NRBF2 (nuclear receptor binding factor 2) is a regulatory subunit of the class III phosphatidylinositol 3-kinase complex I (PI3KC3-C1), essential for autophagy initiation and cellular homeostasis. As a core component of the PI3KC3-C1 complex alongside PIK3C3/VPS34, PIK3R4/VPS15, BECN1, and ATG14, NRBF2 enhances VPS34 lipid kinase activity approximately 10-fold 1, facilitating phosphatidylinositol-3-phosphate (PtdIns3P) synthesis required for autophagosome biogenesis 2. NRBF2 functions as a homodimer that stabilizes PI3KC3-C1 assembly and drives complex dimerization 1, promoting starvation-induced macroautophagy 2. Beyond canonical autophagy, NRBF2 plays critical roles in innate immunity and disease regulation. In intestinal inflammation, NRBF2 is required for apoptotic cell clearance by macrophages through RAB7 activation and phagosome-lysosome fusion, protecting against colitis 3. Elevated NRBF2 in ulcerative colitis patient colon macrophages correlates with disease severity reduction 3. In glioblastoma, NRBF2-mediated autophagy induces metabolic reprogramming that promotes radioresistance through enhanced ATP production and altered metabolite levels 4. These findings establish NRBF2 as a multifunctional autophagy regulator with significant implications for inflammatory bowel disease and cancer therapy resistance.