Network pharmacology, molecular docking, and preliminary in vitro evaluation of Ponatinib in cardiac hypertrophy

Cardiac hypertrophy is a key contributor to adverse remodeling and the progression of cardiovascular diseases. Ponatinib, a multi-targeted tyrosine kinase inhibitor approved for oncology, has been shown to inhibit growth factor signaling pathways implicated in hypertrophy. This study aimed to investigate the molecular targets of Ponatinib and evaluate its effects on cardiac hypertrophy. Network pharmacology was used to identify Ponatinib-associated targets and their overlap with cardiac disease-related genes. Protein–protein interaction (PPI) analysis, Gene Ontology (GO) analysis, and KEGG pathway enrichment analysis were performed to identify key pathways. Molecular docking assessed binding affinities with selected targets. In vitro validation was conducted in H9C2 (2–1) cells subjected to high-salt-induced hypertrophy, in which cell viability, cell size, and α-smooth muscle actin (α-SMA) levels were measured. Twenty-four overlapping targets were identified, with EGFR, MAPK8, MAP3K7, JAK2, and PDGFRB as key regulators enriched in MAPK and PI3K-Akt pathways. Docking showed strong binding affinities, particularly with PDGFRB and JAK2. In vitro, Ponatinib (0.25 µM) significantly reduced cardiomyocyte hypertrophy while maintaining cell viability. However, no significant reduction in α-SMA levels was observed. Ponatinib attenuates cardiac hypertrophy through multi-target modulation of growth factor signaling pathways. Further studies are needed to explore its role in cardiac hypertrophy.