Cross‐Cohort Transcriptomic and Oral Microbiome Analyses Identify Ferroptosis‐Associated Signatures in Periodontitis and Oral Squamous Cell Carcinoma
Year: 2026
Type: article
Abstract: Background: Periodontitis (PD) and oral squamous cell carcinoma (OSCC) have been investigated in relation to inflammation, oral microbial alterations, and iron/redox biology. Whether ferroptosis-associated expression patterns overlap across independently sampled periodontal and cancer cohorts remains uncertain. We characterized these patterns without presuming that the available datasets represent matched individuals or a temporal disease sequence. Methods: We analyzed gingival single-cell RNA-sequencing data (GSE171213), an OSCC discovery expression cohort (GSE30784), and an independent oral tongue squamous cell carcinoma validation cohort (GSE13601). Periodontal microbial functional gene profiles (GSE54290) and a cross-study OSCC 16S abundance resource were examined separately. Analyses included cell annotation, KEGG ferroptosis gene-set scoring, sample- and cell type-level comparisons, differential expression, external transcriptomic signature validation, microbial diversity and abundance analyses, and LPS-stimulated cell-line RT-qPCR and ELISA measurements. The transcriptomic and microbial cohorts were not linked at the individual-patient level. Results: Quality control retained 34,342 cells from 12 gingival samples (four healthy controls [HCs], five PD, and three treated periodontitis [PDT]), assigned to 11 annotated cell populations. Mean sample-level ferroptosis gene-set scores were 0.081 in HC, 0.114 in PD, and 0.076 in PDT; these descriptive scores do not measure ferroptotic cell death. SAT1 showed a positive PD-versus-HC association in cell type pseudobulk analysis (log2 fold change, 0.546; false discovery rate [FDR], 0.012) and positive effects across all three transcriptomic cohorts. A discovery-derived ferroptosis-associated OSCC signature achieved an area under the receiver operating characteristic curve of 0.933 in GSE13601. Periodontal functional profiling identified 25 advanced PD-associated annotations (FDR < 0.05), including lower ferrochelatase signals. Cross-study OSCC microbiome analysis found 293 diagnosis-associated features after project adjustment; project-held-out classification yielded an AUC of 0.674. Following lipopolysaccharide stimulation, GPX4, SLC7A11, and FTH1 increased and ACSL4 decreased at the measured mRNA and protein levels in gingival fibroblasts and THP-1-derived macrophages. Conclusions: Independently sampled periodontal and OSCC cohorts show ferroptosis-associated transcriptomic changes, with SAT1 emerging as a cross-cohort candidate. Parallel microbial datasets identify disease-associated functional gene and taxonomic differences but do not demonstrate within-patient host-microbe interactions or causal mediation. LPS-exposed cell-line measurements show expression changes in selected ferroptosis-associated markers, not ferroptotic cell death or functional resistance. The results are exploratory associations; in the absence of direct ferroptosis assays, paired longitudinal cohorts, and prospective clinical validation, they cannot establish a disease-progression mechanism, clinically deployable biomarker or therapeutic efficacy.
DOI: 10.1155/ijog/7538825
Authors: Chenguang Qiu, Peng She, Lin Wu
Institution: Affiliated Hospital of Jiangsu University
Language: English
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,380
OpenAlex ID: W7225268825