PIKFYVE is a phosphoinositide kinase that plays essential roles in lysosomal function and membrane trafficking through its production of phosphatidylinositol-3,5-bisphosphate (PI(3,5)P2) 1. The enzyme is integral to lysosomal functioning and exists as part of a multi-protein complex with Fig4 and Vac14 that tightly regulates PI(3,5)P2 and PI(5)P levels 1. PIKFYVE functions downstream of AMPK signaling to maintain basal lysosomal function, specifically regulating the lysosomal Ca2+ channel MCOLN1 through PI(3,5)P2 production 2. The kinase is also required for autophagy regulation and endolysosomal trafficking processes 3. In disease contexts, PIKFYVE has emerged as a therapeutic target across diverse conditions. PIKfyve inhibition shows antiviral efficacy against SARS-CoV-2 and other coronaviruses by disrupting receptor-mediated endocytosis 4. In cancer, PIKFYVE represents a targetable vulnerability in pancreatic ductal adenocarcinoma, where its inhibition forces metabolic reprogramming and creates synthetic lethality when combined with KRAS-MAPK pathway inhibitors 5. Additionally, PIKFYVE inhibitors can rescue glutamate toxicity in frontotemporal dementia models 6. Mutations affecting the PIKfyve complex are linked to human diseases, particularly neurological disorders 1.