TMEM219 is a transmembrane death receptor that mediates caspase-8-dependent apoptosis upon binding its ligand, insulin-like growth factor binding protein 3 (IGFBP3) 1. The IGFBP3/TMEM219 signaling axis functions as a physiological regulator of cell homeostasis, particularly in pancreatic beta cells and intestinal stem cells (ISCs) 2. In disease contexts, excessive TMEM219 activation contributes to pathology: elevated IGFBP3 and aberrant TMEM219 signaling impair beta cell mass and function in type 1 and type 2 diabetes 23, while abnormal ISC death via TMEM219 exacerbates colitis and prevents mucosal healing in Crohn's disease 4. TMEM219 also participates in IL-13Rα2-mediated signaling downstream of chitinase 3-like-1, regulating MAPK/Erk and PKB/Akt activation and TGF-β1 production 5. Therapeutically, blocking IGFBP3/TMEM219 signaling preserves beta cells and delays diabetes onset 26, restores ISC self-renewal capacity, and promotes mucosal healing in inflammatory bowel disease 47. These findings establish TMEM219 blockade as a promising therapeutic strategy for metabolic and inflammatory diseases characterized by excessive cell death.