Integrative analysis of levofloxacin-induced liver injury: Insights from pharmacovigilance, human liver organoids, and extracellular vesicle proteomics
Abstract
BACKGROUND: Levofloxacin (LVX), a widely used fluoroquinolone antibiotic, is generally considered to have low hepatotoxic potential compared to its analog trovafloxacin (TVX). Although considered relatively safe, LVX has been implicated in Drug-induced liver injury (DILI) cases, prompting the need for a comprehensive mechanistic assessment.
METHODS: This study employed an integrated strategy combining real-world pharmacovigilance analysis based on FDA Adverse Event Reporting System (FAERS), human liver organoid modeling, and extracellular vesicle (EV) proteomics to systematically assess LVX-associated DILI risks and mechanisms.
RESULTS: A total of 1671 LVX-related DILI cases were identified in FAERS, with a predominance in males and individuals aged 45-65. Disproportionality analysis revealed statistically significant signals indicative of cholestatic liver injury phenotypes, including mixed liver injury, cholestasis, and conjugated hyperbilirubinemia, etc. Furthermore, liver organoid assays revealed that LVX induced moderate hepatocellular injury, which was less severe than that caused by TVX. EV proteomic analysis from LVX-exposed organoids identified glycolysis as the most significantly enriched pathway, with notable upregulation of phosphoglycerate kinase 1 (PGK1), lactate dehydrogenase A (LDHA), and fructose-bisphosphate aldolase A (ALDOA). The expression of these three key glycolysis-related targets was further validated by RT-qPCR and proteomic analysis, and molecular…
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