SELENOT (selenoprotein T) is an endoplasmic reticulum (ER)-resident thioredoxin-like oxidoreductase that plays critical roles in cellular redox homeostasis and proteostasis. 1 As an essential selenocysteine-containing protein, 2 SELENOT exerts selenosulfide oxidoreductase activity 1 and is anchored to the ER membrane where it associates with the oligosaccharyltransferase complex, regulating early N-glycosylation steps. 1 Cellularly, SELENOT maintains ER calcium storage capacity and prevents accumulation of reactive oxygen and nitrogen species. 1 3 SELENOT knockdown reduces expression of pro-apoptotic proteins and regulates antioxidant enzymes, though ER stress can unmask pro-apoptotic effects when SELENOT is depleted. 3 In neural tissues, SELENOT protects dopaminergic neurons against oxidative stress and promotes neural cell proliferation through G1-to-S cell cycle progression via regulation of FOXO3 and CDK4. 4 SELENOT is particularly abundant in endocrine organs, where it regulates insulin and corticotropin biosynthesis and release. 5 Clinically, SELENOT knockout is embryonic lethal in mice, underscoring its developmental necessity. 1 5 SELENOT dysregulation links to Parkinson's disease pathophysiology 4 and heart failure, where SELENOT-mimetic peptides reduce cardiac fibrosis, inflammation, and improve contractile function. 6 Recent evidence identifies SELENOT as a therapeutic target in osteoporosis through gut-immune-bone axis regulation. 7