarization. Co‐immunoprecipitation, molecular docking, and immunofluorescence were performed to confirm the interaction between GBP2 and STAT3. SCU pre‐treatment significantly alleviated lung injury, reduced inflammatory cytokine levels, and improved the wet‐to‐dry lung weight ratio. It modulated macrophage polarization by downregulating LPS‐induced M1 polarization in alveolar macrophages. Mechanistically, SCU downregulated GBP2 expression and suppressed activation of the JAK2/STAT3 signaling pathway in LPS‐stimulated models. SCU ameliorates LPS‐induced ALI by modulating alveolar macrophage polarization through inhibition of the GBP2/JAK2/STAT3 pathway. These findings suggest that SCU may serve as a potential therapeutic agent for ALI.