Sanhua essential oil exerts antidepressant effects in breast cancer-related depression by modulating metabolic pathways.

[BACKGROUND] Breast cancer-related depression (BCRD) is a prevalent and debilitating comorbidity that adversely affects the prognosis and quality of life of cancer patients. Sanhua essential oil (SEO), a compound aromatic formulation derived from traditional Chinese medicine, has shown potential antidepressant effects in the clinic, but its mechanisms of action remain unclear, which deserves further study.

[PURPOSE] Based on spatial metabolomics, this study aimed to investigate the effects of SEO on metabolite levels in the brain and to explore its active components and underlying mechanisms.

[METHODS] A BCRD mouse model was established using 4T1 breast cancer cell inoculation. SEO efficacy was observed based on general status and behavioral assessments. Liquid chromatography-mass spectrometry (LC-MS) was performed on brain tissues to obtain differential metabolites between groups, while functional ultrasound (fUS) was used to scan each brain region, with the correlation analysis performed. The level of differential metabolites in brain regions was detected by Desorption Electrospray Ionization Mass Spectrometry Imaging (DESI-MSI), and fUS was employed again to determine the activation of oil inhalation on brain regions. At the same time, gas chromatography-mass spectrometry (GC-MS) and LC-MS were used to identify the active ingredients and the brain-entry components of SEO, respectively. KEGG enrichment analysis was employed for pathway enrichment and target prediction. Additionally, for verification of the predicted genes, quantitative real-time polymerase chain reaction (qRT-PCR) and Western Blot (WB) were employed.

[RESULTS] SEO significantly improved depressive-like behaviors in BCRD mice, with effects comparable to fluoxetine (p < 0.05). Metabolomic analysis revealed six differential metabolites, including adenosine, glutamate, glutamine, N-acetyl-l-aspartate, taurine, and uridine diphosphate-N-acetylgalactosamine. The fUS imaging and histological staining demonstrated enhanced perfusion, structural recovery, and functional network restoration in the hippocampus, including subregions CA1, CA2, CA3, and dentate gyrus (DG). DESI-MSI revealed a significant reduction in hippocampal adenosine levels and elevated glutamate/glutamine ratios in the 4T1 group, while both FLU and ESS groups exhibited adenosine, glutamate, and glutamine profiles closer to Control group levels. GC-MS analysis identified 31 bioactive components in SEO, with 2-phenylethanol (40.39%) and eugenol (21.98%) as dominant constituents, followed by linalool (9.42%), citronellyl formate (5.67%), and nopinene (5.18%). Notably, eugenol and 2-phenylethanol were confirmed as brain-penetrant components, with eugenol demonstrating higher cerebral accumulation. KEGG pathway enrichment highlighted hsa01100 (Metabolic Pathways) as the shared hub linking differential metabolites and essential oil brain-entry components. ALOX15 and CAII were confirmed to be the main targets.

[CONCLUSION] SEO exerts antidepressant-like effects in BCRD by modulating hippocampus-centered metabolic and functional networks. Eugenol and 2-phenylethanol were identified as key brain-entry components to function through metabolic pathways. ALOX15 inhibition and CAII improvement were proven to be the main molecular mechanisms. These findings provide mechanistic insights and identify SEO as a promising plant-derived therapeutic candidate for managing cancer-related depression.