Integrative Multi-Omics Analysis Suggests a Proteostasis-Translation-Neuroimmune Axis Underlying Moxifloxacin Associated Cognitive Impairment.

Moxifloxacin, a widely used fluoroquinolone antibiotic, has been associated with cognitive impairment, but its molecular mechanisms remain unclear. Here, we applied an integrative multi-omics approach combining network toxicology, transcriptomics, molecular docking, molecular dynamics simulation, and Mendelian randomization to investigate potential mechanisms. We identified 85 overlapping targets linking moxifloxacin to cognitive dysfunction, with HSP90AB1 emerging as a central hub. Molecular docking and molecular dynamics simulations suggested a potential interaction between moxifloxacin and HSP90AB1, which was further supported by biolayer interferometry, yielding an apparent KD of 1.044 ± 0.053 μM. Transcriptomic and enrichment analyses highlighted translation-related pathways and neuroimmune-related signaling, while summary-data-based Mendelian randomization (SMR) analysis implicated APP as a genetically supported candidate component. Experimental validation in BV2 microglial cells showed a reduction in APP protein abundance without a corresponding decrease in APP mRNA, whereas SH-SY5Y cells exhibited a distinct concentration-dependent response. Together, our findings suggest that moxifloxacin-associated cognitive impairment may involve a proteostasis-translation-related-neuroimmune framework, with HSP90AB1 and APP representing candidate molecular components. This study provides a mechanistic framework for fluoroquinolone neurotoxicity and identifies candidate targets for further investigation.