Identification and validation of ferroptosis-related genes in patients infected with dengue virus: implication in the pathogenesis of DENV

Ferroptosis, an iron-dependent form of regulated cell death, has been associated with many virus infections. However, the role of ferroptosis in dengue virus (DENV) infection remains to be clarified. In our study, a dengue fever microarray dataset (GSE51808) of whole blood samples was downloaded from the Gene Expression Omnibus (GEO), and a list of ferroptosis related genes (FRGs) was extracted from the FerrDb. We identified 37 ferroptosis-related differentially expressed genes (FR-DEGs) in DENV-infected patient blood samples compared to healthy individuals. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses as well as protein–protein interaction (PPI) network of FR-DEGs revealed that these 37 FR-DEGs were mainly related to the C-type lectin receptor and p53 signaling pathway. Nine out of the 37 FR-DEGs (HSPA5, CAV1, HRAS, PTGS2, JUN, IL6, ATF3, XBP1, and CDKN2A) were hub genes, of which 5 were validated by qRT-PCR in DENV-infected HepG2 cells. Finally, using miRNA-mRNA regulatory network, we identified has-miR-124-3p and has-miR-16-5p as the most critical miRNAs in regulating the expression of these hub genes. In conclusion, our findings demonstrated that 5 FR-DEGs, JUN, IL6, ATF3, XBP1, and CDKN2A, and two miRNAs, has-miR-124-3p and has-miR-16-5p may implicate an essential role of ferroptosis in DENV infection, and further studies are warranted to explore the underlying mechanisms.