FAERS based disproportionality analysis and network pharmacology investigation of doxorubicin associated drug induced cardiotoxicity

Doxorubicin (DOX) is crucial for cancer treatment but its use is limited by cardiotoxicity. Liposomal doxorubicin (Lip-DOX) was designed to reduce this toxicity compared to conventional doxorubicin (Con-DOX). This study utilized the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) database to compare the cardiotoxicity profiles of the two formulations through disproportionality analysis and to explore potential mechanisms using network pharmacology. We analyzed 10,695 adverse event reports for Con-DOX and 13,164 for Lip-DOX. Disproportionality analysis, measured by the reporting odds ratio (ROR) and 95% confidence intervals, demonstrated that Con-DOX was associated with a higher risk of cardiomyopathy (ROR 34.07) and cardiac failure (ROR 5.88) compared to Lip-DOX (ROR 18.39 and 3.80, respectively). Furthermore, Con-DOX generated safety signals for arrhythmias and myocarditis, while Lip-DOX did not. The rates of serious adverse events were high for both formulations (Con-DOX: 98.74%; Lip-DOX: 98.61%), with reported mortality rates of 26.21% and 23.15%, respectively, indicating no significant difference in the overall severity of reported cardiotoxicity or mortality. Network pharmacology analysis identified 113 overlapping targets associated with DOX-induced cardiotoxicity (DIC), which were refined to 10 core targets. Key enriched Gene Ontology (GO) biological processes included 'response to oxidative stress' and 'regulation of apoptotic signaling pathway'. Significant Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways encompassed the HIF-1 signaling pathway, EGFR tyrosine kinase inhibitor resistance, and the fluid shear stress and atherosclerosis pathway. Our study indicates the cardiotoxic profiles and underlying mechanisms of the two DOX formulations, providing valuable insights for drug safety monitoring and clinical practice.