NOD2 is an intracellular pattern recognition receptor that senses bacterial peptidoglycan to initiate innate immune responses 1. NOD2 activates NF-κB and mitogen-activated protein kinase (MAPK) signaling pathways independently of Toll-like receptors while synergizing with them to trigger proinflammatory and antimicrobial responses 2. The protein's stability is regulated through S-palmitoylation by ZDHHC5, which prevents SQSTM1/p62-mediated autophagic degradation and modulates inflammation 3. NOD2 dysfunction is implicated in multiple inflammatory diseases. Loss-of-function NOD2 mutations impair host defense and increase Crohn's disease susceptibility, with over 140 genetic loci now identified in genome-wide association studies 4. Conversely, gain-of-function mutations cause Blau syndrome, a monogenic autoinflammatory disorder characterized by granulomatous polyarthritis, uveitis, and systemic complications 5. These mutations induce peptidoglycan-independent NF-κB activation 6. The NOD2s-R444C gain-of-function variant promotes excessive inflammation through enhanced S-palmitoylation and reduced autophagic degradation 3. Clinically, early biologic intervention with anti-TNF-α therapies prevents severe Blau syndrome complications like blindness and joint destruction 5. NOD2 mutations may also interact with viral infections to trigger autoinflammatory disease 7, suggesting its importance in precision medicine approaches for inflammatory disease management.