Targeting Ferroptosis and Cuproptosis in Ulcerative Colitis: Findings from Comprehensive Bioinformatics and Experimental Validation

Ulcerative colitis (UC) is a persistent intestinal disorder with an incompletely defined pathogenesis and increasing prevalence and hospitalization rates in newly industrialized countries. In UC, excessive intestinal epithelial cell death disrupts the mucosal barrier and triggers inflammatory responses. Ferroptosis and cuproptosis are two recently described forms of regulated cell death. Most studies of UC have examined these processes separately; however, their combined roles in UC progression remain insufficiently characterized. To investigate their synergistic roles in UC pathogenesis, we used a stepwise approach involving large-scale transcriptomic profiling to identify candidate targets, followed by validation in in vitro models. Differentially expressed genes (DEGs) were intersected with ferroptosis-related genes (FRGs) and cuproptosis-related genes (CRGs). The overlapping targets were prioritized using a consensus of machine learning algorithms and weighted gene co-expression network analysis (WGCNA). Five biomarkers-LCN2, IDO1, CXCL2, NOS2, and CD274-were significantly upregulated in UC. Single-cell analysis characterized their expression across different cell types, with LCN2 and NOS2 primarily enriched in epithelial cells. The mechanistic relevance of these markers was further evaluated through in vitro assays. Treatment with ferroptosis or cuproptosis inhibitors alleviated UC-associated inflammation and modulated biomarker expression in Caco-2 cell models. These findings identify five biomarkers associated with UC progression and provide experimental evidence supporting their potential application in clinical diagnosis and therapeutic intervention.