SELENOS (selenoprotein S) is a selenocysteine-containing protein localized to the endoplasmic reticulum (ER) membrane that plays a central role in protein quality control and cellular stress responses. As a key component of the endoplasmic reticulum-associated degradation (ERAD) complex, SELENOS mediates the retrotranslocation of misfolded ER luminal proteins to the cytosol for proteasomal degradation, likely functioning as a linker between DERL1 and the VCP ATPase complex 1. Beyond ERAD, SELENOS regulates inflammation, oxidative stress, and ER stress—processes implicated in multiple diseases 2. SELENOS exhibits tissue-specific functions: it provides antioxidant protection and anti-ER stress effects in pancreatic and vascular tissues, while paradoxically promoting insulin resistance in liver, adipose, and skeletal muscle 3. Notably, SELENOS gene polymorphisms influence inflammatory responses and are associated with diabetes mellitus and macrovascular complications risk 3. Additionally, SELENOS interacts directly with SARS-CoV-2 nonstructural protein 7 (nsp7), suggesting a role in viral replication machinery hijacking 4. Recent Mendelian randomization analysis revealed that genetically elevated plasma SELENOS levels are causally associated with increased stroke risk across all stroke types, highlighting its importance in cerebrovascular pathogenesis 2. These findings underscore SELENOS as a multifunctional selenoprotein with therapeutic potential in metabolic and cardiovascular diseases.