This study aims to investigate the potential of psoralen (PSO) in ameliorating intestinal barrier dysfunction and secondary liver injury in mice with ulcerative colitis (UC).Forty male C57BL/6J mice were randomly assigned into the following groups:control group (Con),model group (Mod),positive control group treated with sulfasalazine (SASP,200 mg/kg),low-dose PSO group (PSO-L,20 mg/kg),and high-dose PSO group (PSO-H,40 mg/kg).Ulcerative colitis (UC) models were induced by freely drinking 2.25% dextran sulfate sodium salt (DSS) for seven days.During the experiment,the weight of mice and disease activity index (DAI) were recorded.Real-time quantitative polymerasechain reaction(RT-qPCR) was used to detect the expression of zonula occludens-1 (ZO1),Claudin-1 and Occludin in the colon.Biochemical assay kits were employed to measure the levels of aspartate aminotransferase (AST),alanine transaminase (ALT),alkaline phosphatase (AKP) and lactate dehydrogenase (LDH) in the liver.Enzyme-linked immunosorbent assay (ELISA) was conducted to quantify the levels of lipopolysaccharides (LPS),C-reactive protein (CRP),procalcitonin (PCT),interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) in the liver.Western blot analysis was performed to assess the expression of Toll-like receptor 4 (TLR4),myeloid differentiation primary response protein 88 (MyD88) and phosphorylated nuclear factor kappa-B (p-NF-κB) in the liver.The results showed that compared to the Mod group,after PSO treatment,the weight loss of UC mice was alleviated,DAI scores decreased,and colonic length shortening was relieved.The mRNA expression of ZO1,Claudin-1,and Occludin was upregulated.The levels of AST,ALT,AKP and LDH in the liver decreased;the levels of LPS,CRP,PCT,IL-6 and TNF-α in the liver decreased;and the expression of TLR4,MyD88 and p-NF-κB proteins in the liver was downregulated.The above results indicate that PSO can improve intestinal barrier function in DSS-induced mice and ameliorate secondary liver injury by inhibiting the TLR4/MyD88/NF-κB signaling pathway.