Ferroptosis as a novel alternative cell death model in Hashimoto´s thyroiditis.

Autoimmune thyroid disorders (AITD), including Hashimoto's thyroiditis (HT) and Graves' disease (GD), are organ-specific diseases driven by immune dysregulation and autoimmune responses against thyroid antigens. Proinflammatory cytokines and autoantibodies injure thyroid follicular cells (TFCs), increasing reactive oxygen species (ROS), oxidative stress, and cell death, particularly in HT, where apoptosis has been described. Here, ferroptosis - an iron-dependent cell death mechanism characterized by ROS-mediated lipid peroxidation- is proposed as an alternative mechanism in HT. Thyroid tissue from HT patients shows reduced levels of glutathione-dependent peroxidase 4 (GPx4), a key selenoprotein that inhibits ferroptosis, despite increased GPx4 gene expression, along with elevated lipid peroxidation products such as 4-hydroxynonenal (4-HNE). In an in vitro HT model, based on TFCs cultures stimulated with proinflammatory cytokines (IFN-γ and TNF-α), increased lipid peroxidation, free iron and cell death confirm ferroptosis involvement. Mechanistically, reduced expression of peroxiredoxin 6 (PRDX6) and other components of the selenocysteine incorporation pathway likely impairs GPx4 translation. Overall, our data identify ferroptosis as a relevant cell death mechanism in HT pathogenesis driven by the proinflammatory environment.