SETD2 is a methyltransferase critical for the integrity of epithelial barrier. However, the role of SETD2 in safeguarding epithelial barrier integrity remains largely unexplored. Here, we performed proteomics analysis on intact intestinal barrier with SETD2 present and compromised intestinal barrier with SETD2 loss. To characterize biological responses triggered by SETD2 deletion in compromised intestinal barrier at the protein level, we conducted global proteomics studies.