REG3G (regenerating family member 3 gamma) is an antimicrobial peptide with bactericidal activity against Gram-positive pathogens including L. monocytogenes and methicillin-resistant S. aureus 1. Functionally, REG3G operates at the intersection of intestinal barrier integrity and immune homeostasis. IL-22-producing immune cells induce REG3G expression to support mucosal defense, though its specific antimicrobial contribution appears redundant with other IL-22-regulated proteins during pathogenic infection 2. More critically, REG3G maintains intestinal barrier function by promoting tight junction protein expression; deficiency causes increased intestinal permeability and endotoxin translocation via the gut-liver axis, exacerbating metabolic diseases 3. Beyond intestinal immunity, REG3G exhibits pleiotropic roles in metabolic homeostasis. In pancreatic β-cells, REG3G restores mitochondrial function and glucose-stimulated insulin secretion through ERK1/2-STAT3 signaling, ameliorating drug-induced and metabolic dysfunction 4. In type 2 diabetes, REG3G promotes macrophage clearance of damaged mitochondria from β-cells via heparan sulfate-dependent mechanisms, suppressing pancreatic inflammation 5. Therapeutically, REG3G upregulation represents a target for treating liver disease, metabolic dysfunction, and intestinal inflammation by reinforcing barrier function and reducing bacterial translocation.