Natural polyphenol rutin inhibits ferroptosis in ulcerative colitis by regulating lipid metabolism <i>via</i> blocking the LCN2–ALOX15 axis

Ulcerative colitis (UC), a chronic inflammatory disorder with elevated carcinogenic risk, urgently requires multi-target therapeutic strategies. Ferroptosis, characterized by iron-dependent lipid peroxidation, emerges as a promising intervention target for intestinal barrier protection. Rutin, a natural polyphenol with established anti-inflammatory properties, holds therapeutic potential for UC, yet its mechanisms involving ferroptosis regulation and barrier enhancement remain unexplored. This study elucidates rutin's novel role in mitigating UC through ferroptosis inhibition <i>via</i> lipid metabolic modulation. Through network pharmacology and experimental validation, we identified LCN2 as rutin's primary target. <i>In vivo</i> and <i>in vitro</i> studies demonstrated rutin's dual efficacy in reinforcing intestinal barrier integrity and suppressing ferroptosis in colonic epithelial cells. Co-immunoprecipitation, immunofluorescence, and LCN2-knockdown assays revealed rutin's disruption of the LCN2-ALOX15 interaction axis, thereby inhibiting lipid peroxidation cascades. Metabolomics profiling further confirmed rutin's regulatory effects on dysregulated lipid metabolism, particularly arachidonic acid pathways, in UC models. These findings establish that rutin alleviates UC progression by orchestrating lipid metabolic reprogramming through blockade of the LCN2-ALOX15 axis, positioning this natural compound as a promising multi-target therapeutic candidate for ferroptosis-associated intestinal pathologies.