The Vitamin D-NRF2-Selenium Triple Deficiency: Convergent Antioxidant System Failure Through Three Independent Upstream Deficiencies Governing the Same Downstream Selenoprotein Expression Program

This paper proposes that vitamin D, selenium, and zinc converge on the same NRF2-mediated antioxidant gene expression program through independent upstream mechanisms, and that their co-deficiency produces compounded antioxidant reserve failure that no single-nutrient assessment would detect. Vitamin D, through VDR-NRF2 regulatory overlap and Klotho-mediated redox signaling, drives NRF2 nuclear translocation and selenoprotein gene expression. Selenium provides the selenocysteine substrate for selenoprotein synthesis. Zinc provides the structural cofactor for antioxidant enzymes including SOD3 and supports thyroid receptor T3 binding. A 2023 study confirmed that vitamin D improves cognitive impairment and alleviates ferroptosis specifically via the NRF2-GPx4 signaling pathway, connecting vitamin D status to the ferroptosis defense. All claims are hypothesis-level.