Integrating Molecular Analysis and the Pharmacology Network to Discover the Antioxidative Effects of Zanthoxylum piperitum Fruits

Zanthoxylum piperitum is a food and culinary plant commonly used in East Asia. In traditional medicine, its fruits, seeds, and bark have been utilized to treat digestive disorders, pain, and stomachache. Prior research has demonstrated its health benefits, particularly its significant antioxidant properties. However, limited research has investigated the specific metabolites responsible for these pharmacological effects. In this study, the antioxidant activities (EC50: 9.1–1084.5 μg/mL) and metabolite profiles of different organs (fruits, pericarps, and seeds) of Z. piperitum collected from different regions were comparatively analyzed. Chemical structures of 91 metabolites from different organs were identified using UHPLC-Orbitrap-MS/MS based on untargeted metabolomics. The LC-DPPH method was employed to screen antioxidants from the extracts of the most active organ (the pericarps). The potential effects of the active compounds on oxidation-related diseases were evaluated by integrating compound–target interaction network analysis. Protein–protein interaction (PPI) networks revealed EGFR, STAT3, AKT1, TNF, BCL2, CASP3, ESR1, PPARA, CYP19A1, and CDK2 as central hub genes. The significance of compound and target interactions was further supported by molecular docking studies, which demonstrated favorable binding affinities, with most proteins exhibiting docked scores below −4.27 kcal/mol. The extracts of Z. piperitum fruits and pericarps also exhibited antioxidative activity against ROS production in LPS-stimulated RAW264.7 cells. Our findings demonstrate the application of an optimized extraction process and underscore the medicinal value of this food-plant by characterizing its bioactive constituents. The results indicate that Z. piperitum may serve not only as a health-promoting food but also has the potential for prevention or treatment of oxidative-stress-related diseases. Future research should focus on in vivo studies by exploring the therapeutic mechanisms of actions of the active extracts.