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Colorectal cancer (CRC) accounts for over 600,000 deaths annually worldwide. Euxanthone is a flavonoid compound extracted from Polygala caudata, with documented anti-neoplastic actions. The current study aimed to determine the therapeutic potential of euxanthone in CRC.Cell Counting Kit-8 (CCK-8) assay was used to analyze the effect of euxanthone on the cell viability, and apoptosis was detected by the TUNEL assay. The in vitro migratory capacity was determined by wound healing and the invasiveness was assessed by Transwell assay. Western blotting was used to determine the level of relevant proteins. Furthermore, a CRC xenograft murine model was used to analyze the therapeutic efficacy of euxanthone in vivo. Isobaric tags for relative and absolute quantification (iTRAQ) was then performed to identify the potential targets of euxanthone. To validate the role of cancerous inhibitor of PP2A (CIP2A) in the anti-cancer effects of euxanthone, plasmid overexpressing CIP2A and shRNA targeting CIP2A were used in in vitro assays.Euxanthone decreased cell viability and increased apoptosis in CRC cells, in addition to restraining migration, invasion and EMT. Similarly, euxanthone also effectively suppressed tumor growth and pulmonary metastasis in vivo. iTRAQ analysis identified CIP2A as the primary target responsible for the anticancer effects of euxanthone. The mediatory role of CIP2A was validated when the anticancer activity of euxanthone was significantly blocked by CIP2A overexpression, while CIP2A knockdown sensitized the CRC cells to euxanthone.Euxanthone exerts anti-cancer effects in vitro and in vivo in CRC by targeting CIP2A/PP2A signaling.