# Liver fibrosis in biliary atresia: identification of the key gene EDIL3 via integrated bioinformatics

## TL;DR

This study identifies EDIL3 as a key gene in liver fibrosis caused by biliary atresia, suggesting it may influence disease progression through the PI3K-AKT signaling pathway.

## Contribution

The study identifies EDIL3 as a novel key gene in biliary atresia-related liver fibrosis and links it to the PI3K-AKT signaling pathway.

## Key findings

- EDIL3 expression is significantly elevated in biliary atresia liver tissue.
- High EDIL3 expression is associated with apoptosis and activation of the PI3K-AKT signaling pathway.
- EDIL3 is negatively correlated with the survival rate of patients' native livers.

## Abstract

Biliary atresia (BA) is one of the most destructive liver and biliary diseases in neonates and is characterized by progressive fibrous inflammatory obstruction of the intrahepatic and extrahepatic bile ducts, ultimately leading to liver fibrosis and liver failure. This study aimed to use integrated bioinformatics methods to identify differentially expressed genes (DEGs) in BA liver tissue, identify key genes, and explore their mechanisms in liver fibrosis.

We obtained data from the gene expression omnibus (GEO) dataset GSE122340 [171 BA patients and 7 normal controls (NCs)]. DEGs were screened via the limma package, followed by gene ontology (GO)/kyoto encyclopedia of genes and genomes (KEGG) enrichment analysis. A protein-protein interaction (PPI) network was constructed via STRING and Cytoscape, and core genes were selected via the maximum clique centrality (MCC), maximum neighborhood component (MNC), and degree algorithms from the CytoHubba plugin. Further focus was placed on the key gene EGF-like repeats and discoidin I-like domains 3 (EDIL3) through gene set enrichment analysis (GSEA), expression validation, subcellular localization analysis, and clinical tissue sample validation. To minimize batch effects, we performed ComBat correction on the combined gene expression data of GSE122340 and the validation dataset GSE46960 before interdataset comparison.

We identified a total of 3706 DEGs, including 2774 upregulated DEGs and 932 downregulated DEGs. The functional enrichment analysis revealed that the DEGs were involved mainly in biological processes such as the cell cycle, DNA replication, and extracellular matrix organization, as well as signaling pathways such as herpes simplex virus infection, phosphoinositide 3-kinase (PI3K)-protein kinase B (AKT), and tumor necrosis factor (TNF). Protein-protein interaction (PPI) network analysis revealed 7 core genes (BRCA1, TOP2A, BRCA2, BUB1B, HSP90AA1, PLK4, and EDIL3), with EDIL3 showing the greatest increase in BA. EDIL3 is located on chromosome 5, and its encoded protein is expressed primarily in the cell membrane and extracellular region. GSEA indicated that high EDIL3 expression was significantly associated with apoptosis and activation of the PI3K-AKT signaling pathway. Clinical sample validation revealed that EDIL3 expression was significantly elevated in BA liver tissue, and its high expression was significantly negatively correlated with the survival rate of patients’ native livers.

Discoidin I-like domain 3 is a novel gene with a potentially key role in BA-related liver fibrosis, possibly influencing the proliferation and apoptosis of cholangiocytes by regulating the PI3K-AKT signaling pathway, thereby participating in the occurrence and development of liver fibrosis. This study provides new insights into the molecular mechanisms and potential treatment strategies for BA.