Ferroptosis-related differentially expressed genes serve as new biomarkers in ischemic stroke and identification of therapeutic drugs

Yinjiang Zhang; Yashuo Zhang; Rongfei Yao; Xu He; Linyi Zhao; Xiangyu Zuo; Binan Lu; Zongran Pang

doi:10.3389/fnut.2022.1010918

Ferroptosis-related differentially expressed genes serve as new biomarkers in ischemic stroke and identification of therapeutic drugs

Front Nutr. 2022 Nov 10:9:1010918. doi: 10.3389/fnut.2022.1010918. eCollection 2022.

Authors

Yinjiang Zhang^{1

2}, Yashuo Zhang^{1

2}, Rongfei Yao^{1

2}, Xu He^{1

2}, Linyi Zhao^{1

2}, Xiangyu Zuo^{1

2}, Binan Lu^{1

2}, Zongran Pang^{1

2}

Affiliations

¹ School of Pharmacy, Minzu University of China, Beijing, China.
² Key Laboratory of Ethnomedicine, Minzu University of China, Ministry of Education, Beijing, China.

Abstract

Background: Iron is an essential nutrient element, and iron metabolism is related to many diseases. Ferroptosis is an iron-dependent form of regulated cell death associated with ischemic stroke (IS). Hence, this study intended to discover and validate the possible ferroptosis-related genes involved in IS.

Materials and methods: GSE16561, GSE37587, and GSE58294 were retrieved from the GEO database. Using R software, we identified ferroptosis-related differentially expressed genes (DEGs) in IS. Protein-protein interactions (PPIs) and enrichment analyses were conducted. The ROC curve was plotted to explore the diagnostic significance of those identified genes. The consistent clustering method was used to classify the IS samples. The level of immune cell infiltration of different subtypes was evaluated by ssGSEA and CIBERSORT algorithm. Validation was conducted in the test sets GSE37587 and GSE58294.

Results: Twenty-one ferroptosis-related DEGs were detected in IS vs. the normal controls. Enrichment analysis shows that the 21 DEGs are involved in monocarboxylic acid metabolism, iron ion response, and ferroptosis. Moreover, their expression levels were pertinent to the age and gender of IS patients. The ROC analysis demonstrated remarkable diagnostic values of LAMP2, TSC22D3, SLC38A1, and RPL8 for IS. Transcription factors and targeting miRNAs of the 21 DEGs were determined. Vandetanib, FERRIC CITRATE, etc., were confirmed as potential therapeutic drugs for IS. Using 11 hub genes, IS patients were categorized into C1 and C2 subtypes. The two subtypes significantly differed between immune cell infiltration, checkpoints, and HLA genes. The 272 DEGs were identified from two subtypes and their biological functions were explored. Verification was performed in the GSE37587 and GSE58294 datasets.

Conclusion: Our findings indicate that ferroptosis plays a critical role in the diversity and complexity of the IS immune microenvironment.

Keywords: biomarkers; ferroptosis; immune microenvironment; ischemic stroke; subtypes.