Decoding ulcerative colitis pathogenesis through transcriptomics: from dysregulated gene networks to targeted intervention strategies.

Background: Ulcerative colitis (UC) is an immune-mediated chronic inflammatory bowel disease, and with the rising global incidence and the risk of malignant transformation, the treatment of UC is challenged by heterogeneous progression and limited targeted therapies, and its underlying pathogenesis remains unclear. This study aims to identify novel therapeutic targets for UC, elucidate the genetic factors associated with UC development, and advance precision medicine strategies for UC. Methods: Differential expression analysis was performed on three independent UC datasets from the Gene Expression Omnibus (GEO) database, identifying differentially expressed genes (DEGs) associated with UC. An eQTL-MR analysis was conducted to identify UC-related gene expression loci, and the results were intersected with the GEO differential analysis using a Venn diagram. Subsequently, a protein-protein interaction network was constructed based on the 20 intersecting genes identified through both eQTL-MR and differential expression analysis, using STRING. Key hub genes were then identified based on centrality scores calculated in Cytoscape. Additionally, Gene Set Enrichment Analysis (GSEA) and Gene Ontology (GO)/Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were used to explore the functional roles and pathways of these genes. Finally, the results obtained for the target genes were validated. Results: Twenty intersecting genes were identified, specifically PITPNC1, OLFM1, PARP9, BATF2, PDGFRB, LEF1, CST7, HCLS1, SLC16A6, CCR7, KMO, ITGA4, SLC22A5, ASB13, SLC22A4, DNMBP, PGAP3, FAAH, SLC7A9, and BTNL8. These genes are involved in fundamental biological processes and pathways, including immune response modulation and epithelial barrier regulation. Additionally, CIBERSORT analysis revealed a unique immune cell distribution in UC and highlighted the association between immune cells and the intersecting genes. Gene Set Enrichment Analysis (GSEA) showed that high expression levels of HCLS1, ITGA4, and PDGFRB may collectively contribute to the recruitment and activation of inflammatory cells, as well as the amplification of immune signaling. Conversely, lower expression levels of these genes suggest that the tissue may be in a state of reduced inflammation or repair. The MR analysis was consistent with the results of variance analysis in the validation cohort, further reinforcing the reliability of our MR findings. Conclusions: HCLS1, ITGA4, and PDGFRB may represent core modules involved in T/B cell homing and activation, pro-inflammatory macrophage recruitment, and extracellular matrix responses. These genes interact with upregulated genes to promote the amplification of inflammation, counteracting with downregulated metabolic-related genes. Together, they contribute to the molecular foundation of the inflammatory and metabolic protective phenotype observed in ulcerative colitis.