NU2058 induces cell senescence by directly targeting RanBP3‐β‐catenin signaling in CRC cells. A) RNA sequencing and KEGG pathway analysis suggested the involvement of cell senescence in the action mechanisms of NU2058 in CRC cells with nuclear β‐catenin activation. B) β‐Galactosidase staining and quantification showing that NU2058 (0, 10, and 20 µm, 72 h) induced senescence of DLD1 and HCT15 cells but not of RKO and SW620 cells. C) Expression of lamin B1 in NU2058‐treated CRC cells. D,E) The cell cycle distribution of DLD1, HCT15, RKO, and SW620 cells was analyzed by flow cytometry after exposure to increasing concentrations of NU2058 for 72 h. F) Western blotting showing the expression of cyclin D1, CDK4, CDK6, and actin in CRC cells treated with NU2058. G) Expression of CDK4, CDK6, lamin B1, and actin in tumor xenografts established from HCT15 and SW620 cells. H) β‐Galactosidase staining was performed to determine the effect of NU2058 on the senescence of RanBP3‐KO cells. I) RanBP3‐deficient cells were exposed to NU2058, and Western blotting was used to detect lamin B1 expression. Bars, SD; *p < 0.05; **p < 0.01; ***p < 0.001.