REG/Reg family proteins: mediating gut microbiota homeostasis and implications in digestive diseases

The regenerating (REG/Reg) family, a subset of the C-type lectin fold superfamily, is characterized by "C-type lectin-like" domains. Beyond promoting proliferation and differentiation of hepatic, pancreatic, gastric, and intestinal cells, its members have multifunctional secretory activities, especially as antimicrobial peptides (AMPs), a key link between their structural features and roles in gastrointestinal physiology/pathology. These molecules mediate the initiation and progression of various gastrointestinal inflammatory and inflammation-associated diseases. As AMPs, they connect gut microbiome and host immunity by regulating microbiota homeostasis, intestinal mucosal barrier, metabolism, and energy balance; notably, REG3/4 play dual roles in digestive tract diseases. This review proposes the REG Protein Functional Equilibrium Model. REG proteins act as context-dependent "molecular rheostats" switching between protective and pathogenic roles based on microenvironmental cues. The functional equilibrium model provides a new paradigm for developing precision therapeutics that target the microenvironment rather than single molecules, offering critical theoretical foundations for resolving the functional paradox of REG family in inflammation and cancer and advancing its clinical translation.