Scutellarin Attenuates Lipopolysaccharide‐Induced Acute Lung Injury in Mice by Inhibiting <scp>M1</scp> Macrophage Polarization via the <scp>GBP2</scp> / <scp>JAK2</scp> / <scp>STAT3</scp> Signaling Pathway

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.