Investigating the effect of tenuigenin on LPS-induced HPMEC dysfunction by inhibiting SRC activation based on network pharmacology and molecular docking.

BACKGROUND: Adult pneumonia is an infectious lung disease caused by bacteria, viruses, or other microorganisms and exhibits some degree of contagion. Tenuigenin, a bioactive compound derived from Polygala tenuifolia, possesses broad pharmacological effects, but its role in adult pneumonia remains incompletely understood. METHODS: Bioinformatics and database analysis were employed to screen and analyze the Tenuigenin target genes relevant to adult pneumonia. Cell functions were assessed using cell counting kit-8 (CCK8), 5-ethynyl-2'-deoxyuridine (EdU) staining, transwell, tube formation, Fluo-4 calcium assay, and transepithelial electrical resistance (TER) assays. Protein levels were measured by western blot. Network pharmacology and molecular docking were employed to screen core target genes and verify binding interactions. RESULTS: Tenuigenin targets in adult pneumonia were enriched in the pathways related to vascular permeability and calcium signaling. Tenuigenin mitigated lipopolysaccharide (LPS)-induced impairment of human pulmonary microvascular endothelial cell (HPMEC) viability, proliferation, migration, and angiogenesis, while attenuating LPS-induced increases in apoptosis, calcium ion, and reactive oxygen species (ROS) levels. Besides, Tenuigenin also attenuated the TER decrease and permeability increase caused by LPS exposure in HPMECs. Network pharmacology and molecular docking identified steroid receptor coactivator (SRC) as a core target of Tenuigenin, demonstrating binding to specific SRC amino acid residues. Tenuigenin also reduced LPS-induced increase in phosphor-SRC (p-SRC) expression. Crucially, after inhibition of SRC kinase activity, Tenuigenin no longer exerted significant protective effects against LPS-induced HPMEC injury and dysfunction. CONCLUSION: Tenuigenin alleviates LPS-induced injury and dysfunction of HPMECs by targeting the SRC pathway, providing a target for managing adult pneumonia.