Integrative Network Pharmacology and Multi-Omics Analysis Reveal Key Targets and Mechanisms of Saikosaponin B1 Against Acute Lung Injury

<b>Background/Objectives</b>: Acute lung injury (ALI) is a severe condition driven largely by inflammation and has limited therapeutic options. Although saikosaponin B1 (SSB1), a primary bioactive saponin from <i>Bupleurum</i> Radix, has demonstrated anti-inflammatory properties, its efficacy against ALI and its corresponding molecular mechanisms remain largely unexplored. This study employed an integrated approach combining network pharmacology, transcriptomics, and metabolomics to decipher the protective mechanisms of SSB1 against ALI. <b>Methods</b>: Potential targets were identified via network pharmacology, and core targets were validated through molecular docking, dynamics simulations, and independent GEO transcriptomic datasets. Experimental validation was performed in an LPS-induced murine ALI model, combining histopathology, ELISA, and integrated transcriptomic and metabolomic analyses. <b>Results</b>: Integrated analyses identified IL1B, TNF, and IL6 as core targets through which SSB1 exerts its anti-ALI effects. These targets were validated by high-affinity binding in simulations, confirmed in independent GEO transcriptomic datasets, and shown to be normalized by SSB1 treatment in vivo. Mechanistically, SSB1 appears to modulate the NOD-like receptor and cGAS-STING signaling pathways and rectify the key metabolic pathways orchestrated by these targets, including glycerophospholipid, arachidonic acid, and linoleic acid metabolism. <b>Conclusions</b>: This study systematically investigates the therapeutic effects of SSB1 against ALI by identifying its potential targets and underlying pathways. These results provide crucial mechanistic insights and robust experimental support, thereby paving the way for the clinical translation of SSB1.