ATG2B is a lipid transfer protein essential for autophagosome biogenesis and lipid droplet regulation. Mechanistically, ATG2B tethers the isolation membrane (IM) edge to the endoplasmic reticulum (ER) and directly transfers phospholipids from ER to IM for membrane expansion 1. This lipid transfer activity is enhanced by WDR45/WIPI4, which promotes ATG2B association with phosphatidylinositol-3-phosphate (PI3P)-containing membranes 1. ATG2B also functions in autophagosome-lysosome fusion through tethering interactions with SNARE proteins 2. Beyond autophagy initiation, ATG2B is subject to post-translational regulation: SIRT1-mediated deacetylation enhances ATG2B stability and activity 3, while the E3 ubiquitin ligase RNF5 targets it for degradation 4. Clinically, ATG2B dysregulation associates with cancer progression. Germline duplications of ATG2B predispose to myeloproliferative neoplasms by enhancing hematopoietic progenitor differentiation and TPO sensitivity 5. Conversely, ATG2B upregulation via circRNA-mediated RNF5 inhibition promotes gastric cancer malignancy 4, while therapeutic ACSS2 inhibition activates autophagy through SIRT1-mediated ATG2B deacetylation, reducing ovarian cancer chemoresistance 3. ATG2B deletion alone does not impair autophagy but requires GSKIP cooperation for hematopoietic stem cell maintenance 6.