ORIGINAL RESEARCH article
Front. Immunol.
Sec. Autoimmune and Autoinflammatory Disorders : Autoimmune Disorders
This article is part of the Research TopicThe Role of Innate Immunity in the Pathogenesis of Autoimmune and Autoinflammatory DiseasesView all 13 articles
CITED2: A Novel Hub Gene Downregulated in Hashimoto's Thyroiditis and Associated with M1 Macrophages via Bioinformatics Analysis and Clinical Validation
Provisionally accepted
- The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
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Objective: This study aims to define the core transcriptomic signatures of thyroid tissue damage in Hashimoto's thyroiditis (HT), with a specific focus on identifying regulatory hub genes critical for macrophage polarization. Methods: 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)quantitative PCR (qPCR), Western blotting, and immunohistochemistry (IHC). Results: 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, Critically, 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. Conclusions: 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, implysuggest 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.
Keywords: Cited2, Hashimoto's thyroiditis, Immuneinfiltration, M1 macrophage, Transcriptome
Received: 09 Dec 2025; Accepted: 09 Feb 2026.
Copyright: © 2026 Huang, Bai, Duan, Xu and Shi. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Huibin Huang
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