{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T18:08:38Z","timestamp":1789150118504,"version":"build-2803163510"},"reference-count":49,"publisher":"Public Library of Science (PLoS)","issue":"9","license":[{"start":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T00:00:00Z","timestamp":1789084800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Higher Education Department, Government of Khyber Pakhtunkhwa, Pakistan","award":["HEREF-3111"],"award-info":[{"award-number":["HEREF-3111"]}]},{"DOI":"10.13039\/501100002383","name":"King Saud University","doi-asserted-by":"publisher","award":["ORF-2026-470"],"award-info":[{"award-number":["ORF-2026-470"]}],"id":[{"id":"10.13039\/501100002383","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100020508","name":"Universidad Cat\u00f3lica de Temuco","doi-asserted-by":"publisher","award":["MECESUP UCT 0804"],"award-info":[{"award-number":["MECESUP UCT 0804"]}],"id":[{"id":"10.13039\/100020508","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:p>\n                    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\n                    <jats:sup>+<\/jats:sup>\n                    monocytes (GSE294225) from 15 healthy controls and 9 patients with active RA (DAS28\u2009&gt;\u20092.7), we identified 1,410 significantly differentially expressed genes (DEGs) (adjusted P\u2009&lt;\u20090.05, log2 fold change\u2009&gt;\u20091). 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\n                    <jats:italic>FTH1<\/jats:italic>\n                    (\n                    <jats:italic>ferritin heavy chain 1<\/jats:italic>\n                    ),\n                    <jats:italic>SOD2<\/jats:italic>\n                    (\n                    <jats:italic>superoxide dismutase 2<\/jats:italic>\n                    ), and\n                    <jats:italic>CDKN2A<\/jats:italic>\n                    (\n                    <jats:italic>cyclin-dependent kinase inhibitor 2A<\/jats:italic>\n                    ) 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\n                    <jats:italic>FTH1<\/jats:italic>\n                    ,\n                    <jats:italic>SOD2<\/jats:italic>\n                    , and\n                    <jats:italic>CDKN2A<\/jats:italic>\n                    are candidate biomarkers and candidate therapeutic targets.\n                  <\/jats:p>","DOI":"10.1371\/journal.pone.0358176","type":"journal-article","created":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T17:29:57Z","timestamp":1789147797000},"page":"e0358176","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Integrative network analysis identifies candidate genes shared between ferroptosis and cuproptosis pathways in rheumatoid arthritis pathogenesis"],"prefix":"10.1371","volume":"21","author":[{"given":"Abbas","family":"Ahmad","sequence":"first","affiliation":[{"name":"Abdul Wali Khan University Mardan","place":["Khyber Pakhtunkhwa, Pakistan"],"department":["Department of Biotechnology"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shehzad","family":"Khalil","sequence":"additional","affiliation":[{"name":"Institute of Biotechnology and Genetic Engineering, The University of Agriculture Peshawar","place":["Peshawar, Khyber Pakhtunkhwa, Pakistan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Douglas","family":"Law","sequence":"additional","affiliation":[{"name":"INTI International University","place":["Nilai, Negeri Sembilan, Malaysia"],"department":["Faculty of Health and Life Sciences"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricio R.","family":"De los R\u00edos-Escalante","sequence":"additional","affiliation":[{"name":"Universidad Cat\u00f3lica de Temuco","place":["Temuco, Chile"],"department":["Departamento de Ciencias Biol\u00f3gicas y Qu\u00edmicas, Facultad de Recursos Naturales"]},{"name":"Universidad Cat\u00f3lica de Temuco","place":["Temuco, Chile"],"department":["N\u00facleo de Estudios Ambientales, Facultad de Recursos Naturales"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mostafa A.","family":"Abdel-Maksoud","sequence":"additional","affiliation":[{"name":"College of Science, King Saud University","place":["Riyadh, Saudi Arabia"],"department":["Research Chair of Biomedical Applications\u00a0of Nanomaterials, Biochemistry Department"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saeedah","family":"Almutairi","sequence":"additional","affiliation":[{"name":"College of Science, King Saud University","place":["Riyadh, Saudi Arabia"],"department":["Botany and Microbiology Department"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aljawharah Fahad","family":"Alabbad","sequence":"additional","affiliation":[{"name":"College of Science, King Saud University","place":["Riyadh, Saudi Arabia"],"department":["Botany and Microbiology Department"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Waheed","family":"Ahmad","sequence":"additional","affiliation":[{"name":"Minnesota Dental Research Center for Biomaterials and Biomechanics, School of Dentistry, University of Minnesota","place":["Minneapolis, Minnesota, United States of America"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3555-4735","authenticated-orcid":true,"given":"Ayaz","family":"Ahmad","sequence":"additional","affiliation":[{"name":"Abdul Wali Khan University Mardan","place":["Khyber Pakhtunkhwa, Pakistan"],"department":["Department of 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