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Baicalin is a natural flavonoid glycoside which has potent anti-tumor and antioxidant activity in cancer cells. In the present study, we found that baicalin treatment significantly induced senescence in colon cancer cells. Furthermore, baicalin upregulated the expression of decidual protein induced by progesterone (DEPP) in HCT116 colon cancer cells, which accompanied with the activation of Ras/Raf/MEK/ERK and p16INK4A/Rb signaling pathways. Meanwhile, these phenomena also appeared under the anti-oxidation effect exerted by baicalin. In addition, ectopic expression of DEPP in HCT116 cells significantly induced the activity of senescence-associated β-galactosidase (SA-β-Gal) in tumor cells regulated by Ras/Raf/MEK/ERK signaling pathway. Knockdown of DEPP by RNA interference efficiently counteracted the baicalin-mediated growth inhibition, senescence and cell cycle arrest in cancer cells. Importantly, in a xenograft mouse model of human colon cancer, we further confirmed that baicalin treatment dramatically inhibited tumor growth, which was due to the induction of tumor cellular senescence via the upregulation of DEPP and the activation of Ras/Raf/MEK/ERK signaling in vivo. In addition to baicalin treatment, we found that the hypoxia-response protein DEPP functions as a positive regulator involving the regulations of Ras/Raf/MEK/ERK signaling pathway and inhibition of human colon cancer by other anti-oxidative drugs, such as curcumin and sulforaphane, resulting in tumor cellular senescence. These results collectively suggest that baicalin upregulates the expression of DEPP and activates its downstream Ras/Raf/MEK/ERK and p16INK4A/Rb pathways by acting as an antioxidant, leading to senescence in colon cancer cells.