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

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.

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S1046	Vandetanib	Vandetanib is a potent inhibitor of VEGFR2 with IC50 of 40 nM in a cell-free assay. It also inhibits VEGFR3 and EGFR with IC50 of 110 nM and 500 nM, respectively. Not sensitive to PDGFRβ, Flt1, Tie-2 and FGFR1 with IC50 of 1.1-3.6 μM. No activity against MEK, CDK2, c-Kit, erbB2, FAK, PDK1, Akt and IGF-1R with IC50 above 10 μM. Vandetanib (ZD6474) increases apoptosis and induces autophagy by increasing the level of reactive oxygen species (ROS).

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EGFR VEGFR Autophagy Apoptosis related ROS