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Peer-reviewedCC BY 4.0PLOS One

Integrative network analysis identifies candidate genes shared between ferroptosis and cuproptosis pathways in rheumatoid arthritis pathogenesis

  • Abbas Ahmad1
  • Shehzad Khalil2
  • Douglas Law3
  • Patricio R. De los Ríos-Escalante4
  • Mostafa A. Abdel-Maksoud5
  • Saeedah Almutairi6
  • Aljawharah Fahad Alabbad7
  • Waheed Ahmad8
  • Ayaz Ahmad
8 affiliations
  1. 1Department of Biotechnology, Abdul Wali Khan University Mardan, Khyber Pakhtunkhwa, Pakistan
  2. 2Institute of Biotechnology and Genetic Engineering, The University of Agriculture Peshawar, Peshawar, Khyber Pakhtunkhwa, Pakistan
  3. 3Faculty of Health and Life Sciences, INTI International University, Nilai, Negeri Sembilan, Malaysia
  4. 4Departamento de Ciencias Biológicas y Químicas, Facultad de Recursos Naturales, Universidad Católica de Temuco, Temuco, Chile
  5. 5Núcleo de Estudios Ambientales, Facultad de Recursos Naturales, Universidad Católica de Temuco, Temuco, Chile
  6. 6Research Chair of Biomedical Applications of Nanomaterials, Biochemistry Department, College of Science, King Saud University, Riyadh, Saudi Arabia
  7. 7Botany and Microbiology Department, College of Science, King Saud University, Riyadh, Saudi Arabia
  8. 8Minnesota Dental Research Center for Biomaterials and Biomechanics, School of Dentistry, University of Minnesota, Minneapolis, Minnesota, United States of America
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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.

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Cite

BibTeXRIS
BibTeX
@article{ahmad2026integrative,
  title = {{Integrative network analysis identifies candidate genes shared between ferroptosis and cuproptosis pathways in rheumatoid arthritis pathogenesis}},
  author = {Abbas Ahmad and Shehzad Khalil and Douglas Law and Patricio R. De los Ríos-Escalante and Mostafa A. Abdel-Maksoud and Saeedah Almutairi and Aljawharah Fahad Alabbad and Waheed Ahmad and Ayaz Ahmad},
  journal = {PLOS One},
  year = {2026},
  month = sep,
  doi = {10.1371/journal.pone.0358176},
  url = {https://doi.org/10.1371/journal.pone.0358176},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Integrative network analysis identifies candidate genes shared between ferroptosis and cuproptosis pathways in rheumatoid arthritis pathogenesis
AU  - Abbas Ahmad
AU  - Shehzad Khalil
AU  - Douglas Law
AU  - Patricio R. De los Ríos-Escalante
AU  - Mostafa A. Abdel-Maksoud
AU  - Saeedah Almutairi
AU  - Aljawharah Fahad Alabbad
AU  - Waheed Ahmad
AU  - Ayaz Ahmad
PY  - 2026
DA  - 2026/09/11
JO  - PLOS One
DO  - 10.1371/journal.pone.0358176
UR  - https://doi.org/10.1371/journal.pone.0358176
AB  - 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.
SN  - 1932-6203
ER  -