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ETHNOPHARMACOLOGICAL RELEVANCE In traditional oriental medicine, the dried seeds of Psoralea corylifolia L. (PC) have been used to treat various diseases, including gastrointestinal, urinary, orthopedic, diarrheal, ulcer, and inflammatory disorders. AIM OF THE STUDY Although its various biological properties are well-known, there is no information on the therapeutic effects and bioavailable components of PC against inflammatory bowel disease. Therefore, we focused on the relationship between hydroethanolic extract of PC (EPC) that ameliorates colitis in mice and bioactive constituents of EPC that suppress pro-inflammatory cytokines in macrophages. MATERIALS AND METHODS We investigated the therapeutic effects of EPC in a dextran sulfate sodium-induced colitis mouse model and identified the orally absorbed components of EPC using UPLC-MS/MS analysis. In addition, we evaluated and validated the mechanism of action of the bioavailable constituents of EPC using network pharmacology analysis. The effects on nitric oxide (NO) and inflammatory cytokines were measured by Griess reagent and enzyme linked immunosorbent assay in lipopolysaccharide (LPS)-induced macrophages. RESULTS In experimental colitis, EPC improved body weight loss, colon length shortening, and disease activity index. Moreover, EPC reduced the serum levels of pro-inflammatory cytokines and histopathological damage to the colon. Network pharmacological analysis identified 13 phytochemicals that were bioavailable following oral administration of EPC, as well as their potential anti-inflammatory effects. 11 identified EPC constituents markedly reduced the overproduction of NO, tumor necrosis factor-α, and/or interleukin-6 in macrophages induced by LPS. The LPS-induced expression of the nuclear factor kappa-light-chain-enhancer of activated B cells reporter gene was reduced by the 4 EPC constituents. CONCLUSIONS The results indicate that the protective activity of EPC against colitis is a result of the additive effects of each constituent on the expression of inflammatory cytokines. Therefore, it suggests that 11 bioavailable phytochemicals of EPC could aid in the management of intestinal inflammation, and also provides useful insights into the clinical application of PC for the treatment of inflammatory bowel diseases.