Abstract
Ferroptosis is a regulated form of cell death characterized by iron-dependent phospholipid peroxidation and failure of cellular antioxidant defenses. Although increasingly implicated in cancer and other chronic diseases, its role in thyroid physiology and thyroid disease remains incompletely defined. The thyroid gland represents a particularly relevant setting in which to examine ferroptosis because normal thyroid hormone synthesis requires iron-dependent enzymatic activity and controlled reactive oxygen species generation while simultaneously relying on robust antioxidant systems to protect follicular cells from oxidative injury. This review examines the intersection of iron homeostasis, redox regulation, lipid peroxidation, and ferroptosis across the spectrum of thyroid disease. Current evidence suggests substantial differences among disease states. Thyroid malignancy has generated the strongest mechanistic and preclinical evidence for ferroptosis-related pathways, including alterations in glutathione peroxidase 4 (GPX4), solute carrier family 7 member 11 (SLC7A11), acyl-CoA synthetase long-chain family member 4 (ACSL4), and other regulators of ferroptotic susceptibility. In Hashimoto’s thyroiditis, Graves’ disease, and benign thyroid nodular disease, oxidative stress, mitochondrial dysfunction, inflammation, and impaired antioxidant defenses provide biologic plausibility for ferroptotic involvement; however, direct evidence of ferroptotic cell death remains limited. Importantly, oxidative stress and lipid peroxidation alone should not be considered synonymous with ferroptosis. Clarifying the role of ferroptosis in thyroid disease will require thyroid-specific mechanistic studies, validated biomarkers, and translational investigation. Improved understanding of these pathways may ultimately reveal disease-specific opportunities to protect vulnerable thyroid cells in benign disease while exploiting ferroptotic susceptibility therapeutically in thyroid malignancy.