As a target gene of the transcription factor TEAD4, MAD2L1 is subject to transcriptional regulation and mediates the malignant phenotype of colorectal cancer.[38] In cholangiocarcinoma, TBX3 inhibits progression by downregulating MAD2L1.[38] Previous studies have reported that a high‐sugar diet mediates the upregulation of MAD2L1 in murine pancreatic tumors.[12] Our research reveals that lactate, a product of anaerobic glycolysis, is a direct culprit in the activation of MAD2L1, although MAD2L1 protein does not serve as a direct substrate for lactylation modifications. This evidence concerns the gene MAD2L1 and colorectal cancer.