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Identification and validation of potential diagnostic signature and immune cell infiltration for HIRI based on
Fang Xiao1,2,3, Guozhen Huang1,2,3, Guandou Yuan1,2,3
1Division of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, China.
Insights
Cuproptosis-related genes (CRGs) are linked to hepatic ischemia and reperfusion injury (HIRI). Three hub CRGs (NLRP3, ATP7B, NFE2L2) show diagnostic potential for HIRI, offering new therapeutic targets.
Area of Science:
- Biochemistry
- Genetics
- Immunology
Background:
- Cuproptosis, a regulated cell death pathway, is increasingly implicated in disease pathogenesis.
- Hepatic ischemia and reperfusion injury (HIRI) is a critical clinical challenge with significant morbidity.
- Understanding the molecular underpinnings of HIRI is crucial for developing effective treatments.
Purpose of the Study:
- To investigate the role of cuproptosis-related genes (CRGs) in the development of HIRI.
- To identify potential diagnostic biomarkers and therapeutic targets for HIRI based on CRGs.
Main Methods:
- Bioinformatic analysis of HIRI datasets from Gene Expression Omnibus (GEO).
- Differential gene expression analysis of CRGs, correlation analysis, and pathway enrichment.
- Machine learning models to identify hub CRGs, followed by validation using qPCR and Western blotting.
Main Results:
- Three hub CRGs (NLRP3, ATP7B, NFE2L2) were identified and demonstrated high diagnostic accuracy for HIRI (AUC 0.832–0.904).
- Enrichment analyses revealed CRG involvement in HIRI-related pathways.
- Elevated expression of hub CRGs was observed in immune cells within HIRI samples, suggesting immune system involvement.
Conclusions:
- CRGs, particularly NLRP3, ATP7B, and NFE2L2, represent promising diagnostic biomarkers for HIRI.
- These findings provide novel insights into HIRI mechanisms and potential therapeutic strategies targeting cuproptosis.
Background And Aims:
Cuproptosis has emerged as a significant contributor in the progression of various diseases. This study aimed to assess the potential impact of cuproptosis-related genes (CRGs) on the development of hepatic ischemia and reperfusion injury (HIRI).
Methods:
The datasets related to HIRI were sourced from the Gene Expression Omnibus database. The comparative analysis of differential gene expression involving CRGs was performed between HIRI and normal liver samples. Correlation analysis, function enrichment analyses, and protein-protein interactions were employed to understand the interactions and roles of these genes. Machine learning techniques were used to identify hub genes. Additionally, differences in immune cell infiltration between HIRI patients and controls were analyzed. Quantitative real-time PCR and western blotting were used to verify the expression of the hub genes.
Results:
Seventy-five HIRI and 80 control samples from three databases were included in the bioinformatics analysis. Three hub CRGs (NLRP3, ATP7B and NFE2L2) were identified using three machine learning models. Diagnostic accuracy was assessed using a receiver operating characteristic (ROC) curve for the hub genes, which yielded an area under the ROC curve (AUC) of 0.832. Remarkably, in the validation datasets GSE15480 and GSE228782, the three hub genes had AUC reached 0.904. Additional analyses, including nomograms, decision curves, and calibration curves, supported their predictive power for diagnosis. Enrichment analyses indicated the involvement of these genes in multiple pathways associated with HIRI progression. Comparative assessments using CIBERSORT and gene set enrichment analysis suggested elevated expression of these hub genes in activated dendritic cells, neutrophils, activated CD4 memory T cells, and activated mast cells in HIRI samples versus controls. A ceRNA network underscored a complex regulatory interplay among genes. The genes mRNA and protein levels were also verified in HIRI-affected mouse liver tissues.
Conclusion:
Our findings have provided a comprehensive understanding of the association between cuproptosis and HIRI, establishing a promising diagnostic pattern and identifying latent therapeutic targets for HIRI treatment. Additionally, our study offers novel insights to delve deeper into the underlying mechanisms of HIRI.
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