Exploring Molecular Mechanism of Fluoxetine in Animal Models of Depression via Integrated Metabolomic and Proteomic Analysis

ABSTRACT Fluoxetine is a widely used antidepressant, yet integrated analyses of its molecular mechanism remain limited. This study systematically investigated potential molecular mechanisms underlying the antidepressant effects of fluoxetine by integrating these scattered data. Using the ProMENDA database, we identified metabolites and proteins altered by fluoxetine in the brain of animal models of depression. We curated 273 differentially expressed metabolite entries and 791 differentially expressed protein entries from fluoxetine treatment and performed vote‐counting, pathway enrichment, pathway crosstalk and drug‐associated metabolite set enrichment analyses. Vote‐counting analysis showed altered neurotransmitter levels, including increased levels of monoamines and decreased levels of neurotoxic quinolinic acid and glutamate. The results of pathway analyses based on both altered metabolites and proteins showed 121 significantly enriched pathways. Pathway crosstalk analysis identified four pathway‐based modules, which were mainly involved in amino acid metabolism, neurotransmitters and multiple biological processes. Drug‐associated metabolite set enrichment analysis revealed 76 significantly enriched drug‐related pathways, which were mainly involved in antidepressants. This study provides a comprehensive understanding of the antidepressant effects of fluoxetine, which may provide insights for the development of novel antidepressants.