{
  "abstract": "Ferroptosis contributes to rheumatoid arthritis (RA), but the key regulators and their cell-specific functions in the synovial microenvironment remain incompletely understood. This study aimed to identify robust ferroptosis-associated biomarkers and define their cellular context through an integrated transcriptomic framework. Bulk synovial transcriptomic datasets were integrated using differential expression, weighted gene co-expression network analysis, and a curated ferroptosis gene set. Candidate genes were prioritized using three feature-selection algorithms and validated across twelve models. Immune infiltration, single-cell RNA sequencing, pseudotime, CellChat, and virtual gene perturbation analyses characterized their cellular and functional context. Six ferroptosis-related genes (AIM2, HCP5, CAPG, ALOX5, TYMS, and RUNX3) formed a diagnostic signature discriminating RA from healthy synovium (mean leakage-free test AUC 0.977 across five training-only re-derivations; 0.9375 in the primary split), with consistent leave-one-dataset-out and osteoarthritis-control validation. These genes linked to adaptive immune and ferroptosis-associated transcriptional programs. Single-cell analysis localized this transcriptional score to macrophages, where ferroptosis-signature-high macrophages occupied a central communication-network position and showed collagen-pathway enrichment; because RA and healthy samples were not fully independent of dataset origin, this finding is hypothesis-generating. Pseudotime analysis suggested progressive induction of these genes toward an inflammatory NF-κB/TNF/IL-17 terminal state, and virtual perturbation suggested convergence on mitochondrial oxidative phosphorylation networks that persisted after removing sex-chromosome genes, though residual sex-associated effects cannot be fully excluded. This study identifies a biologically interpretable ferroptosis-related gene signature and suggests ferroptosis-associated macrophage reprogramming may contribute to immune dysregulation in RA synovium. The single-cell findings are hypothesis-generating given the cohort design, while the diagnostic signature was supported by leakage-free, cross-cohort, and disease-specificity analyses, providing candidate biomarkers and therapeutic targets for RA.",
  "abstract_shown": true,
  "affiliations": [
    "Faculty of Medicine, Eberhard Karls University of Tübingen, 72076 Tübingen, Germany",
    "Interfaculty Institute of Microbiology and Infection Medicine Tübingen (IMIT), Eberhard Karls University of Tübingen, 72076 Tübingen, Germany"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 2,
  "authors": [
    {
      "affs": [
        0,
        1
      ],
      "name": "Houchen Liu",
      "orcid": "0000-0003-3078-3184"
    },
    {
      "affs": [
        0
      ],
      "name": "Ruizhuo Zhang"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/14vfmd3ta3mm5.bib",
  "cited_by": 0,
  "doi": "10.3390/ijms27219552",
  "fulltext_url": null,
  "id": "14vfmd3ta3mm5",
  "issns": [
    "1422-0067"
  ],
  "landing_url": "https://www.mdpi.com/1422-0067/27/21/9552",
  "language": null,
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "2745|Rheumatoid Arthritis Research and Therapies"
    ]
  ],
  "openalex": "W7223999294",
  "pdf_url": null,
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-26",
  "publisher": "MDPI AG",
  "ris": "https://research.draconitic.com/paper/14vfmd3ta3mm5.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:18:57Z",
      "native_id": "10.3390/ijms27219552",
      "source": "crossref",
      "url": "https://www.mdpi.com/1422-0067/27/21/9552"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2745|Rheumatoid Arthritis Research and Therapies",
      "subfield": "general"
    }
  ],
  "title": "Integrated Transcriptomic Analysis Identifies a Ferroptosis-Related Gene Signature Underlying Macrophage Heterogeneity and Immune Dysregulation in Rheumatoid Arthritis Synovium",
  "title_text": "Integrated Transcriptomic Analysis Identifies a Ferroptosis-Related Gene Signature Underlying Macrophage Heterogeneity and Immune Dysregulation in Rheumatoid Arthritis Synovium",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:18:57Z",
  "url": "https://research.draconitic.com/paper/14vfmd3ta3mm5",
  "venue": "International Journal of Molecular Sciences",
  "versions": []
}