Multi-omics analysis reveals diagnostic and therapeutic biomarkers for aging phenotypes in ulcerative colitis.

BACKGROUND: The incidence of ulcerative colitis (UC) remains high, with an increasing prevalence among elderly patients. Cellular senescence has been widely recognized as a contributor to UC susceptibility; however, the underlying molecular mechanisms remain incompletely understood. This study aimed to identify senescence-associated biomarkers in UC to provide new insight for diagnosis and treatment. METHODS: By integrating transcriptomic data from UC patients with established aging-related databases, we identified aging-associated differentially expressed genes (DEGs). Using weighted gene co-expression network analysis (WGCNA) and Cytoscape, we pinpointed the core genes involved. A diagnostic model for UC was then developed based on these core genes, and their expression patterns were characterized at single-cell resolution. The roles of these genes were ultimately validated through in vitro and animal experiments. RESULTS: We identified 24 aging-related DEGs in UC, which were primarily implicated in inflammatory responses and cytokine-receptor interactions. Further analyses pinpointed three core genes (CXCL1, MMP9, and STAT1) that were predominantly expressed in macrophages. A diagnostic model constructed using these genes exhibited robust predictive performance. Experimental validation confirmed that the expression levels of all three core genes were significantly upregulated in both a UC mouse model and in macrophages compared to controls. Additionally, pathway analyses revealed elevated levels of CXCL12 and VEGFA in the enriched pathways. DISCUSSION: Our findings underscore the pivotal roles of CXCL1, MMP9, and STAT1 in UC-associated cellular senescence. The analysis positions these molecules as promising macrophage-mediated diagnostic biomarkers and therapeutic targets. Collectively, this work provides novel insights into UC pathogenesis and lays a foundation for developing precision medicine strategies that target senescence pathways.