Revealing potential drug targets in liver dysfunction through proteome-wide Mendelian randomization

Area of Science:

• Proteomics and Systems Biology
• Genetics and Bioinformatics
• Drug Discovery and Development

Background:

• Liver damage, encompassing hepatic impairment to failure, poses a global health challenge with limited treatments.
• Identifying molecular targets is essential for advancing liver damage therapies.

Purpose of the Study:

• To identify plasma proteins associated with liver biomarkers using proteomic and genetic data.
• To explore potential therapeutic targets and drug candidates for liver damage.

Main Methods:

• Summary-data-based Mendelian randomization and colocalization analyses were performed on proteomic data.
• Functional enrichment, protein-protein interaction network, and molecular docking studies were conducted.
• Leveraged deCODE cohort proteomic data and 6 liver biomarkers.

Main Results:

• Identified 30 validated protein targets for liver damage through colocalization analysis (PP.H4 > 0.8).
• Enrichment analysis revealed involvement in purine and nucleotide metabolism pathways.
• Molecular docking identified potential compounds like 7,8-benzoflavone and quercetin with strong binding affinities.

Conclusions:

• 30 proteins were identified as promising therapeutic targets for liver damage.
• Novel insights into molecular mechanisms and actionable leads for drug development were provided.
• Further validation is needed for personalized therapeutic strategies.