Cellular senescence defining the disease characteristics of Crohn's disease

Wenyu Zhang¹Xianzong Ma²Wen-Qing Tian³Yongsheng Teng^4*Meihua Ji¹

• ¹Capital Medical University, Beijing, Beijing Municipality, China
• ²The First Medical Center of Chinese PLA General Hospital, bei jing, China
• ³Cancer Hospital, Chongqing University, Chongqing, Anhui, China
• ⁴Chongqing General Hospital, Chongqing, China

Background Crohn's disease (CD) is a complex and heterogeneous inflammatory disease whose most important feature is immune dysregulation. As a basic cell response, cellular senescence (CS) can regulate the immune response involved in a variety of inflammatory diseases. However, the role of CS in the pathogenesis and diagnosis prediction of CD are still unknown.We utilized CD-related datasets from the GEO database for differential gene expression analysis, and CS related differentially expressed genes (CSRDEGs) in CD by a comprehensive bioinformatics analysis encompassing GSEA, WGCNA, and various interaction networks. The support vector machine (SVM) algorithm, random forest algorithm and LASSO regression analysis was used to construct a diagnostic model. And based on CSRDEGs, we further constructed a Cellular senescence score (CSscore) model. Different disease subtypes (cluster1/cluster2) were identified by the consensus clustering method. The assessment of immune cell infiltration and its correlation with CSRDEGs was analyzed by ssGAEA and CIBERSORT. Results We identified 10 hub CS related differentially expressed genes (CSRDEGs) in CD. Based on CSRDEGs, we further constructed a diagnostic model (AUC = 0.880) containing 5 CSRDEGs (CDKN1A, IL1A, PML, SIRT1, and STAT3) through machine learning algorithm and other methods and analyzed the correlation with immune cell infiltration. In addition, a CS Scores model (Low or High) based on the 7 CSRDEGs (CDKN2B, IGFBP7, IL1A, IL6, PML, SIRT1, and STAT3) shows different characteristics, reaffirming the inflammatory regulatory role of CS in CD. Finally, the subtype construction (cluster1 and cluster2) based on 10 CSRDEGs shows the heterogeneity of the disease and affirms that CS is a prominent feature of CD.Conclusions These results suggest that CS is an important feature of CD, and CSRDEGs can be used to construct disease diagnostic models and distinguish disease subtypes. Further investigation of the mechanism of immune dysregulation caused by CS can deepen our understanding of the pathogenesis of CD.