Abstract
Valvular heart disease (VHD) is a common cardiovascular disorder with insidious early symptoms and can progress to heart failure or sudden death. Pharmacological options remain limited, and severe disease often requires surgical intervention. This study aimed to identify key molecular targets and potential therapeutic candidates for VHD using Mendelian randomization (MR) and integrative analyses. A 2-sample MR design was used to evaluate the association between genetically predicted exposures and VHD using publicly available genome-wide association study summary statistics. Downstream analyses included functional enrichment, drug repurposing with molecular docking, protein-protein interaction network construction with hub-gene identification, and single-cell RNA sequencing-based analysis to examine the cell-type distribution of candidate gene expression. MR analysis identified 76 genes associated with VHD, including stathmin 1, ribosomal protein S5, and mitogen-activated protein kinase 8. Enrichment analysis suggested that these genes were involved in multiple signaling pathways potentially related to disease progression. Drug prediction and molecular docking prioritized razoxane, reserpine, and bisindolylmaleimide I as candidate compounds targeting key molecules. Protein-protein interaction network analysis further identified 10 hub genes, such as DEAD-box helicase 6 and apolipoprotein E. Single-cell sequencing showed high expression of these genes in cardiomyocytes, fibroblasts, and smooth muscle cells. This study identified candidate genes and potential drug leads for VHD through an MR-based integrative analysis, providing targets for subsequent mechanistic and experimental validation.