Objective: To investigate the mechanism of Sanguisorbae Radix (SR) in the treatment of Ulcerative Colitis (UC). Methods: The study analyzed GSE92415 from the Gene Expression Omnibus (GEO) database using differentially expressed genes analysis, weighted gene correlation network analysis (WGCNA) and FerrDb. Core genes were identified through protein-protein interaction (PPI) network and correlation analysis. The efficacy of SR in UC was evaluated in a dextran sodium sulphate (DSS)-induced colonic inflammatory mouse model by analyzing DAI, histopathology and colon length. ELISA was used to examine levels of inflammatory cytokines and lipid peroxidation. The expression levels of ZO-1 tight junction protein, PPARG, SLC7A11 and GPX4 protein were examined through Western blotting or immunofluorescence labeling. Results:S Nine differentially expressed genes associated with ferroptosis were screened and PPARG was identified as a key gene. The experimental animal results showed that SR significantly prevented colon shortening and ameliorated histological injuries of colons in DSS-treated mice. SR inhibited cytokine levels of IL-6 and TNF-α, improved the reduction of ZO-1 and levels of MDA and GSH in colon tissues of DSS mice. Meanwhile, it enhanced the activation of PPARG, SLC7A11 and GPX4, which reversed the therapeutic effect of DSS in mice with colitis. Conclusion: Iron death is closely related to UC. SR can inhibit iron death by regulating the PPARG and SCL7A11/GPX4 expression, thereby improving colon epithelial injury and dysfunction in UC mice. This provides ideas and direction for UC treatment strategies.