Liver failure diagnosis: key diagnostic biomarkers discovery and bioinformatic validation

TL;DR

This study identifies GPX3 as a potential diagnostic and prognostic biomarker for liver failure, linking it to oxidative stress and immune dysregulation.

Contribution

The study discovers GPX3 as a novel diagnostic biomarker and explores its role in liver failure pathogenesis through bioinformatics and experimental validation.

Findings

GPX3 is associated with oxidative stress and immune dysregulation in liver failure.

GPX3 expression correlates with immune cell infiltration and inflammatory responses.

Promoter methylation of GPX3 is linked to higher mortality in ACHBLF patients.

Abstract

Glutathione peroxidase 3 (GPX3) is a strong antioxidant. While elevated GPX3 levels are linked to diverse pathologies, its role in liver failure (LF) remains underexplored. This study investigates GPX3’s diagnostic potential and mechanistic contributions to LF pathogenesis.

We integrated two high-quality liver tissue datasets (GSE38941 and GSE14668) from the Gene Expression Omnibus (GEO) database. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses were conducted to identify potential biomarkers associated with liver failure. The Comparative Toxicogenomics Database was used to predict the function of GPX3. In addition, in our study, we verified the target gene mRNA expression level in 40 patients with acute or chronic acute liver failure (ACHBLF) by RT-QCPR experiment and detect the methylation status of GPX3 promoter of ACHBLF patients with methylation specific PCR (MSP).

The results demonstrate that GPX3 drives pathogenic mechanisms in liver failure through oxidative stress-related pathways (e.g., collagen cross-linking, extracellular matrix remodeling) and immune dysregulation (e.g., macrophage activation, PD-1/CTLA-4 signaling). CPX8, PRDX6, GPX4, GSS, GSR, TXN, GPX7, PPARGC1A, ALOX15, and ALOX5 have been identified as key immune-related genes. Furthermore, there were significant differences in immune cell infiltration between the high and low expression groups of GPX3 groups. Immune infiltration analysis demonstrated strong correlations between GPX3 expression and key immune markers (p < 0.05), suggesting its role in modulating inflammatory responses. Additionally, GPX3 increased susceptibility to aerosols, cyclosporin and dexamethasone was observed in patients with elevated levels of GPX3. The mRNA expression of GPX3 was much higher in ACHBLF patients than in other groups. In ACHBLF patients, the group with GPX3 methylated promoter had higher mortality than those without.

In conclusion, GPX3 is a promising diagnostic biomarker for liver failure. Its promoter methylation status may serve as a prognostic indicator, highlighting its therapeutic potential.

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