{ "abstract": "Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease characterized by synovial inflammation, progressive joint destruction, and systemic immune dysregulation. Recent findings suggest that disturbed metal homeostasis and regulated cell death pathways, including ferroptosis (iron-dependent lipid peroxidation) and cuproptosis (copper-dependent mitochondrial proteotoxic stress), contribute to RA pathogenesis. In this study, we used an integrative bioinformatic approach combining weighted gene co-expression network analysis (WGCNA), differential expression analysis, functional enrichment, protein-protein interaction (PPI) network construction, and immune cell infiltration deconvolution to identify key metal-dependent cell death regulators in RA. Using bulk RNA-seq data from peripheral CD14+ monocytes (GSE294225) from 15 healthy controls and 9 patients with active RA (DAS28 > 2.7), we identified 1,410 significantly differentially expressed genes (DEGs) (adjusted P < 0.05, log2 fold change > 1). WGCNA revealed an RA-associated module enriched in oxidative stress, mitochondrial dysfunction, and cell death pathways. Overlap analysis of ferroptosis- and cuproptosis-related gene sets distinguished three upregulated hub genes, including FTH1 (ferritin heavy chain 1), SOD2 (superoxide dismutase 2), and CDKN2A (cyclin-dependent kinase inhibitor 2A) as key candidate regulators. These genes showed high module membership, significant differential expression in RA monocytes, and notable associations with immune infiltration patterns, including increased pro-inflammatory monocytes/macrophages and reduced regulatory T cells. Functional enrichment also highlighted oxidative stress response, iron and copper homeostasis, mitochondrial respiration, and cellular senescence. The single-cell analysis further showed that these hub genes are predominantly expressed in the RA synovial macrophages and fibroblasts, two major mediators of joint pathology. Together, these findings indicate that there may be an association between ferroptosis-related pathways and cuproptosis-related pathways in RA and suggest that FTH1, SOD2, and CDKN2A are candidate biomarkers and candidate therapeutic targets.", "abstract_shown": true, "affiliations": [ "Department of Biotechnology, Abdul Wali Khan University Mardan, Khyber Pakhtunkhwa, Pakistan", "Institute of Biotechnology and Genetic Engineering, The University of Agriculture Peshawar, Peshawar, Khyber Pakhtunkhwa, Pakistan", "Faculty of Health and Life Sciences, INTI International University, Nilai, Negeri Sembilan, Malaysia", "Departamento de Ciencias Biológicas y Químicas, Facultad de Recursos Naturales, Universidad Católica de Temuco, Temuco, Chile", "Núcleo de Estudios Ambientales, Facultad de Recursos Naturales, Universidad Católica de Temuco, Temuco, Chile", "Research Chair of Biomedical Applications of Nanomaterials, Biochemistry Department, College of Science, King Saud University, Riyadh, Saudi Arabia", "Botany and Microbiology Department, College of Science, King Saud University, Riyadh, Saudi Arabia", "Minnesota Dental Research Center for Biomaterials and Biomechanics, School of Dentistry, University of Minnesota, Minneapolis, Minnesota, United States of America" ], "article_type": "Research Article", "arxiv": null, "author_total": 9, "authors": [ { "affs": [ 0 ], "name": "Abbas Ahmad" }, { "affs": [ 1 ], "name": "Shehzad Khalil" }, { "affs": [ 2 ], "name": "Douglas Law" }, { "affs": [ 3 ], "name": "Patricio R. De los Ríos-Escalante" }, { "affs": [ 4 ], "name": "Mostafa A. Abdel-Maksoud" }, { "affs": [ 5 ], "name": "Saeedah Almutairi" }, { "affs": [ 6 ], "name": "Aljawharah Fahad Alabbad" }, { "affs": [ 7 ], "name": "Waheed Ahmad" }, { "name": "Ayaz Ahmad" } ], "bibtex": "https://research.draconitic.com/paper/256eymwnbtq4b.bib", "cited_by": 0, "doi": "10.1371/journal.pone.0358176", "fulltext_url": null, "id": "256eymwnbtq4b", "issns": [ "1932-6203" ], "landing_url": "https://doi.org/10.1371/journal.pone.0358176", "language": null, "licence": "CC-BY-4.0", "licence_label": "CC BY 4.0", "licence_source": "journal", "licence_url": "https://creativecommons.org/licenses/by/4.0/", "metadata_licence": null, "native_subjects": [ [ "openalex", "2740|Ferroptosis and cancer prognosis" ], [ "plos", "/Biology and life sciences/Biochemistry/Bioenergetics/Energy-producing organelles/Mitochondria" ], [ "plos", "/Biology and life sciences/Cell biology/Cell processes/Cell death" ], [ "plos", "/Biology and life sciences/Cell biology/Cellular structures and organelles/Energy-producing organelles/Mitochondria" ], [ "plos", "/Biology and life sciences/Cell biology/Cellular types/Animal cells/Blood cells/White blood cells/Macrophages" ], [ "plos", "/Biology and life sciences/Cell biology/Cellular types/Animal cells/Blood cells/White blood cells/Monocytes" ], [ "plos", "/Biology and life sciences/Cell biology/Cellular types/Animal cells/Immune cells" ], [ "plos", "/Biology and life sciences/Cell biology/Cellular types/Animal cells/Immune cells/White blood cells/Macrophages" ], [ "plos", "/Biology and life sciences/Cell biology/Cellular types/Animal cells/Immune cells/White blood cells/Monocytes" ], [ "plos", "/Biology and life sciences/Genetics/Gene expression" ], [ "plos", "/Biology and life sciences/Genetics/Gene expression/Gene regulation" ], [ "plos", "/Biology and life sciences/Immunology/Clinical immunology/Autoimmune diseases/Rheumatoid arthritis" ], [ "plos", "/Biology and life sciences/Immunology/Immune cells" ], [ "plos", "/Biology and life sciences/Immunology/Immune cells/White blood cells/Macrophages" ], [ "plos", "/Biology and life sciences/Immunology/Immune cells/White blood cells/Monocytes" ], [ "plos", "/Medicine and health sciences/Clinical medicine/Clinical immunology/Autoimmune diseases/Rheumatoid arthritis" ], [ "plos", "/Medicine and health sciences/Immunology/Clinical immunology/Autoimmune diseases/Rheumatoid arthritis" ], [ "plos", "/Medicine and health sciences/Immunology/Immune cells" ], [ "plos", "/Medicine and health sciences/Immunology/Immune cells/White blood cells/Macrophages" ], [ "plos", "/Medicine and health sciences/Immunology/Immune cells/White blood cells/Monocytes" ], [ "plos", "/Medicine and health sciences/Rheumatology/Arthritis/Rheumatoid arthritis" ] ], "openalex": "W7212290561", "pdf_url": "https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0358176&type=printable", "pmcid": null, "pmid": null, "published": "2026-09-11", "publisher": "Public Library of Science", "ris": "https://research.draconitic.com/paper/256eymwnbtq4b.ris", "sources": [ { "first_seen": "2026-10-30T12:17:56Z", "native_id": "10.1371/journal.pone.0358176", "source": "plos", "url": "https://doi.org/10.1371/journal.pone.0358176" } ], "subjects": [ { "field": "biology", "origin": "plos:cell biology", "subfield": "cell-biology" }, { "field": "biology", "origin": "plos:immunology", "subfield": "immunology" } ], "title": "Integrative network analysis identifies candidate genes shared between ferroptosis and cuproptosis pathways in rheumatoid arthritis pathogenesis", "title_text": "Integrative network analysis identifies candidate genes shared between ferroptosis and cuproptosis pathways in rheumatoid arthritis pathogenesis", "type": "peer-reviewed", "updated_at": "2026-10-30T12:17:56Z", "url": "https://research.draconitic.com/paper/256eymwnbtq4b", "venue": "PLOS One", "versions": [] }