Targeting cardiotoxicity: the potential of Annona squamosa L. in doxorubicin therapy.

Abstract

Doxorubicin, a potent anthracycline used in chemotherapy, is limited by dose-dependent cardiotoxicity, leading to irreversible heart damage and heart failure. Common symptoms include fatigue, dyspnea, lower limb edema, hypotension, tachycardia, and transient arrhythmias. Annona squamosa L. (AS), traditionally used in medicine, was investigated for its cardioprotective action against doxorubicin-induced cardiotoxicity through computational studies. Phytocompounds were identified using literature reviews, Dr. Duke's, IMPPAT, and PubChem databases. Targets associated with Doxorubicin induced cardiotoxicity were accessed from GeneCards, and protein-protein interactions were analyzed using the STRING database. Cytoscape was used for network visualization, revealing 18 bioactives targeting 67 proteins across 14 pathways. PIK3R1 emerged as a key target with the highest interaction count among 767 targets. Molecular docking showed that the PIK3R1-Rutin complex had the lowest binding energy (- 11.873 kcal/mol), and a 100 ns molecular dynamics (MD) simulation confirmed its stability. LC-MS analysis of the crude extract indicated the presence of bioactives. In vitro antioxidant activity of AS, assessed using the DPPH assay, showed significant radical scavenging activity, correlating with the high total phenol (TPC) and total flavonoid content (TFC) detected. This integrated approach highlights AS's potential in mitigating doxorubicin-induced cardiotoxicity.

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-025-00333-5.