Exploring the Association Between Upadacitinib and Venous Thromboembolism: An Integrated Analysis of Adverse Drug Events and Network Toxicology Mechanisms

Objective To investigate the association between upadacitinib and venous thromboembolism (VTE) and explore potential toxicological mechanisms by integrating adverse drug events (ADEs) data with network toxicology analyses. Methods A retrospective analysis of upadacitinib-related ADEs reported in the FAERS database from January 2004 to March 2025 was conducted. Signal detection methods included Proportional Reporting Ratio (PRR), Reporting Odds Ratio (ROR), Bayesian Confidence Propagation Neural Network (BCPNN), and Multi-item Gamma Poisson Shrinker (MGPS). Potential molecular mechanisms were explored through network toxicology. Predicted targets of upadacitinib were obtained from TOXRIC, STITCH, and SwissTargetPrediction, while VTE-related targets were retrieved from GeneCards. Protein-protein interaction (PPI) networks were constructed using STRING and visualized with Cytoscape. Functional enrichment analyses (GO and KEGG) were performed using DAVID. Molecular docking was conducted via CB-Dock2. Results A total of 712 reports linked upadacitinib to VTE, showing a significant positive signal (ROR [95% CI]: 1.65 [1.54–1.77]; IC025: 0.72 [0.61]). The median time to VTE onset was 122 days. Network toxicology identified six core targets: STAT3, NFKB1, GSK3B, HIF1A, HSP90AB1, and CCND1. Enriched pathways included Human Cytomegalovirus infection, HIF-1 signaling, Ras signaling, Neurotrophin signaling, and PI3K-Akt signaling. Molecular docking revealed strong binding affinities between upadacitinib and these targets. Conclusion upadacitinib may be associated with an increased risk of VTE, mediated by multiple signaling pathways and key toxicological targets. These findings provide mechanistic insights into upadacitinib-induced VTE and support the need for enhanced pharmacovigilance in clinical settings.