{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T05:45:50Z","timestamp":1785735950657,"version":"3.56.0"},"reference-count":28,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T00:00:00Z","timestamp":1785715200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82400923, 82500959"],"award-info":[{"award-number":["82400923, 82500959"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100018537","name":"National Science and Technology Major Project","doi-asserted-by":"publisher","award":["2023ZD0508905"],"award-info":[{"award-number":["2023ZD0508905"]}],"id":[{"id":"10.13039\/501100018537","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005047","name":"Natural Science Foundation of Liaoning Province","doi-asserted-by":"publisher","award":["2023-BSBA-333, 2024-BSLH-328, 2026-BS-0482"],"award-info":[{"award-number":["2023-BSBA-333, 2024-BSLH-328, 2026-BS-0482"]}],"id":[{"id":"10.13039\/501100005047","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Hashimoto\u2019s 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      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.\n                      <jats:italic>In vitro<\/jats:italic>\n                      , Nthy-ori 3-1 cells were stimulated with TNF-\u03b1, with or without IFN-\u03b3, to characterize necroptosis-associated signaling in thyrocytes.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      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-1\u03b2, IL-1\u03b1) in serum were significantly correlated with thyroid autoantibody (TPOAb, TgAb) titers and TFC dedifferentiation.\n                      <jats:italic>In vitro<\/jats:italic>\n                      , pharmacological inhibition of RIPK3 or MLKL effectively preserved thyrocyte membrane integrity, reduced cell death, and suppressed the secretion of pro-inflammatory cytokines.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      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\n                      <jats:italic>in vivo<\/jats:italic>\n                      HT models.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1902510","type":"journal-article","created":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T05:29:45Z","timestamp":1785734985000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Spatial transcriptomic analysis identifies a necroptosis-prone thyroid follicular cell state in Hashimoto\u2019s thyroiditis"],"prefix":"10.3389","volume":"17","author":[{"given":"Dongyu","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Endocrinology, Shengjing Hospital of China Medical University","place":["Shenyang, Liaoning, 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China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xichang","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Shengjing Hospital of China Medical University","place":["Shenyang, Liaoning, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Shengjing Hospital of China Medical University","place":["Shenyang, Liaoning, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haonan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Shengjing Hospital of China Medical University","place":["Shenyang, Liaoning, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuting","family":"Fan","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Shengjing Hospital of China Medical University","place":["Shenyang, 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