Integration of FAERS database and network toxicology to investigate adverse drug events and potential toxicological mechanisms of triazole antifungal agents.

This study aimed to systematically analyze the characteristics and potential toxicological mechanisms of adverse drug events (ADEs) associated with triazole antifungal agents by integrating the FDA Adverse Event Reporting System (FAERS) database with network toxicology. ADE reports for five triazole antifungals (fluconazole, itraconazole, voriconazole, posaconazole, isavuconazole) from Q1 2010 to Q2 2025 were retrieved from the FAERS database. Positive signals were identified using disproportionality analysis, including the reporting odds ratio (ROR) and proportional reporting ratio (PRR). Potential drug targets were predicted and cross-referenced with ADE-related targets from GeneCards to construct a protein-protein interaction network. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and Gene Ontology (GO) enrichment analyses identified key pathways, and molecular docking evaluated binding affinity with core targets. Analysis of 10,546 ADE reports identified voriconazole (40%) and fluconazole (28%) as the most reported drugs, with patients > 65 years comprising 38% of cases. Signal mining revealed that hepatic function abnormality, liver injury, cholestasis, hepatocellular injury, and QT interval prolongation were significant ADE signals common to all five triazoles. Itraconazole and posaconazole were associated with the strongest cholestasis signals, while posaconazole and voriconazole demonstrated prominent hepatocellular injury signals. Notably, signals for rash and erythema were observed only for fluconazole, whereas visual-disturbance signals were observed only for voriconazole in the present analysis. Network toxicology identified 137 potential targets enriched in drug metabolism-cytochrome P450, apoptosis, PI3K-Akt, MAPK, and TNF signaling pathways, with PIK3CA, TNF, RELA, BCL2, and AKT1 as core targets. Molecular docking suggested potential binding interactions, with itraconazole showing the lowest predicted binding energy with TNF (-9.4 kcal/mol). Integrated analysis of FAERS data and network toxicology suggests that triazole antifungals exhibit both common and unique adverse reaction patterns, with multi-system toxicity potentially involving core pathways such as PI3K-Akt, MAPK, and TNF signaling. These findings provide preliminary hypotheses for clinical safety monitoring and a foundation for future experimental investigation, rather than establishing causal mechanisms.