Mechanistic insights into Plantago major L. for Alzheimer’s disease treatment: Untargeted metabolomic-network pharmacology and molecular docking approach

Context: Alzheimer's disease (AD) is a progressive neurodegenerative disorder with limited therapeutic options. Plantago major, an herbal plant with prominent anti-inflammatory and antioxidant properties, has shown potential antineuroinflammatory effects for AD treatment. Aims: To elucidate the mechanistic basis of P. major in AD treatment using integrated untargeted metabolomics, network pharmacology, and molecular docking. Methods: Dried P. major leaves were extracted using ultrasonic-assisted extraction, and the extract was analysed by UHPLC-HRMS. Identified bioactive metabolites were subjected to ADMET screening and profiling. These metabolites were then evaluated using network pharmacology, validated through molecular docking, and prioritised using the SAW method. Results: Fifteen metabolites met drug-likeness criteria, and network analysis identified 455 overlapping protein targets associated with AD, including ten key nodes such as SRC, PIK3R1, and MAPK1. Aucubin, scutellarein, luteolin, hispidulin, and ursolic acid exhibited strong binding affinities to these targets and ranked among the top six in SAW prioritization. These metabolites were further implicated in PI3K–AKT, JAK–STAT, and MAPK signaling pathways linked to neuroinflammation. Conclusions: The findings support the therapeutic potential of P. major in AD through the modulation of neuroinflammatory mechanisms, particularly via the JAK-STAT, MAPK, and PI3K-AKT pathways, and highlight its potential for further in vitro and in vivo investigations.