Ulcerative colitis (UC) is a chronic inflammatory bowel disease (IBD) caused by multiple factors. Studies have shown that epithelial cell damage was associated with ferroptosis in UC. Therefore, our research focused on the effects and mechanism of iron chelator deferasirox in UC.The UC model was induced by 2.5 % dextran sulfate sodium salt (DSS) and administered with deferasirox (10 mg/kg) for 7 days. Histological pathologies, inflammatory response, ferrous iron contents, oxidative stress and ferroptosis regulators were determined. Intestinal microbiota alteration and short-chain fatty acids (SCFAs) production were analyzed through 16S rRNA gene sequencing and targeted metabolomics.Deferasirox significantly relieved the DSS-induced UC in mice, as evidenced by weight loss, survival rate, colon length shortening disease activity index (DAI) score and histology score. Deferasirox treatment reduced the level of pro inflammatory cytokines (IL-1β, IL-6, TNF-α and INF-γ). Ferroptosis was induced in mice with UC, as evidenced by ferrous iron accumulation, increased ROS production, SOD and GSH depletion, decreased the expression of GPX-4 and FTH, accompanied by increased expression of TF. Deferasirox treatment strongly reversed the alterations caused by ferroptotic characteristics in DSS-induced mice. Moreover, deferasirox treatment reshaped the composition of intestinal microbiota. The results revealed the genera of norank_f__Muribaculaceae, Lachnospiraceae_NK4A136_group, Prevotellaceae_UCG-001, Odoribacter and Blautia were increased distinctly, while Escherichia-Shigella and Streptococcus were significantly decreased by deferasirox treatment. Targeted metabolomics analysis indicated the SCFAs production enhanced in deferasirox-treated mice.Our results suggested that deferasirox could treat DSS-induced UC in mice by inhibiting ferroptosis and improving intestinal microbiota.Copyright © 2022. Published by Elsevier Inc.