BACKGROUND AND AIMS: Crohn's disease is a chronic inflammatory disease of the bowel, often complicated by fibrotic strictures, for which medical treatment is lacking, and surgery is commonly required. The mechanisms underlying the progression from chronic inflammation to fibrosis are not yet defined. We aim to unravel Crohn's disease pathogenesis using a cutting-edge computational pipeline combining several available tools. METHODS: Spatial transcriptomics was performed on 13 surgical specimens, including inflamed and fibrotic Crohn's disease tissues and healthy controls. The resulting spatial data were integrated with single-cell RNA sequencing to trace the cellular and molecular transitions from healthy intestine to fibrotic tissue. Ligand-receptor interaction and pseudotime analyses were employed to infer dynamic cell-cell communication networks and lineage trajectories. Key computational findings were validated through immunostaining in an independent cohort of Crohn's disease patients. Finally, the therapeutic relevance of the identified target was evaluated in a TNBS-induced chronic colitis mouse model upon CD38 inhibitor administration. RESULTS: We demonstrated that intestinal cytoarchitecture was rearranged while chronic inflammation progressed. Crohn's disease-associated fibrosis evolved within the mesenchymal compartment, driven by PECAM2 signaling through PECAM1-CD38 interaction. In parallel, ApoA signaling, particularly APOA1-ABCA interaction, emerged as relevant for maintaining epithelial and stromal homeostasis, while its downregulation was associated with fibrosis development. Moreover, CD38 signaling inhibition effectively reduced colitis symptoms and colon thickening in the experimental TNBS-induced model of chronic inflammation. CONCLUSIONS: Our results provide insights into CD38-driven fibrosis and indicate that PECAM2 signaling blockade could reduce the development of strictures in patients with Crohn's disease, potentially offering a new treatment target.