The role of Nrf2 in thyroid maturation and hormone synthesis in vertebrate models

In vertebrates, the thyroid gland synthesizes hormones that act on almost all tissues and are essential for normal growth and metabolism. Thyroid hormone production relies on iodination of thyroglobulin and requires H 2 O 2 , which contributes to a relatively high basal oxidative stress in the thyroid that must be tightly controlled to prevent cellular damage. The thyroid has efficient antioxidant and detoxifying enzymes that help it resist H 2 O 2 -induced oxidative stress maintaining the homeostasis necessary for hormone synthesis. By regulating the expression of genes involved in cellular detoxification, NRF2 acts as a master regulator of the cellular defense against oxidative stress. Using zebrafish embryos and mouse ESC-derived thyroid organoids, we generated nrf2a/Nrf2 loss-of-function and identified a common dyshormonogenesis phenotype. Although in zebrafish, the driving mechanisms are possibly related to thyroglobulin iodination defects, in thyroid organoids, it is likely due to a reduction in Tg production, consequently affecting folliculogenesis and thyroid hormone production.