A ferroptosis-related ceRNA network for investigating the molecular mechanisms and the treatment of neonatal hypoxic-ischemic encephalopathy

Hongyi Lu; Haiyan Shen; Liming Mao; Michele Mussap; Lei Song

doi:10.21037/tp-23-596

A ferroptosis-related ceRNA network for investigating the molecular mechanisms and the treatment of neonatal hypoxic-ischemic encephalopathy

Transl Pediatr. 2024 Jan 29;13(1):119-136. doi: 10.21037/tp-23-596. Epub 2024 Jan 22.

Authors

Hongyi Lu¹, Haiyan Shen¹, Liming Mao^{2

3}, Michele Mussap⁴, Lei Song¹

Affiliations

¹ Department of Pediatrics, Nantong First People's Hospital (The Second Affiliated Hospital of Nantong University), Nantong, China.
² Department of Immunology, School of Medicine, Nantong University, Nantong, China.
³ Basic Medical Research Center, School of Medicine, Nantong University, Nantong, China.
⁴ Laboratory Unit, Department of Surgical Sciences, University of Cagliari, Monserrato, Italy.

Abstract

Background: Neonatal hypoxic-ischemic brain damage (HIBD) is a clinical syndrome causing brain injury in newborns with obscure etiology. Increasing evidence suggests that ferroptosis plays a role in HIBD. This study aimed to clarify the key ferroptosis-related genes (FRGs) of HIBD, construct a long non-coding RNA-microRNA-messenger RNA (lncRNA-miRNA-mRNA) network, and further investigate the pathogenesis of HIBD.

Methods: Gene expression data were downloaded from the Gene Expression Omnibus and FerrDb databases. The differentially expressed lncRNAs and FRGs were screened, and the related miRNAs and mRNAs were predicted. The obtained mRNA was intersected with the differentially expressed FRGs (DE-FRGs) to identify the key DE-FRGs. Cell-type Identification by Estimating Relative Subsets of RNA Transcripts method was applied to analyze the immune cell infiltration level and the relationship between key genes and immune cells.

Results: Gene differential expression analysis revealed that 1,178 lncRNAs, 207 miRNAs, and 647 mRNAs were differentially expressed in the blood of HIBD patients in comparison to healthy controls. The correlations of the lncRNAs, miRNAs, and mRNAs lead to the establishment of a competing endogenous RNA (ceRNA) network associated with ferroptosis in HIBD. Further validation using an external dataset and quantitative real-time polymerase chain reaction (PCR) analysis of brain tissues from hypoxic-ischemic encephalopathy rats confirmed the expression patterns of three key genes, including HMOX1, MYCN, and QSOX1. Meanwhile, the three key genes were closely correlated with the infiltration of multiple immune cells and might affect the function of HIBD regulatory genes such as CPT2 and GCK. In addition, drug prediction suggested that four drugs, including cephaeline, emetine, mestranol, and sulmazole, might alleviate HIBD.

Conclusions: Our study established a ceRNA network, identified three key genes, and predicted four drugs that are associated with ferroptosis in HIBD, which provides new ideas for the investigation of the disease mechanisms and might facilitate the diagnosis and treatment of the disease.

Keywords: Hypoxic-ischemic brain damage (HIBD); bioinformatics; competing endogenous RNA (ceRNA); ferroptosis; newborn.