Integrated lipid metabolomics and network pharmacology to investigate the potential mechanism of Coix seed in alleviating ulcerative colitis

Coix seed (CS), an agricultural crop often eaten as a staple food, has been used as a functional food treating ulcerative colitis (UC) recently. However, the underlying mechanism of CS on treating UC remains unclear. This study innovatively explored the preventive effects of CS on dextran sulfate sodium (DSS)-induced colitis in mice and its underlying mechanisms using lipid metabolomics and network pharmacology analysis. The results demonstrated that CS significantly reduced body weight loss, DAI scores, colonic damage and pro-inflammatory cytokines levels, such as TNF-α and IL-6, in UC mice. Additionally, CS reversed the DSS-induced downregulation of tight junction proteins, including ZO-1 and Occludin. Lipidomics results indicated a significant difference in lipid status between the normal and UC mice, which was reduced following CS treatment. Notably, levels of phosphatidylethanolamine (PE) and sphingomyelin (SM) were the most significantly altered lipids in UC mice after CS treatment. Furthermore, network pharmacology analysis indicated SRC, PPARG, PTGS2, MAPK1, MAPK3 and ESR1 as key targets for CS in alleviating UC inflammation. The enrichment analysis revealed that CS targeted functional modules associated with MAPK signaling and lipid metabolism. Further experimental validation, molecular docking and molecular dynamics simulation demonstrated that CS exerts significant protective effects through the Src/JNK MAPK and Nrf2/PPARγ signaling pathways. Overall, this study elucidated the potential of CS as a treatment for UC by regulating the lipid metabolism, which may be related to the Src/JNK MAPK and Nrf2/PPARγ signaling pathways. This strategy provides an important support for the utilization and development of CS as a functional food in human wellness, especially in ameliorating UC. • Coix seed (CS) provides the ability of alleviation for colitis symptoms. • CS could improve the disturbed lipid status induced by DSS, particularly in the PE and SM content. • Network pharmacology elucidated that CS focused on 6 key targets (SRC, PPARG, PTGS2, MAPK3, MAPK1 and ESR1) to alleviate UC. • CS alleviates inflammation in UC mice through MAPK signaling pathway. • Nrf2/ PPARγ signaling pathway may be the core pathway for CS in stabilizing the lipid state.