{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T18:05:36Z","timestamp":1779213936051,"version":"3.51.4"},"reference-count":64,"publisher":"American Society for Clinical Investigation","issue":"24","license":[{"start":{"date-parts":[[2025,12,15]],"date-time":"2025-12-15T00:00:00Z","timestamp":1765756800000},"content-version":"vor","delay-in-days":62,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"crossref","award":["R01DK132017,F30DK139717,R01DK15070"],"award-info":[{"award-number":["R01DK132017,F30DK139717,R01DK15070"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,12,15]]},"abstract":"<jats:p>\n                    It is now recognized that patient and animal models expressing genetically encoded misfolded mutant thyroglobulin (TG, the protein precursor for thyroid hormone synthesis) exhibit dramatic swelling of the endoplasmic reticulum (ER), with ER stress and cell death in thyrocytes \u2014 seen both in homozygotes (with severe hypothyroidism) and heterozygotes (with subclinical hypothyroidism). The thyrocyte death phenotype is exacerbated upon thyroidal stimulation (by thyrotropin [TSH]), as cell death is inhibited upon treatment with exogenous thyroxine. TSH stimulation might contribute to cytotoxicity by promoting ER stress or by an independent mechanism. Here we\u2019ve engineered KO mice completely lacking\n                    <jats:italic>Tg<\/jats:italic>\n                    expression. Like other animals\/patients with mutant TG, these animals rapidly developed severe goitrous hypothyroidism; however, thyroidal ER stress was exceedingly low \u2014 lower even than that seen in WT mice. Nevertheless, mice lacking TG exhibited abundant thyroid cell death, which depended upon renegade thyroidal iodination; cell death was completely suppressed in a genetic model lacking effective iodination or in\n                    <jats:italic>Tg-KO<\/jats:italic>\n                    mice treated with propylthiouracil (iodination inhibitor) or iodide deficiency. Thyrocytes in culture were killed not in the presence of H\n                    <jats:sub>2<\/jats:sub>\n                    O\n                    <jats:sub>2<\/jats:sub>\n                    alone, but rather upon peroxidase-mediated iodination, with cell death blocked by propylthiouracil. Thus, in the thyroid gland bearing\n                    <jats:italic>Tg<\/jats:italic>\n                    mutation(s), TSH-stimulated iodination activity triggers thyroid cell death.\n                  <\/jats:p>","DOI":"10.1172\/jci187044","type":"journal-article","created":{"date-parts":[[2025,10,14]],"date-time":"2025-10-14T16:00:36Z","timestamp":1760457636000},"source":"Crossref","is-referenced-by-count":2,"title":["Stimulated thyroid hormone synthesis machinery drives thyrocyte cell death independent of ER stress"],"prefix":"10.1172","volume":"135","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1538-8733","authenticated-orcid":true,"given":"Crystal","family":"Young","sequence":"first","affiliation":[{"name":"Division of Metabolism, Endocrinology & Diabetes and"},{"name":"Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, Michigan, 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