Abstract
Inhibition of epithelial ferroptosis in colonic tissues relieved clinical symptoms and improved endoscopic presentations in inflammatory bowel disease (IBD). Kumatakenin, the main ingredient of traditional Chinese medicinal cloves and Alpinia purpurata, is reported to possess therapeutic benefits. However, whether kumatakenin could inhibit ferroptosis and further alleviate colitis remains unclear. Here, we measured the effects of kumatakenin on ferroptosis of colonic epithelial cells from colitis mice. The colitis model was induced in mice by oral intake of 2.5% dextran sulfate sodium in drinking water. RNA sequencing was performed to investigate the mechanism underlying kumatakenin-mediated effects on colitis. The results showed that different doses of kumatakenin significantly alleviated symptoms and suppressed intestinal inflammation in the colitis mouse model. Kumatakenin supplementation decreased cellular iron levels and suppressed ferroptosis in epithelial cells from colitis mice. RNA sequencing, qPCR, and pharmacological inhibition assays showed that kumatakenin reduced cellular iron levels and suppressed ferroptosis in epithelial cells from colitis mice at least partially by upregulating expression of enolase (Eno-3). Furthermore, kumatakenin decreased iron levels in epithelial cells by modulating the Eno3-iron regulatory protein (IRP1) axis. Molecular docking results revealed that kumatakenin could bind Eno3 via hydrogen bonding with the amino acid residues Thr208, Val206, and Pro203. This work will provide a scientific basis for the clinical use of kumatakenin in the treatment of colitis.