In previous studies, USP25 was reported to promote Wnt signaling by controlling the levels of tankyrases and deletion of USP25 inhibits the cell growth of colon cancer through tankyrases.[36] By screening a compound library, a small molecular, CT1113, was identified as the USP28/USP25 inhibitor, resulting in suppression of the tumor growth in the colon cancer cell line.[37] Our results reveal a novel NHEJ regulatory mechanism by USP25 and suggest a potential therapeutic strategy based on targeting the USP25‐SHLD2 axis in cancer cases with hyperactivated NHEJ. This evidence concerns the gene TNKS and colonic neoplasm.