IRGM (immunity-related GTPase M) is a GTPase that functions as a negative regulator of innate immune responses and inflammation. Mechanistically, IRGM promotes autophagy and selective autophagic degradation of immune signaling complexes. Following microbial infection, IRGM facilitates autophagy-targeted destruction of intracellular pathogens including Mycobacterium tuberculosis and Salmonella typhimurium 1. IRGM negatively regulates NLRP3 inflammasome activation by blocking assembly of NLRP3 and ASC oligomers and mediating their selective autophagy, thereby suppressing IL-1β maturation and pyroptosis 2. Additionally, IRGM suppresses reactive oxygen species production and MAPK signaling in macrophages, inhibiting apoptosis under oxidative stress 3. IRGM is strongly associated with inflammatory bowel disease (IBD) susceptibility 4. Dysfunctional autophagy, including IRGM-mediated pathways, disrupts intestinal epithelial integrity, promotes gut dysbiosis, impairs antimicrobial responses, and drives aberrant immune reactions to pathogenic bacteria in IBD pathogenesis 5. IRGM variants correlate with differential IRGM transcript expression and increased Crohn's disease risk 1. The protective role of IRGM in IBD is demonstrated by studies showing IRGM expression suppresses pro-inflammatory responses triggered by pathogen-associated and damage-associated molecular patterns 2. Understanding IRGM biology may enable novel IBD therapeutic strategies targeting autophagy-mediated immune regulation.