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Background Ulcerative colitis (UC) is a chronic inflammatory disease of the colonic mucosa, representing a significant global health challenge in developing effective therapies. This study investigates the regulatory effects of Schisandrin A (Sch A) on gut microbiota composition in a UC mouse model induced by dextran sulfate sodium (DSS) and elucidates the mechanisms by which Sch A mitigates ferroptosis in intestinal epithelial cells.Methods Mouse models of UC induced by DSS, along with corresponding in vitro cellular models, were established. Techniques such as Western blotting (WB), flow cytometry, and ferrous ion fluorescent labeling were employed to assess the therapeutic efficacy of Sch A. Changes in gut microbiota following Sch A intervention were analyzed using 16S rRNA sequencing. A comprehensive approach, including network pharmacology, molecular docking (MD), kinetic simulations, cellular thermal shift assay (CETSA), and drug affinity responsive target stability (DARTS), identified arachidonate 15-lipoxygenase (ALOX15) as a key target of Sch A in suppressing ferroptosis. Additionally, transcriptomic and untargeted metabolomic analyses revealed complex regulatory influences of Sch A on UC at the omics level.Results Both in vitro and in vivo studies demonstrated that Sch A significantly alleviated UC symptoms in mice. Mechanistically, Sch A treatment reduced the expression of ACSL4 and PTGS2 while increasing levels of SLC7A11 and GPX4. Untargeted metabolomics indicated that Sch A modulated arachidonic acid metabolism in UC mice. Transcriptomic analysis showed a marked decrease in ALOX15 expression following in vitro treatment with Sch A. Network pharmacology confirmed ALOX15 as a potential target for ferroptosis inhibition. Validation through MD, kinetic simulations, CETSA, and DARTS supported these findings. Furthermore, 16S rRNA sequencing revealed an increase in beneficial intestinal probiotics and a decrease in potentially pathogenic bacteria in the Sch A group, indicating a restoration of gut microbiota balance.Conclusions This study provides the first evidence that Sch A, a dietary lignan from Schisandra berry, plays a dual protective role in UC by restoring microbial ecology and directly targeting ALOX15 to inhibit ferroptosis in intestinal epithelial cells ( IDDF2026-ABS-0074 Figure 1. Graphical Abstract). These findings highlight the potential of Sch A as a promising food-derived therapeutic agent for UC management. (Acknowledgements: This study was funded by National Natural Science Foundation of China (82370564))Abstract IDDF2026-ABS-0074 Figure 1