Screening and Validation of LTBP1 as a Key Target of Oxymatrine in Inhibiting Cardiac Fibroblast Differentiation Under High Glucose Conditions: In Vitro and Bioinformatic Studies
Abstract
Diabetic cardiomyopathy (DCM) features progressive fibrotic remodeling, but the shared molecular circuitry connecting diabetes mellitus (DM) to cardiomyopathy (CM) remains unclear. We integrated three DM- and three CM-related Gene Expression Omnibus (GEO) datasets and corrected batch effects with sva, verified by violin plots, principal component analysis (PCA), and silhouette coefficients computed on all common genes (DM: 0.9489 to -0.1016; CM: 0.9693 to -0.045; PC1/PC2 inter-batch differences abolished after normalization). Differential expression analysis identified 2562 DM Differentially expressed genes (DEGs) and 1414 CM DEGs, and their intersection yielded 91 common DEGs (51 upregulated, 40 downregulated). Protein-protein interaction (PPI) analysis prioritized 25 hub genes, whose enrichment profiles implicated insulin resistance/insulin signaling and adrenergic signaling in cardiomyocytes. TRRUST-based inference further defined a regulatory network centered on seven key genes (HIF-1α, ACTN4, ABCB1, LTBP1, CLU, TIMP2, and MYH11). To nominate a candidate target of oxymatrine (OMT), we performed docking and molecular dynamics (MD) simulations for representative complexes; OMT showed the most stable interaction with LTBP1, maintaining a consistently short pocket distance (~0.2 nm), the highest contact frequency, and the lowest MM/PBSA binding free energy (-15.32 kcal/mol), with favorable contributions dominated by van der Waals and nonpolar solvation terms. In primary…
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