Metabolomics and network pharmacology reveal the anti‐inflammatory core substances and mechanisms of a new cultivar of high‐polyphenol lettuce

Abstract BACKGROUND Diet plays a significant role in mitigating inflammation, with lettuce and its polyphenols showing potential for improving inflammatory conditions. However, research on the material basis and mechanisms of action remains unclear. RESULTS This study investigated the primary components and anti‐inflammatory effects of the new lettuce cultivar Binfen‐1, which is rich in polyphenols and may offer enhanced health benefits. There were 65 metabolites with significant changes in Binfen‐1 by metabolomics, comprising mainly polyphenols. Meanwhile, the high‐polyphenol lettuce extract (HPLE) from Binfen‐1 demonstrated superior antioxidant and anti‐inflammatory effects in vitro . Moreover, HPLE showed a significant improvement in mice with dextran sodium sulfate‐induced ulcerative colitis. By integrating network pharmacology with high‐performance liquid chromatographic quantitative results, isoquercitrin and chlorogenic acid were identified as the core active substances in HPLE, and the PI3K‐Akt, MAPK, and JAK–STAT pathways were the key anti‐inflammatory pathways for HPLE, supported by mRNA validation and molecular docking predictions. CONCLUSION The core anti‐inflammatory substances in HPLE were isoquercitrin and chlorogenic acid, with the key anti‐inflammatory pathways being the PI3K‐Akt, MAPK, and JAK–STAT pathways. These findings substantially propel the understanding of the therapeutic potential of lettuce in the treatment of inflammatory diseases. © 2025 Society of Chemical Industry.