ATG16L2 (autophagy related 16 like 2) is an autophagy-related protein and functional paralog of ATG16L1 that plays dual roles in cellular homeostasis and immune defense. As a core component of the Atg12-Atg5-Atg16 complex, ATG16L2 regulates autophagosome assembly and macroautophagy 1. Beyond canonical autophagy, ATG16L2 serves as a critical modulator of innate immunity by augmenting NLRC4 inflammasome activation through facilitating NAIPs-NLRC4 association, thereby enhancing pathogen clearance during intracellular infection 2. In metabolic homeostasis, ATG16L2 is transcriptionally upregulated through the NR3C1-FTO-m6A modifications axis in pancreatic β-cells; excessive upregulation promotes deleterious autophagy overload under glucolipotoxic conditions, impairing insulin secretion and promoting diabetes 3. ATG16L2 exhibits tissue-specific functional distinctions from ATG16L1 across myeloid, lymphoid, and epithelial lineages, with dysregulation contributing to inflammatory bowel disease and systemic lupus erythematosus 4. Loss-of-function variants are associated with increased Crohn's disease susceptibility in Asian populations 5, while East Asian-specific missense variants (p.R220W) associate with coronary artery disease 6. ATG16L2 genetic variants also predict radiation pneumonitis severity and survival outcomes in non-small cell lung cancer patients 7. Expression dysregulation occurs in Alzheimer's disease-type 2 diabetes comorbidity models 8.