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Colorectal cancer (CRC) remains one of the most lethal human malignancies with high incidence and lack of effective therapy. Raddeanin A (RA), an active triterpenoid saponins, has been demonstrated the ability to inhibit the growth of tumor. But the therapeutic effects and mechanisms of RA in CRC remain elusive. Here, we investigated the efficacy and mechanism of RA in CRC both in vitro and in vivo.Cell viability was investigated to evaluate cytotoxic activity by MTT method. Apoptosis induced by RA was studied using Annexin V-FITC/PI binding and JC-1 staining by flow cytometry analysis. The xenograft mouse model of CRC was used to investigate anti-tumor effects in vivo. The key proteins involved in mitochondrial apoptotic, Wnt/β-catenin and NF-κB pathway were detected by Western blotting, Immunofluorescence, and Immunohistochemistry.RA induced apoptosis and inhibited cell proliferation of SW480 and LOVO cells in a concentration-dependent manner. Moreover, RA efficiently inhibited tumor growth in xenograft mouse model. RA could down regulate the Wnt/β-catenin signaling to display anti-tumor effects via suppression of p-LRP6, induction of AKT inactivation, removal of GSK-3β inhibition and attenuation of β-catenin. Meanwhile, RA also suppressed the NF-κB pathway by decreasing the phosphorylation of IKBα to induce subsequently mitochondrial apoptotic pathway.In summary, RA suppressed the growth and triggered the apoptosis of CRC through discontinuing Wnt/β-catenin signaling and inhibiting the NF-κB pathway. These findings suggested that RA may hold a promise as a novel therapeutic agent for CRC therapy.