Xiaoyao San reverses the pro-breast cancer effect of depression by inhibiting glutamate levels in intestinal flora.

[ETHNOPHARMACOLOGICAL RELEVANCE] Xiaoyao San (XYS), a traditional Chinese herbal remedy used to soothe the liver and resolve depression, has long been employed in the treatment of depression and has recently demonstrated promising effects against breast cancer. However, the exact mechanism of its action against depressive breast cancer remains unclear.

[AIM OF THE STUDY] This study aimed to identify the molecular targets of XYS responsible for reversing depressive breast cancer and to elucidate its underlying mechanisms.

[MATERIALS AND METHODS] Behavioral and histopathological analyses will be used to validate the efficacy of XYS in ameliorating depressive breast cancer in chronic unpredictable mild stress (CUMS) models. The differentially expressed genes associated with depressive breast cancer were identified by transcriptomic technology, and network pharmacology was used to predict the target genes of XYS. Furthermore, a pseudogerm-free mouse model was established to explore the mechanistic basis of XYS intervention, and intestinal metabolomics was integrated with 16S rDNA gene sequencing to assess microbiota-related pathways.

[RESULTS] XYS significantly reversed depression-like behaviors and tumor growth-promoting effects in a CUMS model. Taken together, the results of the transcriptomic data and network pharmacology predictions indicate that XYS may alleviate depression-related breast cancer through modulation of the glutamate receptor signaling pathway. Additional metabolomics and 16S rDNA sequencing studies demonstrated that XYS altered glutamate metabolism in depressive breast cancer mice. Furthermore, the elimination of intestinal flora by antibiotics weakened the efficacy of XYS in the treatment of depressive breast cancer.

[CONCLUSION] These findings suggest that XYS has potential therapeutic value for treating depressive breast cancer through inhibition of glutamate level within gut microbiota.