FAERS based disproportionality analysis and network pharmacology investigation of conventional and liposomal formulations of doxorubicin induced cardiotoxicity

Doxorubicin is crucial for cancer treatment but limited by cardiotoxicity. Liposomal doxorubicin (Lip-DOX) was developed to reduce toxicity compared to conventional doxorubicin (Con-DOX). This research analyzes FAERS database to assess cardiotoxicity association via disproportionate analysis and explores mechanisms via network pharmacology. To explore the cardiotoxicity of the two formulations, we analyzed 10,695 Con-DOX and 13,164 Lip-DOX adverse event reports. Results demonstrated Con-DOX had higher relative odds ratios (RORs) for cardiomyopathy (34.07) and cardiac failure (5.88) compared to Lip-DOX (18.39 and 3.80). Lip-DOX lacked signals for arrhythmias/myocarditis, while Con-DOX had these signals. Serious adverse event rates were 98.74% (Con-DOX) and 98.61% (Lip-DOX), with mortality at 26.21% and 23.15%, indicating no significant differences in cardiotoxicity severity or mortality between formulations. Network pharmacology analysis revealed 113 overlapping targets associated with doxorubicin-induced cardiotoxicity, refined to 10 core targets. Main enriched Gene Ontology (GO) biological processes included response to oxidative stress and apoptotic signaling pathway regulation. Key Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways included HIF-1 signaling, EGFR tyrosine kinase inhibitor resistance, and fluid shear stress-atherosclerosis. Our study shows Lip-DOX has lower cardiotoxicity risk than Con-DOX, but severe consequences still require vigilant attention.