SELENOI (selenoprotein I) is an ethanolaminephosphotransferase that catalyzes the final step of phosphatidylethanolamine (PE) synthesis via the Kennedy pathway, transferring phosphoethanolamine from CDP-ethanolamine to lipid acceptors 1. Unlike most selenoproteins, SELENOI does not function in redox reactions; its selenocysteine residue lies outside the catalytic domain and is not directly involved in catalysis 1. SELENOI synthesizes PE and plasmanyl-PE, critical membrane phospholipids essential for myelination and neurodevelopment 2. Mechanistically, SELENOI maintains ether lipid homeostasis by regulating ether-linked PE (ePE) levels. SELENOI deficiency causes ferroptosis through ePE depletion and upregulation of phospholipase A2 and lipoxygenase, independent of GPX4 3. In immune cells, SELENOI promotes T follicular helper (TFH) cell differentiation by coordinating PE synthesis with CXCR5 surface expression and localization 4. In neuronal contexts, SELENOI dysregulation correlates with TDP-43 pathology in ALS, with decreased SELENOI expression and PE levels in affected motor cortex 5. Pathologically, loss-of-function SELENOI mutations cause hereditary spastic paraplegia 81, an autosomal recessive neurological disorder 2. SELENOI upregulation in cancers promotes malignancy and chemotherapy resistance through Akt phosphorylation; SELENOI inhibition restores platinum sensitivity and ferroptosis in ovarian cancer 6.