Mast Cell Activation Syndrome and the Selenoprotein Axis: Ferroptosis-Driven Mast Cell Hyperreactivity, GPx4 Depletion as an Upstream Driver of MCAS, and Selenium as a Direct Mast Cell Stabilizer

This paper proposes that MCAS and histamine intolerance represent an eighth upstream failure mode in the Selenoprotein Axis through a bidirectional ferroptosis-mast cell loop: GPx4 insufficiency from selenium depletion enables ferroptotic cell death in tissue adjacent to mast cells; ferroptosis releases DAMPs that activate mast cells; activated mast cells release reactive oxygen species that further deplete GPx4 in neighboring cells. A 2025 Cell Biology International review confirmed that ferroptosis is directly involved in the pathogenesis of allergic inflammatory diseases. The post-viral MCAS presentations in Long COVID are mechanistically explained by SARS-CoV-2-driven SELENOP negative acute-phase response depleting GPx4. Selenium addresses the MCAS loop through two independent points: GPx4 synthesis (upstream ferroptosis suppression) and direct mast cell membrane stabilization. All claims are hypothesis-level requiring prospective clinical confirmation.