Two-sample Mendelian randomization was used to evaluate the association between genetically predicted expression of crotonylation-related genes and COAD risk, followed by validation and mechanistic analyses centered on DPF2.<h4>Results</h4>Among 16 crotonylation-related candidate genes with available cis-eQTL evidence, only DPF2 showed a significant positive association with COAD risk. This evidence concerns the gene DPF2 and colon adenocarcinoma.