PLPP6 (phospholipid phosphatase 6) is a magnesium-independent polyisoprenoid diphosphatase that catalyzes sequential dephosphorylation of presqualene, farnesyl, geranyl, and geranylgeranyl diphosphates 123. The enzyme plays multiple metabolic roles: it regulates innate immunity by dephosphorylating presqualene diphosphate, which inhibits polymorphonuclear neutrophil activation 14; participates in cholesterol and sterol biosynthesis through presqualene and farnesyl diphosphate dephosphorylation 3; and contributes to protein prenylation by acting on farnesyl and geranylgeranyl diphosphates 3. Additionally, PLPP6 has lower activity toward phosphatidic acid, lysophosphatidic acid, ceramide-1-P, and sphingosine-1-phosphate, potentially influencing phospholipid and triacylglycerol biosynthesis 53. Clinically, PLPP6 has emerged as a critical gene in chromosome 9-related syndromes, being identified as important for 83% of individuals with 9p deletion syndrome 6. In allergic disease, PLPP6 regulates dendritic cell cholesterol content and macropinocytosis, with PLPP6 knockout mice showing decreased airway allergen sensitization 7.