OBJECTIVES: Immune-driven inflammatory angiogenesis is a crucial component in the pathogenesis of inflammatory bowel disease (IBD). Nevertheless, the underlying mechanisms are still poorly understood. This study aims to investigate the role of Transglutaminase 2 (TGM2) in inflammatory angiogenesis in IBD and its potential as a therapeutic target and biomarker. METHODS: We performed an RNA-seq analysis integrated single-cell transcriptomic profiling on IBD biopsies to identify dysregulated genes. Additionally, we explored TGM2 contribution to angiogenesis and colitis under in vitro and in vivo conditions in Tgm2 knockout mouse and human intestinal microvascular endothelial cells (HIMECs). Serum TGM2 levels were measured by Enzyme-Linked Immunosorbent Assay. RESULTS: TGM2 expression was significantly upregulated in intestinal endothelial cells of IBD patients and colitis models. Tgm2 knockout and its inhibitor significantly attenuated intestinal colitis and angiogenesis in mice. In vitro, knockdown of TGM2 significantly suppressed tube formation, migration, and invasion of HIMECs. Mechanistically, inflammation-induced STAT1 activation promoted TGM2 expression, which subsequently interacted with vascular endothelial growth factor receptor 2 (VEGFR2) to drive its phosphorylation (Tyr1059, Tyr1214) and inflammatory angiogenesis. In patients of Crohn's Disease, serum TGM2 concentrations exhibited high diagnostic accuracy (AUC = 0.862) for assessing endoscopic activity. CONCLUSION: Our findings underscore the critical role of STAT1-TGM2-VEGFR2 axis in regulating angiogenesis during intestinal inflammation, suggesting that targeting TGM2 as a viable therapeutic candidate for vascular remodeling in chronic intestinal inflammation.