Colon cancer (CC) is a common malignancy with rising incidence worldwide. Despite advances in treatment strategies, many patients still face a poor prognosis due to the development of drug resistance. Long non-coding RNAs (lncRNAs) have emerged as important regulators of various biological processes and have been implicated in cancer progression. Among them, colorectal neoplasia differentially expressed (CRNDE) has drawn attention for its potential roles in different cancers. However, its specific functions in CC remain unclear. In this study, we identified CRNDE as highly expressed in CC, contributing to tumor progression and drug resistance. Mechanically, CRNDE is regulated by the transcription factor TFAP2A. Additionally, CRNDE inhibits pyroptosis, a form of programmed cell death, by promoting the ubiquitin-mediated degradation of RIPK3, thereby reducing the sensitivity of CC cells to 5-fluorouracil (5-FU). Our findings suggest that the TFAP2A/CRNDE/RIPK3 axis plays critical roles in colon cancer progression and chemoresistance, highlighting potential therapeutic targets for improving treatment outcomes.