Pioglitazone Mitigates Arsenic-Induced Cardiotoxicity via Lipid Metabolism: Network Pharmacology and Molecular...

Heavy metal exposure is an emerging major environmental risk factor associated with metabolic and cardiometabolic disorders. Arsenic exposure via drinking water leads to cardiotoxicity through lipid metabolism. Exposure to arsenic can cause various heart conditions by activating oxidative stress and inflammatory pathways. Pioglitazone is a thiazolidinedione that activates PPARγ and is an approved clinical drug for the treatment of type 2 diabetes, widely used. Pharmacokinetics results indicate pioglitazone has good oral bioavailability. In this study, we employed a network pharmacology approach and a molecular docking approach to identify the potential mechanism by which pioglitazone may mitigate arsenic-induced cardiotoxicity via lipid metabolism. Key genes that target arsenic-induced cardiotoxicity via lipid metabolism and pioglitazone have been identified using the Swiss Target Prediction, Gene Cards, OMIM, and CTD databases. A protein-protein interaction (PPI) network was generated by analysing frequently intersecting genes with the STRING and Cytoscape tools. Shiny GO was used to conduct pathway enrichment analysis for the KEGG and Gene Ontology databases. Pioglitazone and arsenic-related cardiotoxicity shared 54 common targets. Enrichment analysis pathways involved fluid and shear stress atherosclerosis, NAFLD, lipid, and atherosclerosis. Molecular docking was performed using ten targets. The binding affinity of the ten targets was ALB (6M4R) -8.6 Kcal/mol, BCL2 (2YXJ) -8.0 Kcal/mol, CASP3 (4JJE) -7.1 Kcal/mol, EGFR (2ITO) -7.8 Kcal/mol, HSP90AA1 (6GP8) -7.3 Kcal/mol, PPARα (4UND) -8.4 Kcal/mol, PPARγ (5Y20) -8.6 Kcal/mol, SRC (2SRC) -8.1 Kcal/mol, TNF (5UUI) -6.5 Kcal/mol, and TP53 (4MZI) -5.6 Kcal/mol. And also, we carried out docking with known inhibitors (Asciminib, Emricasan, Navitoclax, Osimertinib, Geldanamycin, GW6471, GW9662, Dastinib, Balinatufnib, and pifithrin), and resveratrol as a positive control. Pioglitazone as a multi-target potential against arsenic-induced cardiotoxicity via lipid metabolism by modulating mitochondrial dysfunction. Overall, this study provides a system-level assumption that indicates lipid metabolism to arsenic-induced cardiotoxicity and identifies key molecular targets that show a way to further experimental validation.