original data.rar

Inhibition of ferroptosis in intestinal epithelial cells ameliorates clinical symptom and improves endoscopic presentations in inflammatory bowel disease (IBD). Liquiritin is a main effective ingredient of <i>Glycyrrhiza Radix</i>, which has been applied as a therapeutic strategy in China for thousands of years, and could significantly ameliorate chemically induced colitis. However, whether liquiritin could affect IBD still remains unclear. Herein we evaluated the effects of liquiritin on colitis and whether liquiritin could affect IBD by modulating ferroptosis in epithelial cells. Colitis model was induced in mice by oral treatment with 2.5% DSS dissolved in drinking water. Results showed that liquiritin significantly alleviated symptom, suppressed intestinal inflammation and restored epithelial barrier function in colitis mice model. Liquiritin supplementation upregulated colonic ferritin expression, increasing the storage of cellular iron, reducing cellular iron level and further inhibited ferroptosis in epithelial cells from colitis model. Pharmacological stimulation of ferroptosis largely blocked liquiritin-induced alleviation of colitis. Peroxiredoxin-6 (Prdx6) expression was significantly decreased in DSS group, which was reversed by liquiritin treatment. Genetic or pharmacological silencing of Prdx6 largely reversed liquiritin-induced modulation of ferritin/iron level and ferroptosis in epithelial cells. Molecular docking results showed that liquiritin could bind to Prdx6 through the hydrogen bond interaction with amino acid residues Thr208, Val206 and Pro203. In conclusion, liquiritin treatment largely alleviated DSS induced colitis by inhibiting ferroptosis in epithelial cells. Liquiritin-induced activation of Prdx6 led to reduction of cellular iron content, and further inhibition of epithelial ferroptosis.