PIP4K2B (phosphatidylinositol-5-phosphate 4-kinase type 2 beta) is a stress-regulated lipid kinase that catalyzes the phosphorylation of phosphatidylinositol-5-phosphate (PIP5P) to generate phosphatidylinositol-4,5-bisphosphate [PtdIns(4,5)P2] 1. Unlike other PIP4K isoforms, PIP4K2B localizes predominantly to the nucleus 1 and prefers GTP over ATP as a phosphate donor, with its activity reflecting physiological GTP concentrations—a property critical for metabolic adaptation 2. Mechanistically, PIP4K2B negatively regulates insulin signaling through a catalytic-independent mechanism by binding and suppressing PIP5K activity, thereby reducing insulin-stimulated PI(3,4,5)P3 production 3. PIP4K2B also regulates autophagy and lipid metabolism; deletion of pip4k2a and pip4k2b genes impairs autophagosome clearance and causes lipid accumulation during nutrient stress 4. Additionally, PIP4K2B acts as a mechanoresponsive enzyme that controls nuclear mechanical properties through UHRF1-dependent heterochromatin regulation, affecting YAP signaling and cell motility 5. Clinically, low PIP4K2B expression in breast tumors correlates with reduced E-cadherin expression, enhanced epithelial-to-mesenchymal transition, and poor patient survival 6. High PIP4K2A/2C levels predict resistance to venetoclax in acute myeloid leukemia 7, while anti-PIP4K2B autoantibodies associate with skin and lung fibrosis in systemic sclerosis 8.