{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,25]],"date-time":"2026-02-25T08:01:14Z","timestamp":1772006474835,"version":"3.50.1"},"reference-count":42,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,2,25]],"date-time":"2026-02-25T00:00:00Z","timestamp":1771977600000},"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:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>This study aims to define the core transcriptomic signatures of thyroid tissue damage in Hashimoto\u2019s thyroiditis (HT), with a specific focus on identifying regulatory hub genes critical for macrophage polarization.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We performed an integrated analysis of bulk RNA-seq data from a public dataset (GEO: GSE165724), comparing thyroid tissues from HT patients with those from normal controls. The bioinformatic analysis included differential gene expression analysis, functional enrichment analysis, protein-protein interaction (PPI) network construction, and immune cell infiltration profiling using CIBERSORT. Key findings were experimentally validated in an independent clinical cohort (n=32) using quantitative real-time polymerase chain reaction (qRT-PCR), Western blotting, and immunohistochemistry (IHC).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Our analysis identified a core set of 1,752 HT-specific unique differentially expressed genes (DEGs). Network analysis distilled these to 5 up-regulated (e.g., IFNG, CD4, PTPRC) and 10 down-regulated hub genes (e.g., CITED2, TXN2, FOXA2). The immune landscape in HT tissues was markedly remodeled, featuring a significant increase in M1 macrophages. Correlation analysis revealed that IFNG mRNA positively correlated with M1 abundance, whereas CITED2 mRNA showed a strong negative correlation. Clinical validation confirmed significant IFNG upregulation and CITED2 downregulation at the mRNA level. At the protein level, validation demonstrated a significant suppression of CITED2 in HT tissues. IHC co-localization analysis specifically indicated markedly weakened CITED2 expression in the cytoplasm and nucleus of thyroid follicular cells (TFCs) from HT patients. Furthermore, M1 macrophage markers (CD80\/CD86) were significantly elevated and positively correlated with autoantibody levels and IFNG mRNA expression, but inversely correlated with CITED2.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>This study defines a robust transcriptomic and immune signature for HT. The significant downregulation of CITED2, specifically within thyroid follicular cells, and its inverse correlation with M1 macrophages, imply that its suppression may disrupt thyroid follicular cell function and contribute to the pro-inflammatory immune microenvironment, thereby revealing a novel potential mechanism in HT pathogenesis.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1764100","type":"journal-article","created":{"date-parts":[[2026,2,25]],"date-time":"2026-02-25T07:05:04Z","timestamp":1772003104000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["CITED2: a novel hub gene downregulated in Hashimoto\u2019s thyroiditis and associated with M1 macrophages via bioinformatics analysis and clinical validation"],"prefix":"10.3389","volume":"17","author":[{"given":"Xuefeng","family":"Bai","sequence":"first","affiliation":[{"name":"Department of Endocrinology, the Second Affiliated Hospital of Fujian Medical University","place":["Quanzhou, Fujian, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Honghong","family":"Duan","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, the Second Affiliated Hospital of Fujian Medical University","place":["Quanzhou, Fujian, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yajing","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, the Second Affiliated Hospital of Fujian Medical University","place":["Quanzhou, Fujian, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haihong","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Thyroid Surgery, the Second Affiliated Hospital of Fujian Medical University","place":["Quanzhou, Fujian, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Huibin","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, the Second Affiliated Hospital of Fujian Medical University","place":["Quanzhou, Fujian, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,2,25]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(23)00457-9","article-title":"Incidence, prevalence, and co-occurrence of autoimmune disorders over time and by age, sex, and socioeconomic status: a population-based cohort study of 22 million individuals in the UK","volume":"401","author":"Conrad","year":"2023","journal-title":"Lancet"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.3389\/fpubh.2022.1020709","article-title":"Global prevalence and epidemiological trends of Hashimoto\u2019s 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\u2019s 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","DOI":"10.1038\/bjc.2013.597","article-title":"Cancer risk in patients with Hashimoto\u2019s thyroiditis: a nationwide cohort study","volume":"109","author":"Chen","year":"2013","journal-title":"Br J CA"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.5152\/TurkPediatriArs.2018.01819","article-title":"Neonatal effects of thyroid diseases in pregnancy and approach to the infant with increased TSH: Turkish Neonatal and Pediatric Endocrinology and Diabetes Societies consensus report","volume":"53","author":"\u00d6zon","year":"2018","journal-title":"Turk Pediatri Ars"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.3390\/ijms25136883","article-title":"The role of the immune system in the course of hashimoto\u2019s thyroiditis: the current state of knowledge","volume":"25","author":"Wro\u0144ska","year":"2024","journal-title":"Int J Mol Sci"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2017.00149","article-title":"Epigenetics and autoimmune thyroid diseases","volume":"8","author":"Copped\u00e8","year":"2017","journal-title":"Front Endocrinol (Laus)"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1007\/s12026-021-09241-0","article-title":"Microarray profiling and functional analysis reveal the regulatory role of differentially expressed plasma circular RNAs in Hashimoto\u2019s thyroiditis","volume":"70","author":"Bai","year":"2022","journal-title":"Immunol Res"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1089\/thy.2011.0480","article-title":"Demonstration of innate immune responses in the thyroid gland: potential to sense danger and a possible trigger for autoimmune reactions","volume":"23","author":"Kawashima","year":"2013","journal-title":"Thyroid"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.1009932","article-title":"High iodine promotes autoimmune thyroid disease by activating hexokinase 3 and inducing polarization of macrophages towards M1","volume":"13","author":"Cai","year":"2022","journal-title":"Front Immunol"},{"key":"B11","doi-asserted-by":"publisher","first-page":"775","DOI":"10.1038\/s41467-022-28120-2","article-title":"Lymphocyte infiltration and thyrocyte destruction are driven by stromal and immune cell components in Hashimoto\u2019s thyroiditis","volume":"13","author":"Zhang","year":"2022","journal-title":"Nat Commun"},{"key":"B12","doi-asserted-by":"publisher","first-page":"e11211","DOI":"10.1097\/MD.0000000000011211","article-title":"Heterogeneity of tissue IL-17 and tight junction proteins expression demonstrated in patients with autoimmune thyroid diseases","volume":"97","author":"Zake","year":"2018","journal-title":"Med (Balt)"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/j.cyto.2014.11.005","article-title":"Increased IL-21\/IL-21R expression and its proinflammatory effects in autoimmune thyroid disease","volume":"72","author":"Guan","year":"2015","journal-title":"Cytokine"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.01197","article-title":"Cytokine secretion and pyroptosis of thyroid follicular cells mediated by enhanced NLRP3, NLRP1, NLRC4, and AIM2 inflammasomes are associated with autoimmune thyroiditis","volume":"9","author":"Guo","year":"2018","journal-title":"Front Immunol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1016\/j.autrev.2020.102649","article-title":"Hashimoto\u2019s 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":"B16","doi-asserted-by":"publisher","DOI":"10.1007\/s40618-020-01477-1","article-title":"An update on the pathogenesis of Hashimoto\u2019s thyroiditis","volume":"44","author":"Weetman","year":"2021","journal-title":"J Endocrinol Invest"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1155\/2019\/5368473","article-title":"Analysis of regulatory T cell subsets and their expression of helios and PD-1 in patients with hashimoto thyroiditis","volume":"2019","author":"Hu","year":"2019","journal-title":"Int J Endocrinol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1007\/s12020-015-0569-y","article-title":"The possible role of CD4+CD25(high)Foxp3+\/CD4+IL-17A+ cell imbalance in the autoimmunity of patients with Hashimoto thyroiditis","volume":"50","author":"Xue","year":"2015","journal-title":"Endocrine"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2011-2178","article-title":"Evidence of a combined cytotoxic thyroglobulin and thyroperoxidase epitope-specific cellular immunity in Hashimoto\u2019s thyroiditis","volume":"97","author":"Ehlers","year":"2012","journal-title":"J Clin Endocrinol Metab"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1352946","article-title":"Macrophage polarization: an important role in inflammatory diseases","volume":"15","author":"Luo","year":"2024","journal-title":"Front Immunol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1021\/acs.biochem.8b01290","article-title":"Role of backbone dynamics in modulating the interactions of disordered ligands with the TAZ1 domain of the CREB-binding protein","volume":"58","author":"Berlow","year":"2019","journal-title":"Biochemistry"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1915333117","article-title":"Investigations of the underlying mechanisms of HIF-1\u03b1 and CITED2 binding to TAZ1","volume":"117","author":"Chu","year":"2020","journal-title":"Proc Natl Acad Sci U S A"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddq554","article-title":"Loss of Cited2 causes congenital heart disease by perturbing left-right patterning of the body axis","volume":"20","author":"Lopes Floro","year":"2011","journal-title":"Hum Mol Genet"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1038\/ng768","article-title":"Cardiac malformations, adrenal agenesis, neural crest defects and exencephaly in mice lacking Cited2, a new Tfap2 co-activator","volume":"29","author":"Bamforth","year":"2001","journal-title":"Nat Genet"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1001650","article-title":"Negative feedback regulation of NF-\u03baB action by CITED2 in the nucleus","volume":"186","author":"Lou","year":"2011","journal-title":"J Immunol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1096\/fj.202000864R","article-title":"CITED2 limits pathogenic inflammatory gene programs in myeloid cells","volume":"34","author":"Pong Ng","year":"2020","journal-title":"FASEB J"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.00452-17","article-title":"CITED2 restrains proinflammatory macrophage activation and response","volume":"38","author":"Kim","year":"2018","journal-title":"Mol Cell Biol"},{"key":"B28","doi-asserted-by":"publisher","first-page":"e21833","DOI":"10.1096\/fj.202100792R","article-title":"CITED2 inhibits STAT1-IRF1 signaling and atherogenesis","volume":"35","author":"Zafar","year":"2021","journal-title":"FASEB J"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1530\/eje.1.01847","article-title":"Increase of interferon-gamma inducible alpha chemokine CXCL10 but not beta chemokine CCL2 serum levels in chronic autoimmune thyroiditis","volume":"152","author":"Antonelli","year":"2005","journal-title":"Eur J Endocrinol"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1016\/j.cyto.2011.04.022","article-title":"Circulating chemokine (CXC motif) ligand (CXCL)9 is increased in aggressive chronic autoimmune thyroiditis, in association with CXCL10","volume":"55","author":"Antonelli","year":"2011","journal-title":"Cytokine"},{"key":"B31","doi-asserted-by":"publisher","first-page":"5895","DOI":"10.1038\/s41467-024-50192-5","article-title":"Unraveling the molecular architecture of autoimmune thyroid diseases at spatial resolution","volume":"15","author":"Mart\u00ednez-Hern\u00e1ndez","year":"2024","journal-title":"Nat Commun"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1089\/thy.2008.0295","article-title":"Influence of iodide excess and interferon-gamma on human primary thyroid cell proliferation, thyroglobulin secretion, and intracellular adhesion molecule-1 and human leukocyte antigen-DR expression","volume":"19","author":"Kostic","year":"2009","journal-title":"Thyroid"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2023.110494","article-title":"MIF promotes Th17 cell differentiation in Hashimoto\u2019s thyroiditis by binding HVEM and activating NF-\u03baB signaling pathway","volume":"121","author":"Liu","year":"2023","journal-title":"Int Immunopharmacol"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1155\/2015\/621072","article-title":"Macrophage migration inhibitory factor interacting with Th17 cells may be involved in the pathogenesis of autoimmune damage in Hashimoto\u2019s thyroiditis","volume":"2015","author":"Xue","year":"2015","journal-title":"Mediators Inflamm"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22083806","article-title":"Oxidative stress-induced sirtuin1 downregulation correlates to HIF-1\u03b1, GLUT-1, and VEGF-A upregulation in th1 autoimmune hashimoto\u2019s thyroiditis","volume":"22","author":"Hepp","year":"2021","journal-title":"Int J Mol Sci"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21072391","article-title":"Hepatic lipid catabolism via PPAR\u03b1-lysosomal crosstalk","volume":"21","author":"Sinha","year":"2020","journal-title":"Int J Mol Sci"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2691","article-title":"CITED2 links hormonal signaling to PGC-1\u03b1 acetylation in the regulation of gluconeogenesis","volume":"18","author":"Sakai","year":"2012","journal-title":"Nat Med"},{"key":"B38","doi-asserted-by":"publisher","first-page":"4113","DOI":"10.1038\/s41467-018-06606-2","article-title":"Aberrant expression of CITED2 promotes prostate cancer metastasis by activating the nucleolin-AKT pathway","volume":"9","author":"Shin","year":"2018","journal-title":"Nat Commun"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1038\/s41388-024-03031-2","article-title":"In vivo genome-wide CRISPR screening identifies CITED2 as a driver of prostate cancer bone metastasis","volume":"43","author":"Arriaga","year":"2024","journal-title":"Oncogene"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.24780","article-title":"Identification of prospective factors promoting osteotropism in breast cancer: a potential role for CITED2","volume":"126","author":"Lau","year":"2010","journal-title":"Int J CA"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1158\/1541-7786.MCR-16-0081","article-title":"CITED2 modulates breast cancer metastatic ability through effects on IKK\u03b1","volume":"14","author":"Jayaraman","year":"2016","journal-title":"Mol Cancer Res"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1016\/j.stemcr.2021.10.001","article-title":"CITED2 coordinates key hematopoietic regulatory pathways to maintain the HSC pool in both steady-state hematopoiesis and transplantation","volume":"16","author":"Lawson","year":"2021","journal-title":"Stem Cell Rep"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1764100\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,25]],"date-time":"2026-02-25T07:05:06Z","timestamp":1772003106000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1764100\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,25]]},"references-count":42,"alternative-id":["10.3389\/fimmu.2026.1764100"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1764100","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,25]]},"article-number":"1764100"}}