Abstract Background Sanjie Xiaoliu Granule (XJXLG), a traditional multi-herbal prescription widely used in Chinese medicine, has been historically applied to “disperse nodules, soothe the liver, and relieve depression.” It is clinically prescribed for patients with breast lumps, emotional stagnation, and cancer-related depression. However, the pharmacological basis underlying its dual anticancer and antidepressant effects remains poorly understood.This study aimed to evaluate the therapeutic efficacy and elucidate the molecular and metabolic mechanisms of XJXLG in breast cancer with depression (BCD) through integrated experimental and bioinformatics approaches. In vivo and in vitro BCD models were established to assess tumor growth, behavioral performance, and inflammatory cytokine levels. Liquid chromatography–mass spectrometry (LC–MS) identified active constituents of XJXLG. Bioinformatics analyses were used to screen key genes and signaling pathways, followed by validation via qRT-PCR and Western blot. Untargeted metabolomics was applied to explore the metabolic alterations in tumor tissues after XJXLG intervention. Results XJXLG significantly inhibited breast cancer cell proliferation, migration, and invasion, and improved depressive-like behaviors in tumor-bearing mice. The formula upregulated MAOA, LTF, PTGER3, and IGFBP6 expression and regulated multiple signaling pathways, including PPAR, AMPK, and PI3K-Akt/mTOR, which are involved in lipid metabolism, inflammation, and neurotransmitter synthesis. Untargeted metabolomics further revealed that XJXLG restored metabolic homeostasis by modulating lipid, amino acid, and energy metabolism, alleviating oxidative stress, and rebalancing neurotransmitter-related metabolites. These findings suggest that XJXLG exerts integrative effects through multi-target, multi-pathway regulation. Conclusions XJXLG demonstrates a synergistic anticancer and antidepressant effect through the modulation of metabolic and signaling networks associated with inflammation, oxidative stress, and neurotransmission. These results provide experimental evidence for its ethnopharmacological application in managing body–mind comorbidities such as breast cancer with depression and highlight its potential as a safe and effective adjunct therapy.
Z et al. (Mon,) studied this question.