Mechanism of Excess Iodine-Induced Hypothyroidism via Endoplasmic Reticulum Stress

• 1、Second Affiliated Hospital of Soochow University,Suzhou,Jiangsu Province,215000

Abstract：Excessive iodine intake leads to thyroid cell damage and disrupts thyroid hormone synthesis and secretion, serving as a key contributor to hypothyroidism. Endoplasmic reticulum (ER) stress is a critical cellular response to homeostasis imbalance and can be triggered by high iodine exposure. In this study, human thyroid follicular epithelial cells (Nthy-ori-3-1) were cultured in vitro and treated with 5 mM potassium iodide (KI) for 72 h to establish a damage model. The ER stress inhibitor 4-phenylbutyric acid (4-PBA) was applied as a 24 h pretreatment. The results showed that high iodine inhibited the expression of TSHR and its downstream thyroid hormone synthesis-related genes TG, TPO, and NIS, while increasing the levels of ER stress markers GRP78, ATF4, and CHOP, as well as the apoptosis rate. However, 4-PBA pretreatment alleviated ER stress, restored TSHR and downstream gene expression, and reduced apoptosis. Additionally, although the adenylate cyclase agonist Forskolin failed to restore TSHR expression, it bypassed the damaged receptor to directly activate the downstream cAMP pathway and partially improved the expression of TG, TPO, and NIS. These findings indicate that high iodine impairs the TSH-TSHR signaling axis by inducing ER stress, thereby suppressing hormone synthesis-related gene expression and promoting apoptosis. Targeting ER stress may represent a novel strategy for the prevention and treatment of high iodine-induced hypothyroidism.

Keywords： Internal medicine Hypothyroidism Endoplasmic Reticulum Stress Iodine Apotosis