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Abstract
Introduction
Sepsis is a worldwide epidemic, with high morbidity and mortality. Cuproptosis is a form of cell death that is associated with a wide range of diseases. This study aimed to explore genes associated with cuproptosis in sepsis, construct predictive models and screen for potential targets.
Methods
The LASSO algorithm and SVM-RFE model has been analysed the expression of cuproptosis-related genes in sepsis and immune infiltration characteristics and identified the marker genes under a diagnostic model. Gene-drug networks, mRNA-miRNA networks and PPI networks were constructed to screen for potential biological targets. The expression of marker genes was validated based on the GSE57065 dataset. Consensus clustering method was used to classify sepsis samples.
Results
We found 381 genes associated with the development of sepsis and discovered significantly differentially expressed cuproptosis-related genes of 16 cell types in sepsis and immune infiltration with CD8/CD4 T cells being lower. NFE2L2, NLRP3, SLC31A1, DLD, DLAT, PDHB, MTF1, CDKN2A and DLST were identified as marker genes by the LASSO algorithm and the SVM-RFE model. AUC > 0.9 was constructed for PDHB and MTF1 alone respectively. The validation group data for PDHB (P=0.00099) and MTF1 (P=7.2e-14) were statistically significant. Consistent clustering analysis confirmed two subtypes. The C1 subtype may be more relevant to cellular metabolism and the C2 subtype has some relevance to immune molecules.The results of animal experiments showed that the gene expression was consistent with the bioinformatics analysis.
Discussion
Our study systematically explored the relationship between sepsis and cuproptosis and constructed a diagnostic model. And, several cuproptosis-related genes may interfere with the progression of sepsis through immune cell infiltration.
Availability of Data and Materials
The dataset analyzed in the current study is available on GEO database. In addition, according to China’s “Measures for Ethical Review of Life Science and Medical Research Involving Humans”, our research involving humans meets the relevant requirements for ethical approval exemption. The original contributions presented in the study are included in the article/Supplementary Material. Further inquiries can be directed to the corresponding author.
Animal and Ethical Matters
The study was approved by the Animal Ethics Committee of Wenzhou Medical University(Ethics approval number: wydw2023-0561). The research followed Laboratory animals—Guideline ethical review of animal welfare (GB/T 35892-2018). In addition, all operations on laboratory animals are carried out in accordance with the Measures for the Management of Laboratory Animals of Zhejiang Province (Zhejiang Provincial Government Order No. 263).
Acknowledgments
Yuanfeng Wang, Xu Qiu and Jiao Liu are co-first authors for this study. We appreciate the National Natural Science Foundation of China and the National Innovative Training Program for college students. We acknowledge the editors and reviewers for their helpful comments on this paper.
Author Contributions
YF wrote and submit the manuscript. QX, LJ collected and analyzed data. JL, JY, XY made key changes to the manuscript and drew pictures. XD and SG provide ideas and participated in the coordination of the study and reviewed the manuscript. All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.
Disclosure
All authors declare that they have no conflict of interest.