Plantaginis Semen, a Novel Natural S1PR1 Agonist, Inhibits Oxidative Stress and Inflammation to Treat Lipopolysaccharide‐Induced Acute Lung Injury

Background Acute lung injury (ALI) is a critical condition with high clinical morbidity, mortality, and poor prognosis. Existing therapeutic drugs and methods have side effects and limitations that seriously affect patients' quality of life. Therefore, it is crucial to research the pathogenesis of ALI and explore safe and effective treatment. Objective We aimed to validate the potential of plantaginis semen (PS) against ALI and clarify its underlying mechanism of action in ALI treatment using integrated analytical methods and tools. These findings provide a basis for the development of safe and effective therapeutic drugs based on PS for ALI. Methods ALI mice were used to test the overall efficacy of PS in vivo. Metabolomics was used to explore the metabolic pathways involved in ALI. The PS extract was analyzed using LC‐MS/MS and a network pharmacology analysis was performed. This analysis led to a better understanding of the key active ingredients and pathways. Finally, BEAS‐2B cells were used to construct an in vitro model of ALI and to functionally validate the key targets and mediate the effects of the active ingredients using a series of molecular biology tools, such as immunoblotting, siRNA, and immunoprecipitation. Additionally, the expression of key targets in mouse lung tissues was verified and analyzed. Results PS effectively alleviated inflammation and histopathological changes in mice lungs. Metabolomic and network pharmacology results showed that sphingolipid metabolism is a key pathway for PS in ALI treatment. Therefore, plantamajoside may be a crucial active ingredient in PS. After exposure to lipopolysaccharide (LPS), the activities of S1PR targets in BEAS‐2B cells were inhibited, with S1PR1 inhibition being the most pronounced, and inflammation levels, S1P and ROS were significantly upregulated. Plantamajoside (PE) treatment significantly reversed these functional phenotypes. Additionally, co‐immunoprecipitation results established AKT as a downstream target of S1PR1 and S1PR1 knockdown significantly reduced LPS‐induced inflammation levels, lipid activity, and oxidative stress. Overexpression of S1PR1and PE treatment restored homeostasis. Further studies showed that PE promotes S1PR1 expression and inhibits AKT phosphorylation, thereby alleviating apoptosis. Conclusion These comprehensive analytical approaches identified S1PR1 as a significant target for the development of ALI, which can help elucidate the pathogenesis of PF and provide a basis for drug development. These findings also contribute to understanding the anti‐ALI effects of PS.