ATG3 is an E2-conjugating enzyme essential for autophagosome formation through its catalysis of ATG8-like protein (LC3/GABARAP) lipidation to phosphatidylethanolamine on membranes 1. ATG3 cycles between binding to the E1 enzyme ATG7 for substrate loading and the E3 complex (ATG12-ATG5-ATG16L1) to promote lipidation 2. Functionally, ATG3-mediated LC3 lipidation is regulated by ATG7 acetylation status, with deacetylation of ATG7 enhancing ATG3 interaction and activating macroautophagy and LC3-associated microautophagy 3. Beyond canonical autophagy, ATG3 regulates lipid metabolism independent of autophagic flux—hepatic ATG3 inhibition ameliorates non-alcoholic fatty liver disease by increasing mitochondrial function through SIRT1 and CPT1a pathways 4. ATG3 also contributes to ferroptotic cell death through autophagy-dependent mechanisms 5 and influences cancer cell resistance to CAR-T immunotherapy, with elevated ATG3 correlating with poor treatment response in B-cell malignancies 6. Additionally, ATG3 mediates impaired lipophagy in diabetes-associated cognitive impairment microglia 7 and regulates autophagy-dependent granulosa cell function in polycystic ovary syndrome 8. These findings establish ATG3 as a multifunctional protein with roles extending beyond canonical autophagy to lipid homeostasis, cell death, and immune responses.