Effects of Obacunone Against Myocardial Fibrosis: Mechanistic Insights from Network Pharmacology and Experimental Validation

Myocardial fibrosis (MF), a common pathological consequence of cardiovascular diseases, compromises cardiac function and elevates the risk of heart failure and arrhythmias. Considering the limited therapeutic options, this study explored the antifibrotic potential of Obacunone (OB), focusing on its links to lipid metabolism pathways. Potential OB targets, MF-associated genes, and lipid metabolism-related genes were curated from databases and literature. Transcriptomic datasets were analyzed to identify differentially expressed genes (DEGs) in MF, and lipid metabolism-related DEGs (LMDEGs) were subsequently intersected with these target sets to identify OB-associated targets. These core targets were further investigated via protein-protein interaction (PPI) network, consensus clustering, functional enrichment, and molecular docking analysis. Key findings were validated via western blotting. Intersection analysis identified ten LMDEGs associated with OB. Moreover, PPI network analysis highlighted a subnetwork of seven strongly interacting targets-CYP19A1, STAT3, LGALS3, PDGFRA, SCN5A, SLC9A1, and SERPINE1. Functional enrichment indicated OB's involvement in the epidermal growth factor receptor (EGFR), advanced glycation end-product-receptor for advanced lycation end-products (AGE-RAGE), and hypoxia-inducible factor-1 (HIF-1) signaling pathways. Furthermore, consensus clustering revealed distinct subtypes of MF. Molecular docking confirmed strong binding affinities between OB and core targets. In vivo, OB attenuated fibrosis, downregulated SLC9A1 and SERPINE1 expression, and upregulated CYP19A1, LGALS3, PDGFRA, and SCN5A. This integrated study demonstrates that OB exerts antifibrotic effects by regulating lipid metabolism-related genes and pathways. The identification of MF subtypes supports personalized therapy, positioning OB as a promising candidate for MF treatment.