High-fat diet alleviates colitis by inhibiting ferroptosis via solute carrier family seven member 11.

A high-fat diet (HFD) is reported to exacerbate ulcerative colitis by inducing obesity, which conceals the effect of the diet itself. Ferroptosis, a type of regulated cell death induced by lipid hydroperoxides, has recently been reported in colitis. Here, we aimed to determine whether HFD affects ferroptosis and colitis progression in an obesity-independent manner. We subjected male C57BL/6J mice to either an HFD (60% fat diet) or isocaloric control diet (10% fat diet) for 4 weeks, followed by inducing colitis with 2.5% dextran sulfate sodium (DSS). Compared with the isocaloric control diet, non-obesogenic HFD reduced DSS-induced colonic mucosal injury, as shown by disease activity index, colon thickness, inflammatory infiltrations, and mucosal damage index; however, there were no differences in body weight, Lee's index, and omental fat weight between the two groups. HFD mice exhibited decreased lipid peroxidation and ferroptosis markers expression in colon tissues. Furthermore, a lipid mixture protected gut organoids and normal colonic epithelial cells from RSL3-induced ferroptosis. Mechanistically, the lipid mixture prevented glutathione deficiency by upregulating the cysteine transporter, solute carrier family seven member 11. Collectively, these findings suggest that an HFD ameliorates DSS-induced colitis through ferroptosis repression in an obesity-independent manner and provide new evidence to evaluate the effects of an HFD on colitis.