| アブストラクト | 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 explore plausible mechanisms underlying its primary reporting signal. FDA Adverse Event Reporting System (FAERS) records (Q1 2004-Q1 2025) were analyzed using four disproportionality algorithms. Additional stratified analyses were performed across reporting-source subgroups and across two reporting periods (2018-2021 and 2022-2025) to assess whether the principal PT-level safety signals remained generally consistent under different reporting conditions and over time. 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. Among 5318 baricitinib-associated reports, infections, thromboembolism, and hepatotoxicity defined the safety profile, with HZ exhibiting the highest disproportionality (ROR = 12.58). Additional stratified analyses showed that HZ and major thromboembolic signals remained prominent across reporting-source subgroups and across the two reporting periods, supporting the robustness of the principal pharmacovigilance findings. Network pharmacology associated HZ susceptibility with the PI3K-Akt pathway and identified EGFR and MMP9 as putative core targets. Molecular docking supported the structural plausibility of baricitinib binding to EGFR (- 8.8 kcal/mol) and MMP9 (- 7.2 kcal/mol), while MD simulations suggested stable albumin-mediated transport and a persistent interaction with MMP9 under dynamic conditions. The observed conformational rearrangement of MMP9 may have potential biological relevance, but its functional implications require further experimental validation. Baricitinib is associated with a significant risk of herpes zoster (HZ). Our integrated analysis suggests that this risk may involve EGFR/PI3K-related signaling and MMP9-associated immune microenvironment changes, although these mechanisms remain hypothetical and require experimental confirmation. These findings provide a rationale for further mechanistic investigation, support careful HZ risk assessment before treatment, and suggest that VZV vaccination may be considered in appropriate patients according to current clinical recommendations. |
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| ジャーナル名 | Naunyn-Schmiedeberg's archives of pharmacology |
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| Pubmed追加日 | 2026/4/8 |
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| 投稿者 | He, Yulei; Wang, Yanyan; Lv, Jie; Luo, Xiaofeng; Xia, Quan |
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| 組織名 | Department of Chinese Integrative Medicine Oncology, The First Affiliated;Hospital of Anhui Medical University, Hefei, China.;Department of Pharmacy, The First Affiliated Hospital of Anhui Medical;University, Hefei, China.;School of Pharmaceutical Sciences, Anhui Medical University, Hefei, China.;University, Hefei, China. xiaquan@ahmu.edu.cn. |
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| Pubmed リンク | https://www.ncbi.nlm.nih.gov/pubmed/41949598/ |
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