Objective To explore the mechanism of Hedysarum multijugum⁃Rhizoma dioscoreae herb pair for the treatment of acute lung injury (ALI) based on network pharmacology and molecular docking technique. Methods  Active components and corresponding effect targets of Hedysarum multijugum and Rhizoma dioscoreae were obtained through the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform, and targets related to ALI were acquired from the GeneCards® database, after then the aforementioned targets were intersected (the intersection targets). The Cytoscape software was used to establish a network of drug⁃component⁃target⁃disease for screening the core active components of Hedysarum multijugum⁃Rhizoma dioscoreae herb pair. The STRING platform was employed to establish protein⁃protein interaction network for screening the core targets of Hedysarum multijugum⁃Rhizoma dioscoreae herb pair for the treatment of ALI. The R language software was used for performing Gene Ontology functional enrichment analysis and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis. The Schrödinger software was employed to perform molecular docking between the core active components and the core target proteins. Results A total of 16 active components of Hedysarum multijugum and 12 of Rhizoma dioscoreae were screened, concerning 179 corresponding effect targets, 8905 targets related to ALI, and 170 intersection targets. The core active components of Hedysarum multijugum⁃Rhizoma dioscoreae herb pair were quercetin, kaempferol, 7⁃O⁃methylisomucronulatol, stigmasterol, formononetin and isorhamnetin. The core targets of Hedysarum multijugum⁃Rhizoma dioscoreae herb pair for the treatment of ALI were serine/threonine protein kinase (AKT)1, prostaglandin⁃endoperoxide synthase 2 (PTGS2), tumor necrosis factor (TNF), tumor protein p53 (TP53), interleukin (IL)⁃6, and IL⁃1β. The intersection targets were involved in biological processes such as response to nutrient levels, response to exogenous stimuli, and response to lipopolysaccharide, in cellular compositions such as membrane rafts, membrane microzones, and synaptic membranes, and in molecular functions such as DNA⁃binding transcription factor binding and DNA⁃binding transcription activator activity. The intersection targets were mainly enriched in signaling pathways such as phosphoinositide 3⁃kinase (PI3K)/AKT, IL⁃17, TNF, and hypoxia inducible factor 1 (HIF⁃1). The results of molecular docking revealed that the core active components of Hedysarum multijugum⁃Rhizoma dioscoreae herb pair exerted favorable binding activity with the core target proteins PTGS2, IL⁃6, and AKT1. Conclusion The core active components of Hedysarum multijugum⁃Rhizoma dioscoreae herb pair such as quercetin, kaempferol, 7⁃O⁃methylisomucronulatol, stigmasterol, formononetin and isorhamnetin may regulate signaling pathways such as PI3K/AKT, IL⁃17, TNF, and HIF⁃1, exerting therapeutic effect of ALI through acting on the core targets such as PTGS2, IL⁃6, and AKT1.

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