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Ethnopharmacological Relevance: Sishen Wan (SSW) is a commercial and frequently used Chinese patent medicine listed in the Chinese Pharmacopeia, which is usually used to treat chronic colitis., Aim of the Study: We explored the pharmacological mechanism of Sishen Wan attenuated experimental chronic colitis by inhibiting Wnt/β-catenin pathway., Materials and Methods: Experimental chronic colitis was induced by trinitrobenzene sulfonic acid (TNBS). The therapeutic effect of SSW were analyzed by index of colonic weight, colonic length, pathological score. Cytokines expression were analyzed by ELISA, while the apoptosis level was checked by TUNEL staining. These proteins of Wnt/β-catenin signaling pathway was analyzed by Western blot assay., Results: Rats with TNBS-induced chronic colitis were treated by SSW for 10 days. The efficacy of SSW was demonstrated by improved macroscopic and microscopic colonic damage. SSW increased the level of ATP in colonic mucosa, while SSW inhibited β-catenin, ubiquitination of Nemo-like-kinase-associated ring finger protein and T-cell factor, and expression of Wnt/β-catenin downstream proteins (including c-Myc, cyclo-oxygenase-2, cyclin D1, survivin, signal transducer and activator of transcription 3 and zipper-interacting protein kinase), and improved lymphoid enhancer factor ubiquitination and β-TrCP activity, followed by excessive apoptosis of colonic epithelial cells., Conclusions: SSW effectively attenuated experimental chronic colitis induced by TNBS, which was realized by inhibition of the Wnt/β-catenin signaling pathway., (Copyright © 2019. Published by Elsevier B.V.)