Objective To explore the underlying mechanisms of ulcerative colitis(UC)pathogenesis using single-cell transcriptomic bioinformatics approaches.Methods Single-cell transcriptome dataset GSE125527,consisting of UC samples,was downloaded from a high-throughput Gene Expression Omnibus for this study.Data filtering and normalization were conducted using the Seurat package in R.Cells with similar gene expression profiles were clustered and annotated.Cell subgroups associated with UC pathogenesis were identified,and differ-entially expressed genes(DEGs)were extracted.Enrichment analysis of these DEGs was performed to uncover potential signaling pathways involved in UC.High-dimensional weighted gene co-expression network analysis(hdW-GCNA)was applied to the cell subgroup with the greatest differences to select UC-related gene modules.Additional datasets,GSE36807,GSE42911,GSE65114,and GSE6731,were downloaded for DEG screening.By integrating single-cell DEGs with UC-related gene modules,core genes involved in UC pathogenesis were identified.Receiver operating characteristic(ROC)curves were plotted to evaluate the predictive value of these core genes for UC pathogenesis.The expression of core genes was validated in a UC rat model.Results After filtering,18642 cells from UC samples and 4298 cells from normal colonic tissue were obtained and clustered into ten subgroups,with a high proportion of B cells in UC samples.Eighty-one upregulated and twenty-one downregulated DEGs related to mononuclear cells were identified.Significant enrichment of DEGs was observed in pathways related to tumor necro-sis factor-alpha,nuclear factor Kappa B,interleukin-2,signal transducer and activator of transcription 5,and interferon-alpha.Two UC-related gene modules were identified through hdWGCNA.After screening and validation,LAPTM5 was confirmed as a core gene in UC pathogenesis.Compared to control rats,LAPTM5 expression was significantly higher in the colonic tissues of UC model rats.Conclusions There are significant differences in cell distribution between UC and normal colonic tissues,with B cells closely related to UC pathogenesis,serving as potential targets for prevention and treatment.LAPTM5 is identified as a potential core gene in UC pathogenesis.