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Background <p>Levofloxacin is a widely used quinolone antibiotic with good antibacterial properties and high oral utilization. Nevertheless, it is associated with adverse reactions affecting central nervous system (CNS), which in severe cases may include cognitive impairment and epilepsy --potentially life-threatening outcomes. And research on factors contributing to these severe adverse reactions remains limited. Therefore, it is of great significance to investigate the molecular mechanisms underlying levofloxacin-induced CNS injury.</p> Methods <p>This study investigated the molecular mechanisms underlying levofloxacin-induced CNS injury by integrating bioinformatics, network toxicology, molecular docking and dynamics simulation. Differentially expressed genes were identified from databases like GEO and Genecards, leading to 33 overlapping drug-disease targets. Subsequently, Protein interaction networks and cytoHubba algorithms identified HSP90AA1 as a key target. Its central role was further validated by receiver operating characteristics (ROC) curves and molecular dynamics simulation. Additionally, GSEA analysis revealed that several pathways that are likely involved.</p> Results <p>This study revealed that levofloxacin may induces CNS injury likely by targeting HSP90AA1 and perturbing key signaling pathways. The key signaling pathways include NOD-like receptor (NLR) signaling pathway, neutrophil extracellular trap (NET) formation, and MAPK signaling pathway. Furthermore, molecular docking revealed a strong binding affinity between levofloxacin and HSP90AA1(-9.9&#xa0;kcal/mol) and molecular dynamics simulation over 100-ns simulations made further validation.</p> Conclusion <p>These findings indicate that levofloxacin disrupts neuronal homeostasis via HSP90AA1-mediated inflammatory pathways, providing critical implications for optimizing clinical application of levofloxacin and mitigating its CNS-related risks.</p> Graphical Abstract <p></p>

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Revealing the molecular mechanisms of levofloxacin-induced cognitive impairment and epilepsy: an integrated bioinformatics and molecular dynamics simulation

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月25日

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  • Yixuan Zhang,
  • Yimao Wu,
  • Jing Du,
  • Jingtao Chen,
  • Haocheng Yu,
  • Kaibo Yang,
  • Fen Huang,
  • Jianjun Xie,
  • Jiangyun Peng

摘要

Background

Levofloxacin is a widely used quinolone antibiotic with good antibacterial properties and high oral utilization. Nevertheless, it is associated with adverse reactions affecting central nervous system (CNS), which in severe cases may include cognitive impairment and epilepsy --potentially life-threatening outcomes. And research on factors contributing to these severe adverse reactions remains limited. Therefore, it is of great significance to investigate the molecular mechanisms underlying levofloxacin-induced CNS injury.

Methods

This study investigated the molecular mechanisms underlying levofloxacin-induced CNS injury by integrating bioinformatics, network toxicology, molecular docking and dynamics simulation. Differentially expressed genes were identified from databases like GEO and Genecards, leading to 33 overlapping drug-disease targets. Subsequently, Protein interaction networks and cytoHubba algorithms identified HSP90AA1 as a key target. Its central role was further validated by receiver operating characteristics (ROC) curves and molecular dynamics simulation. Additionally, GSEA analysis revealed that several pathways that are likely involved.

Results

This study revealed that levofloxacin may induces CNS injury likely by targeting HSP90AA1 and perturbing key signaling pathways. The key signaling pathways include NOD-like receptor (NLR) signaling pathway, neutrophil extracellular trap (NET) formation, and MAPK signaling pathway. Furthermore, molecular docking revealed a strong binding affinity between levofloxacin and HSP90AA1(-9.9 kcal/mol) and molecular dynamics simulation over 100-ns simulations made further validation.

Conclusion

These findings indicate that levofloxacin disrupts neuronal homeostasis via HSP90AA1-mediated inflammatory pathways, providing critical implications for optimizing clinical application of levofloxacin and mitigating its CNS-related risks.

Graphical Abstract