Identification of Diagnostic Biomarkers, Immune Infiltration Characteristics, and Molecular Subtypes Based on Histamine-related Genes in Sepsis
Abstract
Sepsis is a life-threatening systemic inflammatory response syndrome marked by high mortality and immune dysfunction. Histamine, synthesized from histidine, by histidine decarboxylase (HDC), regulates immune cell recruitment and inflammatory mediators, playing a key role in inflammatory diseases. The precise mechanisms and clinical significance of histamine in sepsis require further study.
Gene expression data from the Gene Expression Omnibus (GEO) database were analyzed. Differential expression analysis and weighted gene co-expression network analysis (WGCNA) were used to identify differentially expressed histamine-related genes (DEHRGs). Machine learning algorithms, including the least absolute shrinkage and selection operator (LASSO), support vector machine-recursive feature elimination (SVM-RFE), and random forest (RF), were utilized to screen diagnostic genes, and a predictive model was constructed and validated using receiver operating characteristic analysis and decision curve analysis (DCA). Functional enrichment, immune infiltration assessment, using single-sample gene set enrichment analysis (ssGSEA), cell-type identification by estimating relative subsets of RNA transcripts (CIBERSORT), regulatory network construction, and drug prediction were subsequently conducted.
Nine DEHRGs were identified. Three key diagnostic genes-FYN, IL2RB, and MMP8-were selected and validated across multiple cohorts, showing high diagnostic accuracy (area under the curve [AUC]>0.85). The study revealed distinct immune patterns, including increased regulatory T cell (Treg) infiltration in the sepsis group. Two sepsis molecular subtypes with differential immune characteristics were also identified.
This study systematically explored the association between histamine and sepsis pathogenesis, defining a three-gene diagnostic model and elucidating complex immune and molecular regulatory mechanisms. These findings offer new insights for developing targeted diagnostic and therapeutic strategies for sepsis.
2. Dai W, Zheng P, Wu J, et al. Integrated analysis of single-cell RNA-seq and chipset data unravels PANoptosis-related genes in sepsis. Front Immunol. 2023;14:1247131. doi:10.3389/fimmu.2023.1247131
3. Yang S, Guo J, Kong Z, et al. Causal effects of gut microbiota on sepsis and sepsis-related death: insights from genome-wide Mendelian randomization, single-cell RNA, bulk RNA sequencing, and network pharmacology. J Transl Med. 2024;22:10. doi:10.1186/s12967-023-04835-8
4. Li H, Liu L, Zhang D, et al. SARS-CoV-2 and viral sepsis: observations and hypotheses. Lancet. 2020;395(10235):1517-1520. doi:10.1016/s0140-6736 (20)30920-x
5. Wang Y, Zhu K, Dai R, et al. Specific Interleukin-1 Inhibitors, Specific Interleukin-6 Inhibitors, and GM-CSF Blockades for COVID-19 (at the Edge of Sepsis): A Systematic Review. Front Pharmacol. 2021;12:804250. doi:10.3389/fphar.2021.804250
6. Moriguchi T, Takai J. Histamine and histidine decarboxylase: Immunomodulatory functions and regulatory mechanisms. Genes Cells. 2020;25(7):443-9. doi:10.1111/gtc.12774
7. Thangam EB, Jemima EA, Singh H, et al. The Role of Histamine and Histamine Receptors in Mast Cell-Mediated Allergy and Inflammation: The Hunt for New Therapeutic Targets. Front Immunol. 2018;9:1873. doi:10.3389/fimmu.2018.01873
8. Neugebauer E, Lorenz W, Rixen D, et al. Histamine release in sepsis: a prospective, controlled, clinical study. Crit Care Med. 1996;24(10):1670-7. doi:10.1097/00003246-199610000-00012
9. Hattori M, Yamazaki M, Ohashi W, et al. Critical role of endogenous histamine in promoting end-organ tissue injury in sepsis. Intensive Care Med Exp. 2016;4(1):36. doi:10.1186/s40635-016-0109-y
10. Hattori Y. [Role of histamine in sepsis-induced organ dysfunction: study using knockout mice of histamine-related genes]. Nihon Yakurigaku Zasshi. 2018;152(1):10-5. doi:10.1254/fpj.152.10
11. Nielsen HJ. Histamine-2 receptor antagonists as immunomodulators: new therapeutic views?. Ann Med. 1996;28(2):107-13. doi:10.3109/07853899609092934
12. Hotchkiss RS, Monneret G, Payen D. Sepsis-induced immunosuppression: from cellular dysfunctions to immunotherapy. Nat Rev Immunol. 2013;13(12):862-74. doi:10.1038/nri3552
13. Adderley SP, Zhang XE, Breslin JW. Involvement of the H1 Histamine Receptor, p38 MAP Kinase, Myosin Light Chains Kinase, and Rho/ROCK in Histamine-Induced Endothelial Barrier Dysfunction. Microcirculation. 2015;22(4):237-48. doi:10.1111/micc.12189
14. Juurikka K, Dufour A, Pehkonen K, et al. MMP8 increases tongue carcinoma cell-cell adhesion and diminishes migration via cleavage of anti-adhesive FXYD5. Oncogenesis. 2021;10(6):44. doi:10.1038/s41389-021-00334-x
15. Fang X, Duan SF, Hu ZY, et al. Inhibition of Matrix Metalloproteinase-8 Protects Against Sepsis Serum Mediated Leukocyte Adhesion. Front Med (Lausanne). 2022;9:814890. doi:10.3389/fmed.2022.814890
16. Solan PD, Dunsmore KE, Denenberg AG, et al. A novel role for matrix metalloproteinase-8 in sepsis. Crit Care Med. 2012;40(2):379-87. doi:10.1097/CCM. 0b013e318232e404
17. Atkinson SJ, Varisco BM, Sandquist M, et al. Matrix Metalloproteinase-8 Augments Bacterial Clearance in a Juvenile Sepsis Model. Mol Med. 2016;22:455-63. doi:10.2119/molmed.2016.00058
18. Forsblom E, Tervahartiala T, Ruotsalainen E, et al. Matrix metalloproteinase MMP-8, TIMP-1 and MMP-8/TIMP-1 ratio in plasma in methicillin-sensitive Staphylococcus aureus bacteremia. PLoS One. 2021;16(5):e0252046. doi:10.1371/journal.pone.0252046
19. Ran L, Zhao Q, Hu G, Zhang C. The overexpression of IL2RB indicates poor prognosis in renal clear cell carcinoma. Asian J Surg. 2024. doi:10.1016/ j.asjsur.2024.09.053
20. Zhou J, Zhang Y, Zhuang Q. IL2RB affects Th1/Th2 and Th17 responses of peripheral blood mononuclear cells from septic patients. Allergol Immunopathol (Madr). 2023;51(3):1-7. doi:10.15586/aei.v51i3.757
21. Lou W, Yan J, Wang W. Downregulation of miR-497-5p Improves Sepsis-Induced Acute Lung Injury by Targeting IL2RB. Biomed Res Int. 2021;2021:6624702. doi:10.1155/2021/6624702
22. Peng S, Fu Y. FYN: emerging biological roles and potential therapeutic targets in cancer. J Transl Med. 2023;21(1):84. doi:10.1186/s12967-023-03930-0
23. Wang H, Huang J, Yi W, et al. Identification of Immune-Related Key Genes as Potential Diagnostic Biomarkers of Sepsis in Children. J Inflamm Res. 2022;15:2441-59. doi:10.2147/jir.S359908
24. Ran X, Zhang J, Wu Y, et al. Prognostic gene landscapes and therapeutic insights in sepsis-induced coagulopathy. Thromb Res. 2024;237:1-13. doi:10.1016/j.thromres. 2024.03.011
25. Jiang Y, Miao Q, Hu L, et al. FYN and CD247: Key Genes for Septic Shock Based on Bioinformatics and Meta-Analysis. Comb Chem High Throughput Screen. 2022;25(10):1722-30. doi:10.2174/ 1386207324666210816123508
26. Ge J, Deng Q, Zhou R, et al. Identification of key biomarkers and therapeutic targets in sepsis through coagulation-related gene expression and immune pathway analysis. Front Immunol. 2024;15:1470842. doi:10.3389/fimmu.2024.1470842
27. Saito YD, Jensen AR, Salgia R, et al. Fyn: a novel molecular target in cancer. Cancer. 2010;116(7):1629-37. doi:10.1002/cncr.24879
28. Wu X, Yuan C, Pan J, et al. CXCL9, IL2RB, and SPP1, potential diagnostic biomarkers in the co-morbidity pattern of atherosclerosis and non-alcoholic steatohepatitis. Sci Rep. 2024;14(1):16364. doi:10.1038/s41598-024-66287-4
29. Pan T, Sun S, Chen Y, et al. Immune effects of PI3K/Akt/HIF-1α-regulated glycolysis in polymorphonuclear neutrophils during sepsis. Crit Care. 2022;26(1):29. doi:10.1186/s13054-022-03893-6
30. Xiao W, Mindrinos MN, Seok J, et al. A genomic storm in critically injured humans. J Exp Med. 2011;208(13):2581-90. doi:10.1084/jem.20111354
31. Qin Y, Zhang J. The Multifaceted Role of Regulatory T Cells in Sepsis: Mechanisms, Heterogeneity, and Pathogen-Tailored Therapies. Int J Mol Sci. 2025;26. doi:10.3390/ijms26157436
32. Zhu G, Liao Y, Liu S, et al. Dysregulated Immune Responses in Sepsis: Insights From Treg-Related Gene Expression. J Inflamm Res. 2025;18:11689-702. doi:10.2147/jir.S523019
33. Mehta S, Gill SE. Improving clinical outcomes in sepsis and multiple organ dysfunction through precision medicine. J Thorac Dis. 2019;11(Suppl 1):S21-8. doi:10.21037/jtd.2018.11.74
34. Reséndiz-Martínez J, Asbun-Bojalil J, Huerta-Yepez S, et al. Correlation of the expression of YY1 and Fas cell surface death receptor with apoptosis of peripheral blood mononuclear cells, and the development of multiple organ dysfunction in children with sepsis. Mol Med Rep. 2017;15(4):2433-42. doi:10.3892/mmr.2017.6310
35. Li M, Hu L, Ke Q, et al. Arginine methyltransferase PRMT1 promotes ferroptosis through EGR1/GLS2 axis in sepsis-related acute lung injury. Commun Biol. 2025;8(1):159. doi:10.1038/s42003-025-07531-z
36. Weber B, Henrich D, Marzi I, et al. Decrease of exosomal miR-21-5p and the increase of CD62p+ exosomes are associated with the development of sepsis in polytraumatized patients. Mol Cell Probes. 2024;74:101954. doi:10.1016/j.mcp.2024.101954
37. Xue J, Liu J, Xu B, et al. miR-21-5p inhibits inflammation injuries in LPS-treated H9c2 cells by regulating PDCD4. Am J Transl Res. 2021;13(10):11450-60. PMID: 34786071
| Files | ||
| Issue | Articles in Press | |
| Section | Original Article(s) | |
| Keywords | ||
| Biomarkers Histamine Immune system phenomena Molecular typing Sepsis | ||
| Rights and permissions | |
|
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. |
