Endoplasmic reticulum stress in Hashimoto’s thyroiditis: a candidate amplification node linking thyroid-specific vulnerability and immune dysregulation

Spatial transcriptomic analysis identifies a necroptosis-prone thyroid follicular cell state in Hashimoto’s thyroiditis

Background Hashimoto’s Thyroiditis (HT) is the leading cause of primary hypothyroidism, characterized by progressive thyroid follicular cell (TFC) loss and diffuse lymphocytic infiltration. While apoptosis dominates TFC death in HT, the role of pro-inflammatory necroptosis in TFC destruction, especially its cellular heterogeneity, spatial distribution, and inflammatory microenvironmental regulation, remains incompletely elucidated. Methods We integrated spatial transcriptomics and multilevel functional validation to map necroptosis-associated cellular and molecular programs in HT. Thyroid tissues from a local clinical cohort were analyzed using transmission electron microscopy (TEM), immunohistochemistry, and immunoblotting to validate necroptosis-associated signatures. In vitro, Nthy-ori 3-1 cells were stimulated with TNF-α, with or without IFN-γ, to characterize necroptosis-associated signaling in thyrocytes. Results We identified a distinct TFC subpopulation (Cluster 2) with high enrichment of the TNF signaling pathway and TNFRSF1A expression, which exhibited a necroptosis-susceptible phenotype and served as the core receiver of inflammatory signals from the immune microenvironment. Pseudotime trajectory analysis showed synchronous upregulation of transcripts of core necroptotic molecules (RIPK3, MLKL) at a critical threshold during TFC dedifferentiation. The TEM revealed necroptosis-compatible ultrastructural features in HT thyrocytes. Notably, HT tissues showed an RIPK3-MLKL-predominant necroptosis-associated pattern, with no significant changes in total or phosphorylated RIPK1. Clinically, the expression of necroptosis-related markers (ZBP1, RIPK3, MLKL) in thyroid tissues and circulating pro-inflammatory cytokines (IL-6, IL-1β, IL-1α) in serum were significantly correlated with thyroid autoantibody (TPOAb, TgAb) titers and TFC dedifferentiation. In vitro, pharmacological inhibition of RIPK3 or MLKL effectively preserved thyrocyte membrane integrity, reduced cell death, and suppressed the secretion of pro-inflammatory cytokines. Conclusions Our study provides a multimodal characterization of necroptosis in HT, showing that the inflammatory immune microenvironment is associated with TFC loss and activation of an RIPK3-MLKL-predominant necroptosis-related program, without detectable upregulation of total or phosphorylated RIPK1. Targeting the RIPK3-MLKL axis may represent an experimental therapeutic hypothesis that requires further validation in primary thyrocytes, organoids, and in vivo HT models.

Thyroid follicular cell-derived GDF15 attenuates inflammation and lipid dysregulation in Hashimoto's thyroiditis

Introduction Hashimoto's thyroiditis (HT) is a prevalent autoimmune thyroid disorder, typically triggers localized thyroid inflammation and systemic dyslipidemia, and progression to hypothyroidism. While growth differentiation factor 15 (GDF15) is recognized for its role in lipid metabolism and inflammatory diseases, its specific involvement in HT remains elusive. Methods We conducted plasma metabolomic profiling in HT patients and matched healthy controls to identify altered metabolic pathways. Correlation analysis was performed between serum GDF15 and clinical indicators. In vitro thyroid follicular cell models and NaI-induced in vivo thyroid inflammatory models were applied with GDF15 overexpression, knockdown, recombinant protein and siRNA treatment to explore the functional role of GDF15. Results Plasma metabolomic profiling in HT patients revealed that differentially expressed metabolites are predominantly enriched in lipid metabolism pathways. GDF15 expression was increased by 1.98-fold in HT serum compared to controls (p < 0.001), and serum GDF15 levels were negatively correlated with thyroid-stimulating hormone (TSH, R = −0.4943, p = 0.0040), aspartate aminotransferase (AST, R = −0.4506, p = 0.0238) and ultrasound attenuation parameter (UAP, R = −0.4894, p = 0.0071) in HT patients. Functional assays demonstrated that GDF15 overexpression tends to attenuate NaI-induced thyroid and systemic inflammation, relatively improving lipid profiles and reduces hepatic lipid deposition; however, GDF15 knockdown appeared to exacerbate these pathologies. Furthermore, recombinant GDF15 protein mitigates NaI-induced inflammatory responses in thyroid follicular cells, whereas GDF15 siRNA intensifies the inflammation. Discussion Given the limitations of the NaI-induced model and the lack of thyroid-specific genetic manipulation, these findings suggest a significant association between GDF15 and HT, though further research is required to establish definitive causality.

Extracellular vesicles at the immune–metabolic crossroads of Hashimoto’s thyroiditis and diabetes mellitus

This review compares how EVs remodel the immune microenvironment in HT, type 2 diabetes mellitus (T2DM), and related disease contexts, with attention to donor cells, cargo, recipient pathways, biomarkers, and therapeutic implications.

Exosome in Hashimoto’s thyroiditis: from pathogenesis to diagnostic and therapeutic potential

Endocrine-immune interactions in Hashimoto’s thyroiditis and human papillomavirus-induced cervical cancer: The role of Epstein-Barr, hepatitis C, and hepatitis D viruses in shared pathogenesis

Current evidence remains insufficient to confirm a direct association between HT and an increased risk of developing CC, and further experimental and epidemiological studies are required to elucidate the potential relationship between HT and HPV-induced CC.

Hashimoto’s thyroiditis influences tumor cell states and intratumoral microbiota in papillary thyroid carcinoma

It is suggested that Hashimoto’s thyroiditis reshapes both epithelial transcriptional states and the intratumoral microbial environment, potentially contributing to a less aggressive tumor phenotype.