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RAB7B as a Potential Therapeutic Target in Liver Cirrhosis: Insights from Protein Expression and Bioinformatics
Jinyao Dai1, Shuaibing Ying1, Jie Lin2
1State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, Zhejiang Provincial Key Laboratory for Drug Evaluation and Clinical Research of Zhejiang Province, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.
Abstract:
Liver cirrhosis remains a major global health challenge, with liver transplantation currently representing the most effective treatment. Elucidating its molecular pathogenesis is therefore critical for the development of novel therapeutic strategies. Emerging evidence indicates that mitophagy plays a pivotal role in cirrhosis progression. In this study, we employed integrative bioinformatics to explore the association between mitophagy and liver cirrhosis, aiming to identify potential therapeutic targets. Differentially expressed genes (DEGs) were obtained from GSE77627 and GSE139602 data sets, followed by functional enrichment analysis. Mitophagy-related differentially expressed genes (mito-DEGs) were screened and assessed through receiver operating characteristic (ROC) analysis, immune cell infiltration profiling, and protein-protein interaction (PPI). Weighted gene coexpression network analysis (WGCNA) identified key modules, and intersecting genes with mito-DEGs highlighted RAB7B as a candidate hub gene, which was validated in external data sets. Experimental verification confirmed elevated RAB7B expression in activated hepatic stellate cells (HSCs) and a mouse model of liver cirrhosis. Functional assays demonstrated that RAB7B inhibition attenuated HSC activation, and molecular docking revealed strong binding affinity between RAB7B and predicted anticirrhosis compounds. We found that RAB7B knockdown restored TGF-β-induced mitophagy inhibition, enhanced mitochondria-lysosome colocalization, and showed dynamic regulation by mitophagy status, indicating its role as a negative and responsive regulator of mitochondrial clearance. Collectively, our findings identify RAB7B as a mitophagy-related hub gene driving liver cirrhosis progression and provide novel insights into its therapeutic potential.
Insights
This study identifies RAB7B as a key gene in liver cirrhosis progression, linking it to mitophagy. Inhibiting RAB7B shows therapeutic potential for treating liver cirrhosis.
Area of Science:
- Hepatology and Molecular Biology
- Cellular Biology
- Bioinformatics
Background:
- Liver cirrhosis is a significant global health issue requiring effective treatments.
- Mitophagy, the selective removal of damaged mitochondria, is implicated in cirrhosis progression.
- Understanding the molecular mechanisms of cirrhosis is crucial for developing new therapies.
Purpose of the Study:
- To investigate the association between mitophagy and liver cirrhosis using bioinformatics.
- To identify potential therapeutic targets for liver cirrhosis by analyzing mitophagy-related genes.
- To elucidate the role of the hub gene RAB7B in liver cirrhosis pathogenesis.
Main Methods:
- Integrative bioinformatics analysis of gene expression datasets (GSE77627, GSE139602).
- Identification and screening of mitophagy-related differentially expressed genes (mito-DEGs).
- Weighted gene coexpression network analysis (WGCNA), protein-protein interaction (PPI) analysis, and experimental validation in cell and animal models.
Main Results:
- RAB7B was identified as a candidate hub gene associated with mitophagy in liver cirrhosis.
- Elevated RAB7B expression was observed in activated hepatic stellate cells (HSCs) and a mouse model of liver cirrhosis.
- RAB7B inhibition attenuated HSC activation and modulated mitophagy, suggesting its role in mitochondrial clearance regulation.
Conclusions:
- RAB7B is a mitophagy-related hub gene that drives liver cirrhosis progression.
- Targeting RAB7B presents a novel therapeutic strategy for liver cirrhosis.
- The study provides insights into the dynamic regulation of mitophagy in liver cirrhosis.
