REG3G (Regenerating Islet-Derived 3 Gamma) is a small intestinal C-type lectin-like antimicrobial peptide mainly secreted by Paneth cells. First identified in regenerating pancreas, it is now recognized as a key defender of the gut barrier: it kills Gram-positive bacteria, limits bacterial contact with the epithelium, and thus helps prevent systemic inflammation and metabolic disease. Beyond its antimicrobial role, REG3G acts as a gut-derived hormone that links the intestinal microbiome to host metabolism. Its expression is boosted by dietary fiber, beneficial bacteria, interleukin-22 (IL-22) and bariatric surgery, and it reciprocally improves glucose control, reduces hepatic steatosis, accelerates wound healing and protects pancreatic β-cells by activating the JAK2/STAT3 pathway . Conversely, chronic alcohol intake or dysbiosis lowers REG3G levels, weakening the gut barrier and promoting alcoholic liver disease.