Integrative Proteomics and Phosphoproteomics Profiling of Chronic Enteropathy Associated with SLCO2A1 Gene Reveals Mucosal Barrier Impairment and Focal Adhesion Pathway Alterations

Background: Chronic enteropathy associated with the SLCO2A1 gene (CEAS) is a rare disease characterized by multiple small intestinal ulcers whose pathogenesis remains poorly understood. This study aimed to characterize the proteomic and phosphoproteomic profiles of CEAS and to identify molecular pathways involved in its pathogenesis. Methods: Quantitative proteomics and phosphoproteomics were performed on intestinal mucosal tissues from patients with CEAS (n = 3), Crohn’s disease (CD, n = 3), and healthy controls (n = 3). Differentially expressed proteins (DEPs) and differentially phosphorylated proteins (DPPs) were analyzed using functional enrichment, gene set enrichment analysis (GSEA), protein–protein interaction (PPI) networks, and integrative analysis. Results: A total of 900 DEPs were identified in CEAS and 277 in CD relative to controls, including 717 CEAS-specific proteins. CEAS-specific alterations were strongly enriched in focal adhesion and extracellular matrix-related pathways, whereas shared proteins between CEAS and CD were primarily associated with epithelial barrier function, including tight junction and adherens junction pathways. GSEA revealed that CEAS was characterized by upregulation of tissue remodeling and focal adhesion pathways, accompanied by suppression of digestive and metabolic processes, while CD exhibited prominent adaptive immune activation. PPI network analysis identified POSTN, CDH1, TLN1, and VIM as candidate hub proteins; however, none retained significance after FDR correction, whereas brush-border components (CDHR2, MUC3A, MUC13, ALPI) and actin cytoskeletal regulators remained the most statistically robust alterations. Integrated analysis further highlighted focal adhesion-related proteins with coordinated expression and phosphorylation changes. Conclusions: This exploratory study provides the first integrative proteomic and phosphoproteomic characterization of CEAS, suggesting that impairment of the intestinal brush border and mucosal barrier, together with actin cytoskeletal reorganization, may distinguish CEAS from immune-dominant CD. These findings are hypothesis-generating and require validation in larger cohorts.