Chrysanthemum, a traditional Chinese medicinal herb, exhibits various biological activities, including anti-inflammatory, anti-tumor, and antiviral effects. However, its potential role in preventing inflammatory bowel disease (IBD) and the underlying mechanisms remain unclear. In this study, we cultivated and identified a chrysanthemum variety, Hong Lian, with a high content of flavonoid. We extracted components from the plant and applied Chrysanthemum ‘Honglian’ extract (CM-HLE) to DSS-induced colitis C57BL6 mice. We found that CM-HLE pretreatment could significantly alleviate symptoms of intestinal inflammation in mice, including weight loss, colon shortening, intestinal epithelial injury, and immune cell infiltration. Further, we found that CM-HLE treatment effectively prevented intestinal epithelial CCD841 cells from DSS-induced ferroptosis, a programmed cell death triggered by iron accumulation and lipid peroxidation in cells. Mechanistically, we validated the enrichment of ferroptosis-related signaling pathways in intestinal epithelial cells of mice treated with CM-HLE in the RNA-seq analysis and demonstrated that CM-HLE inhibited ferroptosis in intestinal epithelial cells by upregulating SLC7A11. The untargeted metabolomics analysis of CM-HLE revealed that its main components, apigenin-7-glucuronide and apigenin-7-glucoside, both inhibit ferroptosis via the ATF3/SLC7A11 axis. In conclusion, our study reveals a novel medicinal value of chrysanthemum, offering a new strategy for the prevention and treatment of IBD.

3-Epi-betulinic acid 3-O-β-D-glucopyranoside (eBAG) is a pentacyclic triterpene mainly distributed in food and medicinal plants, which exhibits various pharmacological properties. However, whether these functions are attributed to eBAG or additional components in these plants remain unknown. Herein, we report that eBAG exerted an inhibitory activity against hepatocellular carcinoma and esophageal cancer cells. EBAG induced non-apoptotic cell death in hepatocellular carcinoma cells. The eBAG-induced cell death was inhibited by knock-down of autophagy related gene (ATG) 5 and ATG7, by administration of 3-methyladenine, a selective autophagy inhibitor that suppresses phosphoinositide 3-kinase (PI3K), and by chloroquine, a classic autophagy f lux inhibitor. We demonstrated that eBAG induced an autophagy-mediated cell death. Application of eBAG mimicked cellular bioenergetics depletion leading to the reduction of intracellular ATP, activation of AMP-activated protein kinase (AMPK), and inhibition of mTOR. Co-treatment with compound C, an AMPK inhibitor, abrogated cell death induced by eBAG. We further validated the anti-tumor effect of eBAG in the murine xenograft model of hepatocellular carcinoma and found that eBAG treatment promoted the induction of autophagy and reduction of tumor growth in mice. As a functional food ingredient, eBAG is a potential therapeutic agent for the treatment of hepatocellular carcinoma and esophageal cancer.