Real-World Safety Profile of Baricitinib and the Structural Basis of Viral Reactivation: A Multi-Disciplinary Analysis

Background Baricitinib, a JAK1/2 inhibitor for rheumatoid arthritis, carries boxed warnings for infections and thrombosis. However, its real-world adverse event profile and the molecular mechanisms driving specific risks—particularly herpes zoster (HZ)—remain incompletely understood. We integrated pharmacovigilance and systems biology to characterize baricitinib’s safety profile and elucidate the mechanistic basis of its primary risk signal. Methods FDA Adverse Event Reporting System (FAERS) records (Q1 2004–Q1 2025) were analyzed using four disproportionality algorithms. After identifying HZ as the predominant signal, we constructed a drug-target-disease network. Mechanistic predictions were corroborated via molecular docking and 100-ns molecular dynamics (MD) simulations. Results Among 5,318 baricitinib-associated reports, infections, thromboembolism, and hepatotoxicity defined the safety profile, with HZ exhibiting the highest disproportionality (ROR = 12.58). Network pharmacology linked HZ susceptibility to the PI3K-Akt pathway, pinpointing EGFR and MMP9 as core targets. Docking confirmed high-affinity baricitinib binding to EGFR (− 8.8 kcal/mol) and MMP9 (− 7.2 kcal/mol). MD simulations demonstrated stable albumin-mediated transport and an induced-fit modulation of MMP9. This interaction triggered substantial conformational expansion (radius of gyration shift: 15 to 24 Å), suggesting structural interference with immune cell migration. Conclusion Baricitinib confers a pronounced HZ risk exceeding generic immunosuppression, driven by off-target EGFR/PI3K axis disruption and direct MMP9 structural modulation. These molecular insights provide a rationale for risk stratification and strongly support prophylactic VZV vaccination prior to therapy.