ArticleFrontiers in cell and developmental biology2026
Ferroptosis-driven cell death perpetuates the chronic inflammatory cycle in periodontitis: a single-cell transcriptomic study.
Article in Frontiers in cell and developmental biology, 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: Periodontitis represents one of the most prevalent chronic inflammatory diseases, characterized by progressive periodontal tissue destruction driven by immune dysregulation. Emerging evidence establishes ferroptosis-an iron-dependent, lipid-peroxidation-driven form of regulated cell death-as a pivotal but underexplored driver of the pathological "cell death-inflammation-re-death" 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. Methods: 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-receptor 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) Results: 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-RAGE, IL-33-ST2, and MIF-CD74 axes that triggered secondary necroptotic and pyroptotic cascades. NFE2L2 (NRF2)-BACH1 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. Conclusion: 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-inflammation cycle.
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