The Relationship Between Ferroptosis Regulatory Genes and Lung Injury Induced by Sepsis Based on Bioinformatics_Chinese Journal of Respiratory and Critical Care Medicine

Authors：

ZENG Qin ¹ , XIE Rongcheng ² , MA Jiefei ² ,  CHEN Bin ¹

1. Department of emergency, Xiamen Branch, Zhongshan hospital, Fudan University, Xiamen, Fujian 361000, P.R.China;
2. Department of Critical Care, Xiamen Hospital, Zhongshan Hospital Affiliated to Fudan University, Xiamen, Fujian 361000, P.R.China;

Corresponding author：

CHEN Bin, Email: chen.bin2@zs-hospital.sh.cn

Keywords：

Sepsis; Lung injury; Ferroptosis; Bioinformatics

DOI：

10.7507/1671-6205.202403042

Video：

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Objective The role of ferroptosis-related genes in the occurrence and development of lung injury caused by sepsis was investigated by bioinformatics methods, and the closely related genes were predicted. Methods The Dataset GSE154653 was downloaded from the gene expression database (GEO), and a total of 8 cases of microarray gene set were included in normal group and lipopolysaccharide (LPS)-induced sepsis lung tissue. The differential expression genes (DEGs) were screened out under conditions of |log₂ FC|>1 and P.adj<0.05. Meanwhile, the selected DEGs were combined with the driver and suppressor genes of ferroptosis downloaded from the ferroptosis database (FerrDb) to obtain the differential genes associated with ferroptosis in sepsis (Fe-DEGs). These Fe-DEGs were further analyzed using R language, DAVID, and STRING online tools to identify GO-KEGG functions and pathways, and the construction of PPI network. Results The Bioinformatics approach screened out 3533 DEGs and intersected 53 key genes related to ferroptosis. The further biological process (BP) of GO enrichment analysis mainly involves the positive regulation of transcription, the positive regulation of RNA polymerase II promoter transcription, the cytokine mediated signaling pathway, and the positive regulation of angiogenesis. The molecular function (MF) mainly involves the same protein binding, transcriptional activation activity and REDOX enzyme activity. The pathways are enriched in iron death, HIF-1 signaling pathway and AGE-RAGE signaling pathway. Five key Fe-DEGs genes were screened by constructing PPI network, including CYBB, LCN2, HMOX1, TIMP1 and CDKN1A. Conclusion CYBB、LCN2、HMOX1、TIMP1 and CDKNIA genes may be key genes involved in ferroptosis of lung tissue caused by sepsis.

Citation： ZENG Qin, XIE Rongcheng, MA Jiefei, CHEN Bin. The Relationship Between Ferroptosis Regulatory Genes and Lung Injury Induced by Sepsis Based on Bioinformatics. Chinese Journal of Respiratory and Critical Care Medicine, 2024, 23(9): 617-624. doi: 10.7507/1671-6205.202403042 Copy

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2.	Liu Z, Ting Y, Li M, et al. From immune dysregulation to organ dysfunction: understanding the enigma of Sepsis. Front Microbiol, 2024, 15: 1415274.
3.	Angus DC, van der Poll T. Severe sepsis and septic shock. N Engl J Med, 2013, 369(9): 840-851.
4.	Almalki WH. The sepsis induced defective aggravation of immune cells: a translational science underling chemico-biological interactions from altered bioenergetics and/or cellular metabolism to organ dysfunction. Mol Cell Biochem, 2021, 476(6): 2337-2344.
5.	Kim WY, Hong SB. Sepsis and Acute Respiratory Distress Syndrome: Recent Update. Tuberc Respir Dis, 2016, 79(2): 53-57.
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16.	Liu J, Han X, Zhou J, et al. Molecular Mechanisms of Ferroptosis and Their Involvement in Acute Kidney Injury. J Inflamm Res, 2023, 16: 4941-4951.
17.	Clough, E. ; Barrett, T. The gene expression omnibus database. Methods Mol Biol, 2016, 1418: 93-110.
18.	. Zhou N, Yuan X, Du Q, et al. FerrDb V2: update of the manually curated database of ferroptosis regulators and ferroptosis-disease associations, Nucleic Acids Res, 2023, 51(D1), D571–D582.
19.	Kanehisa M, Goto S. KEGG: Kyoto encyclopedia of genes and genomes. Nucleic Acids Res, 2000, 28(1): 27-30.
20.	Szklarczyk D. , Kirsch R. , Koutrouli M. , et al. The STRING database in 2023: protein–protein association networks and functional enrichment analyses for any sequenced genome of interest. Nucleic Acids Res, 2023, 51(D): D638-D646.
21.	Dumas J, Gargano MA, Dancik GM, et al. shinyGEO: a web-based application for analyzing gene expression omnibus datasets. Bioinformatics, 2016, 32(23): 3679-3681.

1. Font MD, Thyagarajan B, Khanna AK. Sepsis and Septic Shock - Basics of diagnosis, pathophysiology and clinical decision making. Med Clin North Am, 2020, 104(4): 573-585.
2. Liu Z, Ting Y, Li M, et al. From immune dysregulation to organ dysfunction: understanding the enigma of Sepsis. Front Microbiol, 2024, 15: 1415274.
3. Angus DC, van der Poll T. Severe sepsis and septic shock. N Engl J Med, 2013, 369(9): 840-851.
4. Almalki WH. The sepsis induced defective aggravation of immune cells: a translational science underling chemico-biological interactions from altered bioenergetics and/or cellular metabolism to organ dysfunction. Mol Cell Biochem, 2021, 476(6): 2337-2344.
5. Kim WY, Hong SB. Sepsis and Acute Respiratory Distress Syndrome: Recent Update. Tuberc Respir Dis, 2016, 79(2): 53-57.
6. Iscimen R, Cartin-Ceba R, Yilmaz M, et al. Risk factors for the development of acute lung injury in patients with septic shock: an observational cohort study. Crit Care Med, 2008, 36(5): 1518-1522.
7. Thompson BT, Chambers RC, Liu KD. Acute Respiratory Distress Syndrome. N Engl J Med, 2017, 377(6): 562-572.
8. . Auriemma CL, Zhuo H, Delucchi K, et al. Acute respiratory distress syndrome-attributable mortality in critically ill patients with sepsis. Intensive Care Med. 2020, 46(6): 1222-1231.
9. Mikkelsen ME, Shah CV, Meyer NJ, et al. The epidemiology of acute respiratory distress syndrome in patients presenting to the emergency department with severe sepsis. Shock, 2013, 40(5): 375-381.
10. Meng D, Zhu C, Jia R, et al. The molecular mechanism of ferroptosis and its role in COPD. Front Med (Lausanne), 2023, 9: 1052540.
11. Rizzardi N, Pezzolesi L, Samorì C, et al. Natural Astaxanthin Is a Green Antioxidant Able to Counteract Lipid Peroxidation and Ferroptotic Cell Death. Int J Mol Sci, 2022, 23(23): 15137.
12. Nishizawa H, Matsumoto M, Chen G, et al. Lipid peroxidation and the subsequent cell death transmitting from ferroptotic cells to neighboring cells. Cell Death Dis, 2021, 12(4): 332.
13. Yan HF, Zou T, Tuo QZ, et al. Ferroptosis: mechanisms and links with diseases. Signal Transduct Target Ther, 2021, 6(1): 49.
14. Wang YM, Gong FC, Qi X, et al. Mucin 1 inhibits ferroptosis and sensitizes vitamin E to alleviate sepsis-induced acute lung injury through GSK3beta/Keap1-Nrf2-GPX4 pathway. Oxid. Med. Cell Longev, 2022, 2022: 2405943.
15. Shen Y, He Y, Pan Y, et al. Role and mechanisms of autophagy, ferroptosis, and pyroptosis in sepsis-induced acute lung injury. Front, Pharmacol, 2024, 15: 1415145.
16. Liu J, Han X, Zhou J, et al. Molecular Mechanisms of Ferroptosis and Their Involvement in Acute Kidney Injury. J Inflamm Res, 2023, 16: 4941-4951.
17. Clough, E. ; Barrett, T. The gene expression omnibus database. Methods Mol Biol, 2016, 1418: 93-110.
18. . Zhou N, Yuan X, Du Q, et al. FerrDb V2: update of the manually curated database of ferroptosis regulators and ferroptosis-disease associations, Nucleic Acids Res, 2023, 51(D1), D571–D582.
19. Kanehisa M, Goto S. KEGG: Kyoto encyclopedia of genes and genomes. Nucleic Acids Res, 2000, 28(1): 27-30.
20. Szklarczyk D. , Kirsch R. , Koutrouli M. , et al. The STRING database in 2023: protein–protein association networks and functional enrichment analyses for any sequenced genome of interest. Nucleic Acids Res, 2023, 51(D): D638-D646.
21. Dumas J, Gargano MA, Dancik GM, et al. shinyGEO: a web-based application for analyzing gene expression omnibus datasets. Bioinformatics, 2016, 32(23): 3679-3681.

Chinese Journal of Respiratory and Critical Care Medicine

The Relationship Between Ferroptosis Regulatory Genes and Lung Injury Induced by Sepsis Based on Bioinformatics

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