PIP5K1C (phosphatidylinositol-4-phosphate 5-kinase type 1 gamma) is a lipid kinase that catalyzes phosphorylation of phosphatidylinositol 4-phosphate (PI4P) to generate phosphatidylinositol 4,5-bisphosphate (PIP2), a critical second messenger regulating signal transduction, vesicle trafficking, cytoskeleton dynamics, and cell adhesion 12. PIP5K1C controls the plasma membrane pool of PIP2 essential for synaptic vesicle endocytosis and exocytosis 3, clathrin-coated pit assembly 4, and focal adhesion dynamics by modulating talin targeting to the plasma membrane 1. The enzyme mediates Arf6-driven exocyst recruitment and membrane tethering through rapid PIP2 synthesis 5. PIP5K1C loss in osteocytes impairs bone remodeling through reduced collagen expression and increased sclerostin, with decreased focal adhesion proteins and elevated apoptosis 6. In chondrocytes, PIP5K1C deletion causes age-related osteoarthritis-like lesions with cartilage degradation and impaired chondrocyte adhesion 7. Clinically, PIP5K1C deficiency in cancer cells increases dependence on PIKFYVE, making them sensitive to PIKFYVE inhibitors through disrupted lysosome homeostasis and autophagy 89. Additionally, dual PIP5K1C/PIKfyve inhibition prevents SARS-CoV-2 entry by blocking ACE2-mediated endocytosis and cathepsin L activation 10. PIP5K1C mutations are associated with lethal congenital contracture syndrome 3.