Bioinformatic validation of LCN2 as a common hub gene for ferroptosis, pyroptosis and necroptosis in ulcerative colitis

Ulcerative colitis (UC) is a chronic inflammatory disease with an unclear etiology. Recent research has indicated that specific cell death modalities, such as ferroptosis, pyroptosis, and necroptosis, are associated with the progression of UC. This study aims to identify hub genes potentially associated with these three forms of cell death in the context of UC. For this analysis, we utilized data obtained from the GEO, FerrDB, and GeneCards databases. We conducted differential expression and WGCNA analyses on colon samples from GSE75214 to uncover hub genes related to ferroptosis, pyroptosis, necroptosis, and UC. Subsequently, we performed enrichment analysis, single-cell distribution assessments, and immune infiltration analysis of the hub genes. Additional validation was conducted utilizing supplementary GEO datasets and the DSS colitis model. We identified 50 common genes associated with ferroptosis, pyroptosis, and necroptosis, of which Lipocalin 2 (LCN2) presented significant differential expression in UC tissue samples. GSEA enrichment analysis showed that LCN2 has a vital role in modulating the immune response and the production of inflammatory mediators. Single-cell sequencing analysis demonstrated a predominant distribution of LCN2 in intestinal epithelial cells. Correlation analysis revealed a link between LCN2 and the infiltration of plasma cells and M0 macrophages in UC. Furthermore, mouse colon samples detected by qRT-PCR and immunohistochemical staining confirmed that LCN2 expression was upregulated in the DSS-induced colitis model. In summary, this study reveals an association between LCN2 expression and genes involved in ferroptosis, pyroptosis, and necroptosis pathways in patients with UC. This discovery opens new avenues for further exploration into the pathogenesis of the disease and the search for effective therapeutic targets.