Selenoproteins: Minute yet vital players governing cellular fate

Selenoproteins represent a distinct class of proteins that incorporate selenocysteine (Sec), whose biosynthesis and translational integration are dependent on selenium availability and the presence of a selenocysteine insertion sequence (SECIS). These proteins are indispensable for redox regulation, antioxidant defense, and thyroid hormone metabolism, among other vital biological processes. Remarkably, selenoproteins act as critical regulators of cellular fate decisions, a function that hinges on Sec-a residue whose biosynthesis and translational incorporation into protein involve machinery far more intricate than that of canonical amino acids. This evolutionary adaptation, whether arising from stochastic mutational events or as an obligatory trade-off for functional precision, underscores the sophisticated molecular regulatory strategies in living organisms. Despite their small number, selenoproteins are evolutionarily conserved across archaea, bacteria, and eukaryotes. Notably, the Sec biosynthesis and incorporation machinery features both conserved core components and species-specific adaptations. Strikingly, this limited set of proteins executes diverse yet irreplaceable cellular functions. Thus, a comprehensive understanding of Sec biosynthesis, its incorporation into selenoproteins, and the regulatory mechanisms governing these processes in eukaryotic cells will facilitate the development of selenoproteins-targeted therapeutic strategies for cancer. In this review, we comprehensively outline the uptake and metabolic pathways of selenoamino acids in eukaryotes, with particular emphasis on the biosynthetic mechanism of Sec and its unique translational incorporation into selenoproteins. We systematically elucidate the multi-layered regulatory networks that govern these biological processes within cells. Furthermore, we present a taxonomic classification and functional synthesis of eukaryotic selenoproteins, accompanied by an in-depth analysis of their molecular roles in various pathological states. Special emphasis is placed on the glutathione peroxidase (GPX) family, especially GPX4, in ferroptosis regulation and its sophisticated control mechanisms. Additionally, this review summarizes key challenges in current selenoproteins research and explores potential therapeutic strategies for cancer treatment by targeting selenoproteins.