{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T09:27:50Z","timestamp":1786958870129,"version":"build-2736575974"},"reference-count":113,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T00:00:00Z","timestamp":1786924800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Hashimoto\u2019s thyroiditis (HT) is the most prevalent autoimmune thyroid disease, characterized by lymphocytic infiltration and destruction of thyroid follicular architecture. Prior research has predominantly focused on aberrant adaptive immune activation, whereas the contribution of the thyroid follicular cell itself to this process remains incompletely elucidated. This narrative review synthesizes evidence implicating endoplasmic reticulum stress (ERS) in HT pathogenesis, stratifying the evidence by its proximity to HT pathology into three tiers: direct evidence, thyroid-cell evidence, and extrapolated evidence. Thyroid follicular cells continuously produce large quantities of structurally complex thyroglobulin, placing the ER under near-saturated folding load even under physiological conditions, thereby conferring an organ-specific vulnerability. Multiple HT-associated factors can activate the unfolded protein response (UPR), mediating thyrocyte apoptosis, suppression of functional genes, and loss of epithelial phenotype in thyroid cell models; individual UPR branches may also regulate the differentiation and function of infiltrating immune cells. Integrating the above evidence, this review proposes a testable positive-feedback perspective in which thyrocyte ERS injury and immune effector amplification may mutually reinforce one another. This perspective comprises six steps, and for each step, the strength of supporting evidence is assessed. Among these, only thyrocyte ERS activation and the macrophage IRE1\u03b1 pathway have received preliminary direct evidence in HT or experimental autoimmune thyroiditis (EAT); support for the remaining steps derives primarily from thyroid cell lines or non-thyroid experimental systems.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1909257","type":"journal-article","created":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T08:55:57Z","timestamp":1786956957000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Endoplasmic reticulum stress in Hashimoto\u2019s thyroiditis: a candidate amplification node linking thyroid-specific vulnerability and immune dysregulation"],"prefix":"10.3389","volume":"17","author":[{"given":"Xinying","family":"Si","sequence":"first","affiliation":[{"name":"Dongzhimen Hospital, Beijing University of Chinese Medicine","place":["Beijing, China"]},{"name":"Sunsimiao Hospital, Beijing University of Chinese Medicine","place":["Tongchuan, Shaanxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhixun","family":"Guo","sequence":"additional","affiliation":[{"name":"Dongzhimen Hospital, Beijing University of Chinese Medicine","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gena","family":"Jiao","sequence":"additional","affiliation":[{"name":"Sunsimiao Hospital, Beijing University of Chinese Medicine","place":["Tongchuan, Shaanxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaomei","family":"Zhang","sequence":"additional","affiliation":[{"name":"Dongzhimen Hospital, Beijing University of Chinese Medicine","place":["Beijing, China"]},{"name":"Sunsimiao Hospital, Beijing University of Chinese Medicine","place":["Tongchuan, Shaanxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaxue","family":"Ge","sequence":"additional","affiliation":[{"name":"Dongzhimen Hospital, Beijing University of Chinese Medicine","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiahui","family":"Qian","sequence":"additional","affiliation":[{"name":"Dongzhimen Hospital, Beijing University of Chinese Medicine","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyi","family":"Li","sequence":"additional","affiliation":[{"name":"Beijing Health Vocational College","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenqian","family":"Geng","sequence":"additional","affiliation":[{"name":"Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simiao","family":"Yao","sequence":"additional","affiliation":[{"name":"Dongzhimen Hospital, Beijing University of Chinese Medicine","place":["Beijing, China"]},{"name":"Sunsimiao Hospital, Beijing University of Chinese Medicine","place":["Tongchuan, Shaanxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiguo","family":"Ding","sequence":"additional","affiliation":[{"name":"Dongzhimen Hospital, Beijing University of Chinese Medicine","place":["Beijing, China"]},{"name":"Sunsimiao Hospital, Beijing University of Chinese Medicine","place":["Tongchuan, Shaanxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanke","family":"Wu","sequence":"additional","affiliation":[{"name":"Dongzhimen Hospital, Beijing University of Chinese Medicine","place":["Beijing, China"]},{"name":"Sunsimiao Hospital, Beijing University of Chinese Medicine","place":["Tongchuan, Shaanxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,17]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/j.autrev.2020.102649","article-title":"Hashimoto's thyroiditis: an update on pathogenic mechanisms, diagnostic protocols, therapeutic strategies, and potential malignant transformation","volume":"19","author":"Ralli","year":"2020","journal-title":"Autoimmun Rev"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.3389\/fpubh.2022.1020709","article-title":"Global prevalence and epidemiological trends of Hashimoto's thyroiditis in adults: a systematic review and meta-analysis","volume":"10","author":"Hu","year":"2022","journal-title":"Front Public Health"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2014-2990","article-title":"Hashimoto's thyroiditis, risk of coronary heart disease, and L-thyroxine treatment: a nationwide cohort study","volume":"100","author":"Chen","year":"2015","journal-title":"J Clin Endocrinol Metab"},{"key":"B4","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1186\/s13044-021-00117-x","article-title":"Is Hashimoto thyroiditis associated with increasing risk of thyroid malignancies? 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