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

Abstract

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. Supplementary Information The online version contains supplementary material available at 10.1007/s11262-023-01985-1.

LncRNA SNHG1 knockdown inhibits hyperglycemia induced ferroptosis viamiR‐16‐5p/ACSL4 axis to alleviate diabetic nephropathy

“…Owing to a deeper understanding of disease‐relevant miRNAs and mRNAs and advances in in vivo delivery systems, the administration of miRNA/mRNA‐based therapeutics has recently been shown to be feasible and safe in humans with encouraging efficacy results in early‐phase clinical trials 43 . miR‐16‐5p implicates an essential role of ferroptosis in diseases 18 , 44 . And ACSL4 is a critical determinant of ferroptosis sensitivity which functions in inducing ferroptosis, and its deletion presents an unprecedented resistance to ferroptosis 39 .…”

Flaviviruses in AntiTumor Therapy

“…Importantly, p53 was shown to significantly interfere with replication of Dengue virus in liver cancer HEpG2 cells [96]. On the molecular level, recently published data [97] indicate that Dengue virus may trigger ferroptosis in the target cells, which is amplified in the presence of active p53.…”

The Dual Roles of Activating Transcription Factor 3 (ATF3) in Inflammation, Apoptosis, Ferroptosis, and Pathogen Infection Responses

“…Infection with the Dengue virus (DENV) can induce a robust cytokine storm in the brain, leading to neurological symptoms or death in the host [160]. An upregulation of ATF3 expression has been observed in blood samples of patients infected with DENV [161]. Research has discovered that monocytes infected with DENV secrete extracellular vesicles (EV), which are internalized by microglia [142].…”