Integrated UHPLC-MS/MS Metabolomics, Network Pharmacology, Molecular Docking, and Experimental Validation Reveal the Anti-Inflammatory Mechanisms of Pyrus pyrifolia Peel Extract

Abstract

Pyrus pyrifolia (Burm. f.) Nakai has long been utilized in traditional East Asian medicine to treat respiratory disorders, fever, cough, and inflammatory conditions. This study aimed to evaluate the antioxidative and anti-inflammatory effects of P. pyrifolia. UHPLC-MS/MS analysis revealed that P. pyrifolia contained 22 primary and other putative compounds belonging to diverse phytochemical groups—phenolics, flavonoids, fatty acids, terpenoids, alkaloids, and other compounds. Network pharmacology identified a subset of overlapping targets associated with inflammatory diseases, which were significantly enriched in immune- and inflammation-related biological processes. KEGG pathway analysis demonstrated that the Toll-like receptor was the principal pathway potentially regulated by overlapping targets. PPI network analysis revealed TNF to be the most influential hub target, which was verified by molecular docking analysis. Interestingly, the P. pyrifolia extract significantly inhibited LPS-induced TNF-α production by modulating IκBα phosphorylation and restoring IκBα expression in the NF-κB signaling pathway. Additionally, the P. pyrifolia extract also markedly reduced the phosphorylation of ERK, p38, and JNK, thereby affecting MAPK signaling pathways. Our findings provide mechanistic evidence supporting the traditional medicinal use of P. pyrifolia to establish a theoretical framework to develop phytopharmaceuticals for inflammatory diseases.