SEPHS2 (selenophosphate synthetase 2) is a critical enzyme in selenocysteine biosynthesis that catalyzes the formation of selenophosphate from selenide and ATP, providing the essential selenium donor for selenocysteine-tRNA synthesis 1. This enzyme plays a dual role in cellular function: supporting selenoprotein production while simultaneously detoxifying toxic selenide intermediates 2. SEPHS2 is particularly important for cancer cell survival, as malignant cells exhibit increased selenium uptake through the cystine/glutamate antiporter SLC7A11, making them dependent on SEPHS2 for selenide detoxification 2. The enzyme's expression is elevated in various cancers including breast cancer, multiple myeloma, and acute myeloid leukemia (AML), where it supports antioxidant function and prevents ferroptosis 234. In AML, SEPHS2 is regulated by an oncogenic enhancer and promotes selenoprotein production required for leukemic cell survival 4. The protein can interact with peroxiredoxin 6 (PRDX6) in an alternative selenium metabolism pathway independent of selenocysteine lyase 1. Recent research has also implicated SEPHS2 in neurodegenerative diseases, with genetic variants associated with subjective cognitive decline 5.