ArticleFrontiers in immunology2026
Spatial transcriptomic analysis identifies a necroptosis-prone thyroid follicular cell state in Hashimoto's thyroiditis.
Article in Frontiers in immunology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
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. 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. 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
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