Novel hub genes and regulatory network related to ferroptosis in tetralogy of Fallot

Yu Wang; Junjie Yang; Jieru Lu; Qingjie Wang; Jian Wang; Jianyuan Zhao; Yuqiang Huang; Kun Sun

doi:10.3389/fped.2023.1177993

Novel hub genes and regulatory network related to ferroptosis in tetralogy of Fallot

Front Pediatr. 2023 Oct 18:11:1177993. doi: 10.3389/fped.2023.1177993. eCollection 2023.

Authors

Yu Wang^#^{1

2}, Junjie Yang^#^{1

2}, Jieru Lu^{1

2}, Qingjie Wang², Jian Wang², Jianyuan Zhao², Yuqiang Huang³, Kun Sun^{1

2}

Affiliations

¹ Department of Pediatric Cardiology, The Second Affiliated Hospital, Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.
² Department of Pediatric Cardiology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
³ Linyi Maternal and Child Health Care Hospital, Linyi, China.

^# Contributed equally.

Abstract

Ferroptosis is a newly discovered type of cell death mainly triggered by uncontrolled lipid peroxidation, and it could potentially have a significant impact on the development and progression of tetralogy of Fallot (TOF). Our project aims to identify and validate potential genes related to ferroptosis in TOF. We obtained sequencing data of TOF from the GEO database and ferroptosis-related genes from the ferroptosis database. We employed bioinformatics methods to analyze the differentially expressed mRNAs (DEmRNAs) and microRNAs between the normal control group and TOF group and identify DEmRNAs related to ferroptosis. Protein-protein interaction analysis was conducted to screen hub genes. Furthermore, a miRNA-mRNA-TF co-regulatory network was constructed to utilize prediction software. The expression of hub genes was further validated through quantitative real-time reverse-transcription polymerase chain reaction (qRT-PCR). After conducting the differential gene analysis, we observed that in TOF, 41 upregulated mRNAs and three downregulated mRNAs associated with ferroptosis genes were found. Further Gene Ontology/Kyoto Encyclopedia of Genes and Genomes analysis revealed that these genes were primarily involved in molecular functions and biological processes related to chemical stress, oxidative stress, cellular response to starvation, response to nutrient levels, cellular response to external stimulus, and cellular response to extracellular stimulus. Furthermore, we constructed a miRNA-mRNA-TF co-regulatory network. qRT-PCR analysis of the right ventricular tissues from human cases showed an upregulation in the mRNA levels of KEAP1 and SQSTM1. Our bioinformatics analysis successfully identified 44 potential genes that are associated with ferroptosis in TOF. This finding significantly contributes to our understanding of the molecular mechanisms underlying the development of TOF. Moreover, these findings have the potential to open new avenues for the development of innovative therapeutic approaches for the treatment of this condition.

Keywords: DEmRNAs; DEmiRs; GEO; TOF; ferroptosis; network.