The Autonomic Gate: Chronic HPA Dysregulation, Vagal Tone Reduction, and Circadian GPx Suppression as a Seventh Upstream Failure Mode in the Selenoprotein Axis

This paper proposes that chronic psychological and physiological stress represents a seventh upstream failure mode in the Selenoprotein Axis, operating through three simultaneous mechanisms: (1) cortisol-mediated suppression of NRF2-dependent antioxidant gene expression through glucocorticoid receptor-Keap1 stabilization; (2) reduced vagal tone impairing the cholinergic anti-inflammatory pathway, unchecking TNF-alpha and IL-6 production and amplifying hepcidin elevation; and (3) sleep disruption suppressing the circadian peak of GPx and mitochondrial repair. The relationship is bidirectional: selenium deficiency impairs HPA function, and HPA dysregulation depletes selenoproteins. Key anchor: Motrenikova et al. Antioxidants 2025. All claims are hypothesis-level requiring prospective clinical confirmation.