The Sepsis-Ferroptosis Axis: Identifying the Regulatory Role of Hub Genes Networks in Cellular Dysfunction

• Eiman Sehar

  Institute of Zoology, University of the Punjab, Quaid-i-Azam Campus, Lahore, 54590, Pakistan

  Author

  https://orcid.org/0009-0000-5848-9302

• Aqsa Batool

  Institute of Zoology, University of the Punjab, Quaid-i-Azam Campus, Lahore, 54590, Pakistan

  Author

  https://orcid.org/0009-0000-7191-7922

• Iqra Aslam

  Institute of Zoology, University of the Punjab, Quaid-i-Azam Campus, Lahore, 54590, Pakistan

  Author

  https://orcid.org/0009-0003-5209-2672

• Maryam Latif

  Institute of Zoology, University of the Punjab, Quaid-i-Azam Campus, Lahore, 54590, Pakistan

  Author

  https://orcid.org/0009-0000-2992-2250

• Nadeem Sheikh

  Institute of Zoology, University of the Punjab, Quaid-i-Azam Campus, Lahore, 54590, Pakistan

  Author

  https://orcid.org/0000-0001-9503-9538

Background: Sepsis is a serious, life-threatening condition caused by a dysregulated host response to infection, frequently leading to multi-organ dysfunction, high morbidity, and mortality worldwide. Despite innovations in medical care, it continues to pose a significant global health burden. Regulated cell death pathways, particularly ferroptosis, have been identified as a major factor in sepsis-induced organ damage.

Methods: In this study, the RNA-Seq dataset GSE154918 was analyzed to identify ferroptosis-related differentially expressed genes (DEGs) in sepsis patients, while the RNA-Seq dataset GSE185263 was used for results validation. Protein–protein interaction networks were created using STRING and depicted in Cytoscape, with hub genes identified through the CytoHubba MCC algorithm.

Results: A systematically compiled list of 2,083 human ferroptosis-related genes from FerrDb V3 was intersected with DEGs, resulting in 394 ferroptosis-associated candidates. Functional annotation analyses (GO and KEGG) indicated that these hub genes are involved in cell cycle regulation, p53 signaling, and mitotic checkpoint pathways. Consistent downregulation of key hub genes such as CDK1, AURKA, AURKB, CDC20, PLK1, TOP2A, RRM2, BUB1, NEK2, and BIRC5 were found during validation across datasets, suggesting their vital role in ferroptosis-induced pathology.

Conclusion: These outcomes endorsed that the hub genes stand as a promising biomarker for sepsis. Furthermore, this also confirms the significant role of ferroptosis in sepsis. Modulating ferroptosis via pharmacological inhibitors or gene-targeted interventions may offer a prospective approach to attenuate organ injury and ameliorate clinical consequences in septic patients.

Artusi, I., Rubin, M., Cravin, G., & Cozza, G. (2025). Ferroptosis in Human Diseases: Fundamental Roles and Emerging Therapeutic Perspectives. Antioxidants, 14(12). https://doi.org/10.3390/antiox14121411

Baghela, A., Pena, O. M., Lee, A. H., Baquir, B., Falsafi, R., An, A., Farmer, S. W., Hurlburt, A., Mondragon-Cardona, A., Rivera, J. D., Baker, A., Trahtemberg, U., Shojaei, M., Jimenez-Canizales, C. E., dos Santos, C. C., Tang, B., Bouma, H. R., Cohen Freue, G. V., & Hancock, R. E. W. (2022). Predicting sepsis severity at first clinical presentation: The role of endotypes and mechanistic signatures. eBioMedicine, 75. https://doi.org/10.1016/j.ebiom.2021.103776

Cassini, A., Allegranzi, B., Fleischmann-Struzek, C., Kortz, T., Markwart, R., Saito, H., Bonet, M., Brizuela, V., Mehrtash, H., Tuncalp Mingard, Ö., Moller, A.-B., Lincetto, O., Bellizzi, S., Bin Nasr, Y., Cao, B., Jakob, R., Tomaska, N., Eremin, S., Lambach, P., & Moussy, F. (2020). Global report on the epidemiology and burden of sepsis: Current evidence, identifying gaps and future directions. World Health Organization, Geneva. https://www.who.int/publications/i/item/9789240010789

Chen, F., Kang, R., Tang, D., & Liu, J. (2024). Ferroptosis: principles and significance in health and disease. Journal of Hematology and Oncology,17(1). https://doi.org/10.1186/s13045-024-01564-3

Cheng, K., Guo, Q., Shen, Z., Yang, W., Zhou, Y., Sun, Z., Yao, X., & Wu, H. (2022). Frontiers of ferroptosis research: An analysis from the top 100 most influential articles in the field. In Frontiers in Oncology, 12. https://doi.org/10.3389/fonc.2022.948389

Dixon, S. J., Lemberg, K. M., Lamprecht, M. R., Skouta, R., Zaitsev, E. M., Gleason, C. E., Patel, D. N., Bauer, A. J., Cantley, A. M., Yang, W. S., Morrison, B., & Stockwell, B. R. (2012). Ferroptosis: An iron-dependent form of nonapoptotic cell death. Cell, 149(5). https://doi.org/10.1016/j.cell.2012.03.042

Dong, H., Qiang, Z., Chai, D., Peng, J., Xia, Y., Hu, R., & Jiang, H. (2020). Nrf2 inhibits ferroptosis and protects against acute lung injury due to intestinal ischemia reperfusion via regulating SLC7A11 and HO-1. Aging, 12(13). https://doi.org/10.18632/aging.103378

Gao, N., Tang, A. L., Liu, X. Y., Chen, J., & Zhang, G. Q. (2023). p53-Dependent ferroptosis pathways in sepsis. International Immunopharmacology,118. https://doi.org/10.1016/j.intimp.2023.110083

He, S., He, Y., Deng, L., Guo, Y., Wang, X., Wang, Q., Luo, L., & Liu, Q. (2024). Identification of RRM2 as a key ferroptosis-related gene in sepsis. Inflammation Research, 73(3). https://doi.org/10.1007/s00011-023-01849-2

Herwanto, V., Tang, B., Wang, Y., Shojaei, M., Nalos, M., Shetty, A., Lai, K., McLean, A. S., & Schughart, K. (2021). Blood transcriptome analysis of patients with uncomplicated bacterial infection and sepsis. BMC Research Notes, 14(1). https://doi.org/10.1186/s13104-021-05488-w

Heydari, A., Yaghmoorian Khojini, J., Hayati, M. J., Khara, F., Abootorabi, S. M. S., Manoochehri, H., & Mousavi, M. J. (2025). Evaluation of genes and molecular pathways involved in ferroptosis in breast cancer: A systems biology and bioinformatics approach. Biochemistry and Biophysics Reports, 44. https://doi.org/10.1016/j.bbrep.2025.102335

La Via, L., Sangiorgio, G., Stefani, S., Marino, A., Nunnari, G., Cocuzza, S., La Mantia, I., Cacopardo, B., Stracquadanio, S., Spampinato, S., Lavalle, S., & Maniaci, A. (2024). The Global Burden of Sepsis and Septic Shock. Epidemiologia, 5(3). https://doi.org/10.3390/epidemiologia5030032

Latunde-Dada, G. O. (2017). Ferroptosis: Role of lipid peroxidation, iron and ferritinophagy. In Biochimica et Biophysica Acta - General Subjects, 1861(8). https://doi.org/10.1016/j.bbagen.2017.05.019

Liu, Y., Tan, S., Wu, Y., & Tan, S. (2022). The Emerging Role of Ferroptosis in Sepsis. DNA and Cell Biology, 41(4). https://doi.org/10.1089/dna.2021.1072

Ma, J., Li, Q., Ji, D., Hong, L., & Luo, L. (2021). Predicting candidate therapeutic drugs for sepsis-induced acute respiratory distress syndrome based on transcriptome profiling. Bioengineered, 12(1). https://doi.org/10.1080/21655979.2021.1917981

Markwart, R., Saito, H., Harder, T., Tomczyk, S., Cassini, A., Fleischmann-Struzek, C., Reichert, F., Eckmanns, T., & Allegranzi, B. (2020). Epidemiology and burden of sepsis acquired in hospitals and intensive care units: a systematic review and meta-analysis. Intensive Care Medicine, 46(8). https://doi.org/10.1007/s00134-020-06106-2

Oliveros, J. C. (2007). VENNY. An interactive tool for comparing lists with Venn Diagrams. http://bioinfogp.cnb.csic.es/tools/venny/index.html. Bioinfogp.Cnb.Csic.Es/Tools/Venny/Index.Html.

Qu, M., Wang, Y., Qiu, Z., Zhu, S., Guo, K., Chen, W., Miao, C., & Zhang, H. (2022). Necroptosis, Pyroptosis, Ferroptosis in Sepsis and Treatment. Shock, 57(6). https://doi.org/10.1097/SHK.0000000000001936

Rudd, K. E., Johnson, S. C., Agesa, K. M., Shackelford, K. A., Tsoi, D., Kievlan, D. R., Colombara, D. V., Ikuta, K. S., Kissoon, N., Finfer, S., Fleischmann-Struzek, C., Machado, F. R., Reinhart, K. K., Rowan, K., Seymour, C. W., Watson, R. S., West, T. E., Marinho, F., Hay, S. I., … Naghavi, M. (2020). Global, regional, and national sepsis incidence and mortality, 1990–2017: Analysis for the Global Burden of Disease Study. The Lancet, 395(10219). https://doi.org/10.1016/S0140-6736(19)32989-7

Shannon, P., Markiel, A., Ozier, O., Baliga, N. S., Wang, J. T., Ramage, D., Amin, N., Schwikowski, B., & Ideker, T. (2003). Cytoscape: A software environment for integrated models of biomolecular interaction networks. Genome Research, 13(11). https://doi.org/10.1101/gr.1239303

Shen, Y., He, Y., Pan, Y., Liu, L., Liu, Y., & Jia, J. (2024). Role and mechanisms of autophagy, ferroptosis, and pyroptosis in sepsis-induced acute lung injury. Frontiers in Pharmacology, 15. https://doi.org/10.3389/fphar.2024.1415145

ShilinLi, & Hu, Y. (2024). Identification of four mitochondria-related genes in sepsis based on RNA sequencing technology. BMC Immunology, 25(1). https://doi.org/10.1186/s12865-024-00623-1

Szklarczyk, D., Kirsch, R., Koutrouli, M., Nastou, K., Mehryary, F., Hachilif, R., Gable, A. L., Fang, T., Doncheva, N. T., Pyysalo, S., Bork, P., Jensen, L. J., & Von Mering, C. (2023). The STRING database in 2023: protein-protein association networks and functional enrichment analyses for any sequenced genome of interest. Nucleic Acids Research, 51(1D). https://doi.org/10.1093/nar/gkac1000

Taha, S., Bindayna, K., Aljishi, M., Sultan, A., & Almansour, N. (2025). Transcriptomic Profiling Reveals Distinct Immune Dysregulation in Early-Stage Sepsis Patients. International Journal of Molecular Sciences, 26(14). https://doi.org/10.3390/ijms26146647

Tian, Z., Wang, W., Hao, H., Kong, L., & Li, G. (2025). Comprehensive Analysis of Gene Expression and Biomarkers in Sepsis Using Bioinformatics, Network Pharmacology and Molecular Modeling Approaches. Biotechnology and Applied Biochemistry. https://doi.org/10.1002/bab.70049

van der Poll, T., Shankar-Hari, M., & Wiersinga, W. J. (2021). The immunology of sepsis. Immunity, 54(11), 2450–2464. https://doi.org/10.1016/j.immuni.2021.10.012

Vastrad, B., & Vastrad, C. (2023). Bioinformatics and next generation data analysis reveals the potential role of inflammation in sepsis and its associated complications. BioRxiv.

Vella, R., Panci, D., Carini, F., Malta, G., Vieni, S., David, S., Albano, G. D., Puntarello, M., Zerbo, S., & Argo, A. (2025). Cytokines in sepsis: a critical review of the literature on systemic inflammation and multiple organ dysfunction. Frontiers in Immunology, 16. https://doi.org/10.3389/fimmu.2025.1682306

Wang, Y., Weng, L., Wu, X., & Du, B. (2025). The role of programmed cell death in organ dysfunction induced by opportunistic pathogens. Critical Care, 29(1). https://doi.org/10.1186/s13054-025-05278-x

Xl, L., Gy, Z., R, G., & N, C. (2022). Ferroptosis in sepsis: The mechanism, the role and the therapeutic potential. Frontiers in Immunology, 13, 956361. https://doi.org/10.3389/fimmu.2022.956361

Yu, Y., Yan, Y., Niu, F., Wang, Y., Chen, X., Su, G., Liu, Y., Zhao, X., Qian, L., Liu, P., & Xiong, Y. (2021). Ferroptosis: a cell death connecting oxidative stress, inflammation and cardiovascular diseases. Cell Death Discovery, 7(1). https://doi.org/10.1038/s41420-021-00579-w

Zhang, H., Wang, Y., Wang, S., Xue, X., Huang, K., Xu, D., Jiang, L., Li, S., & Zhang, Y. (2025). Tangeretin alleviates sepsis-induced acute lung injury by inhibiting ferroptosis of macrophage via Nrf2 signaling pathway. Chinese Medicine, 20(1). https://doi.org/10.1186/s13020-025-01063-8

Zhou, H. T., Huang, J., Liu, Y. K., Wang, J. H., & Wang, J. (2025). The emerging role of ferroptosis in the pathological development and progression of sepsis. Military Medical Research, 12(1). https://doi.org/10.1186/s40779-025-00665-5

Zhou, N., Peng, L., Luo, Q., Yin, T., Sun, H., Zhang, Y., Shi, X., Peng, X., Bao, J., Ning, Y., & Yuan, X. (2025). FerrDb V3: Expanding the manually curated resource for regulators and disease associations from ferroptosis to regulated cell death. Nucleic Acids Research, gkaf1119. https://doi.org/10.1093/NAR/GKAF1119/8307356

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Copyright (c) 2025 Eiman Sehar, Aqsa Batool, Iqra Aslam, Maryam Latif, Nadeem Sheikh (Author)

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