Aims: Ulcerative colitis (UC) is a common inflammatory bowel disease producing intestinal inflammation and tissue damage.The precise aetiology of UC remains unknown.UPF1 (up-frameshift mutantl) is a novel molecule for UC predicted by a computational approach.Our study aimed to validate underlying mechanism of UPF1 in UC.Method: We applied a rank-based expression profile comparative algorithm, gene set enrichment analysis (GSEA), to evaluate the expression profiles of UC patients and small interfering RNA (siRNA)-perturbed cells to predict proteins that might be essential in UC from publicly available expression profiles.UPF1 expression was detected by quantitative PCR (qPCR), western blot and immunohistochemistry in dextran sodium sulfate-induced colitic mice.To simulate the intestinal inflammation microenvironment for epithelial cells, NCM460 cells were exposed to a mixture of inflammatory mediators.NCM460 cells were transfected with siRNA (siUPF1) or UPFl-expressing plasmid pENTER and associated cytokines expression were detected by qPCR or ELISA.Possible mechanism involving inflammatory pathways activation was addressed by western blot and reporter gene assays.