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Ruscogenin-1-O-[β-D-glucopyranosyl (1→2)][β-D-xylopyranosyl (1→3)] -β-D-fucopyranoside (Rus-GXF) is a ruscogenin glycoside of (Decaisne) L. H. Bailey, yet its protective effects against acute lung injury-a condition characterized by exacerbated inflammation and barrier damage have not been fully elucidated. In this study, the preventive and therapeutic effects of Rus-GXF on acute lung injury (ALI) were investigated using transcriptome RNA sequencing, network pharmacology, molecular docking, molecular dynamics simulation and other and experiments. Rus-GXF suppressed inflammatory responses in two key cell types involved in lung injury. In immune cells (RAW264.7), it inhibited the production of pivotal pro-inflammatory mediators and their regulatory genes. Similarly, in pulmonary epithelial cells (BEAS-2B), it reduced the expression of inflammatory signals and concurrently enhanced markers of cellular tight junction proteins. In mice, Rus-GXF alleviated ALI severity, evidenced by decreased lung wet/dry ratio, bronchoalveolar lavage fluid protein content, pro-inflammatory cytokine levels, and histopathological scores. Integrated network pharmacology and transcriptomics indicated that Rus-GXF acts through multi-target mechanisms in ALI. Molecular docking and dynamics simulations revealed that Rus-GXF acts as an allosteric inhibitor of JAK1, thereby preventing its activation and subsequent STAT3 phosphorylation. The inhibitory effect of Rus-GXF on the JAK1/STAT3 signaling pathway was investigated by immunohistochemistry (IHC) and Western blot analysis (WB). These results demonstrate that Rus-GXF suppresses the macrophage-derived cytokine storm, alleviates inflammation, and improves barrier function. It functions as a JAK1 inhibitor to regulate ALI progression via the JAK1/STAT3 signaling pathway.