{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T11:10:10Z","timestamp":1788952210952,"version":"build-2803163510"},"reference-count":36,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T00:00:00Z","timestamp":1788912000000},"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. Cell Dev. Biol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Periodontitis represents one of the most prevalent chronic inflammatory diseases, characterized by progressive periodontal tissue destruction driven by immune dysregulation. Emerging evidence establishes ferroptosis\u2014an iron-dependent, lipid-peroxidation-driven form of regulated cell death\u2014as a pivotal but underexplored driver of the pathological \u201ccell death\u2013inflammation\u2013re-death\u201d cycle in periodontitis. Ferroptotic cells release damage-associated molecular patterns (DAMPs) including oxidized lipids, HMGB1, and iron species that amplify inflammation. The spatiotemporal heterogeneity of ferroptosis susceptibility among periodontal cell subtypes, the identity of DAMPs-mediated intercellular signaling networks, and the epigenetic mechanisms governing ferroptosis-susceptibility transitions remain incompletely characterized.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We employed a single-arm cross-sectional design: a prospective single-cell RNA sequencing (scRNA-seq) study of gingival tissue from 6 periodontitis patients and 4 controls, integrating UMAP clustering, pseudotime trajectory, RNA velocity, CellChat-based ligand\u2013receptor analysis, pySCENIC regulon inference, and epigenetic landscape analysis via published ATAC-seq\/methylation dataset integration from independent cohorts. To functionally validate key transcriptomic findings, LPS-stimulated human cementoblast (HCEM)\n                      <jats:italic>in vitro<\/jats:italic>\n                      experiments with Ferrostatin-1 rescue were performed, and gene expression was quantified by RT-qPCR.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The scRNA-seq atlas resolved three cementoblast subtypes with distinct ferroptosis susceptibility profiles; ferroptosis-sensitive cementoblasts (FS-CEM) functioned as dominant DAMPs-releasing hubs engaging fibroblasts, endothelial cells, and immune cells via HMGB1\u2013RAGE, IL-33\u2013ST2, and MIF\u2013CD74 axes that triggered secondary necroptotic and pyroptotic cascades. NFE2L2 (NRF2)\u2013BACH1 was identified as the transcription factor master switch governing ferroptosis susceptibility. Epigenetic analysis, derived from integration with publicly available ATAC-seq and methylation datasets from independent cohorts (GEO: GSE194276; ENCODE), revealed hypermethylation of GPX4\/SLC7A11 promoters and EZH2-mediated H3K27me3 enrichment at NFE2L2 target loci in ferroptosis-sensitive cells, representing hypothesis-generating epigenetic inferences requiring direct experimental validation.\n                      <jats:italic>In vitro<\/jats:italic>\n                      LPS stimulation of HCEM cells confirmed dose-dependent downregulation of GPX4 and SLC7A11 and upregulation of ACSL4, PTGS2, and HMGB1; these changes were significantly reversed by Ferrostatin-1 pre-treatment, validating the ferroptosis specificity of the identified molecular signatures.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This study provides mechanistic evidence that ferroptosis drives the chronic inflammatory cycle in periodontitis, and proposes NFE2L2 activation, BACH1 inhibition, EZH2 inhibition, and HMGB1 neutralization as precision therapeutic targets to break the pathological cell death\u2013inflammation cycle.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fcell.2026.1904996","type":"journal-article","created":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T10:16:04Z","timestamp":1788948964000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Ferroptosis-driven cell death perpetuates the chronic inflammatory cycle in periodontitis: a single-cell transcriptomic study"],"prefix":"10.3389","volume":"14","author":[{"given":"Hongmei","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Stomatology, People\u2019s Hospital of Chongqing Liangjiang New Area","place":["Chongqing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhao","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Stomatology, People\u2019s Hospital of Liangping District","place":["Chongqing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,9]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"21140","DOI":"10.3390\/ijms141021140","article-title":"The effect on proliferation and differentiation of cementoblast by using sclerostin as inhibitor","volume":"14","author":"Bao","year":"2013","journal-title":"Int. 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