Integrated network pharmacology, transcriptomics analysis and experimental validation elucidated the underlying mechanisms of Siwu Decoction in the treatment of LPS-induced acute lung injury

ETHNOPHARMACOLOGICAL RELEVANCE: Siwu Decoction (SWT) is a classic traditional Chinese herbal formula originating from Taiping Huimin Heji Ju Fang, which has been used for centuries to nourish blood and promote circulation. Recent evidence suggests its broader potential in modulating inflammatory disorders. AIM OF THE STUDY: This study aimed to investigate the therapeutic efficacy of SWT against lipopolysaccharide (LPS)-induced acute lung injury (ALI) and elucidate its multi-target molecular mechanisms. MATERIALS AND METHODS: SWT chemical profiling was performed via UPLC-MS. An LPS-induced mouse model was utilized to assess lung histopathology, pulmonary edema, and cytokine production. Mechanisms were explored through integrated transcriptomics and network pharmacology, followed by molecular docking and immunofluorescence validation. RESULTS: SWT treatment dose-dependently attenuated lung pathological damage, neutrophil infiltration, and pro-inflammatory cytokine levels. Transcriptomics and network analysis indicate the PI3K-AKT and TNF signaling pathways as critical regulatory hubs. UPLC-MS and network pharmacology identified paeoniflorin, ferulic acid, and kaempferol as major chemical constituents. Subsequent validation confirmed that paeoniflorin and kaempferol are the primary drivers of these effects, significantly inhibiting the TNFR1/AKT/NF-κB signaling cascade. CONCLUSIONS: SWT effectively alleviates LPS-induced ALI by suppressing the inflammatory response and preserving alveolar barrier integrity. Its effect is primarily mediated by the synergistic action of paeoniflorin and kaempferol in modulating the TNFR1/AKT/NF-κB pathway.