Drug repositioning of inflammatory bowel disease based on co-target gene expression signature of glucocorticoid receptor and TET2
The glucocorticoid receptor (GR) and ten-eleven translocation 2 (TET2) respectively play a crucial role in regulating immunity and inflammation, and GR interacts with TET2. However, their syn-ergetic roles in inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), remain unclear. This study aimed to investigate the co-target gene signatures of GR and TET2 in IBD and provide potential therapeutic interventions for IBD. By integrating public data, we identified 179 GR- and TET2-targeted differentially expressed genes (DEGs) in CD and 401 in UC. These genes were closely associated with immunometabolism, inflammatory responses, and cell stress pathways. In vitro inflammatory cellular models were constructed using LPS-treated HT29 and HCT116 cells, respectively. Drug repositioning based on the co-target gene signatures of GR and TET2 derived from transcriptomic data of UC, CD, and the in vitro model were performed using the Connectivity Map (CMap). BMS-536924 emerged as a top therapeutic candidate, and its validation experiment within the in vitro inflammatory model confirmed its ef-ficacy in mitigating the LPS-induced inflammatory response. This study sheds light on the path-ogenesis of IBD from a new perspective and may accelerate the development of novel therapeutic agents for inflammatory diseases including IBD. Overall design: To compare the similarities and differences between  two cell lines with different GR basal expression in response to LPS-induced inflammation and identify sepecific expression signatures useful for screening anti-inflammatory compounds, we utilized two types of intestinal epithelial-derived cells, HT29 and HCT116, stimulating them with 1 ug/mL LPS for 24 h. Subsequently, next-generation RNA sequencing was performed.