Effects of guaiane sesquiterpenoids from the invasive species Ambrosia trifida on inflammatory bowel disease by targeting JAK2/STAT3 signaling

Ambrosia trifida, known worldwide as an invasive species, threatens agriculture and ecosystems and causes severe allergic reactions in humans. As part of the effort to valorize this harmful plant, a phytochemical investigation of A. trifida led to the isolation of one new guaiane sesquiterpenoid (1S,7R,10R)-10,11-dihydroxy-4-guaien-3-one (1), together with two diastereomers (2 and 3). Their structures were elucidated using various spectroscopic methods, including NMR, HRMS, optical rotation, and ECD calculations. (1S,7R,10R)-11-Hydroxy-4-guaien-3-one (2) was isolated for the first time from nature. Its (1R,7R,10S)-diastereomer (3) has not been previously reported in the Compositae family. Based on network pharmacology and molecular docking analyses, the effects of 1-3 on inflammatory bowel disease (IBD) were examined. Among the isolates, only 2 exhibited anti-inflammatory and tight junction regulatory activities by targeting the JAK2/STAT3 signaling pathway in Caco-2 cells. In contrast, its diastereomer 3 was inactive, indicating that the stereochemical configuration at C-1 and C-10 plays a critical role in biological activity. This study suggests that guaiane sesquiterpenoids may be useful for the treatment of IBD, and the findings serve as a basis for a wide range of applications of this invasive plant as a useful resource.