Emerging tools to investigate the contribution of selenium to ferroptosis and beyond

Selenium has a paradoxical role in biology, being essential at trace levels yet toxic at slightly higher doses. To operate within this narrow range, organisms have developed specialized pathways for selenium uptake, transport and usage/storage, primarily through selenoprotein biosynthesis. This Review summarizes current understanding of selenium handling and selenoprotein production, and discusses how selenium metabolism shapes susceptibility to ferroptotic cell death. We highlight both the role of selenoproteins in cellular defense and the unexpected roles of small-molecule metabolites, such as hydrogen selenide. We further discuss recent progress in analytical and chemical approaches, including mass spectrometry, activity-based probes and synthetic selenium donors, which are beginning to enable direct interrogation of these transient species. Together, these developments position selenium metabolism as a dynamic, chemically tractable regulator of redox biology and a promising therapeutic target.