Fang-Xia-Dihuang decoction inhibits breast cancer progression induced by psychological stress via down-regulation of PI3K/AKT and JAK2/STAT3 pathways: An in vivo and a network pharmacology assessment

Background: The development and prognosis of breast cancer are intricately linked to psychological stress. In addition, depression is the most common psychological comorbidity among breast cancer survivors, and reportedly, Fang-Xia-Dihuang decoction (FXDH) can effectively manage depression in such patients. However, its pharmacological and molecular mechanisms remain obscure. Methods: Public databases were used for obtaining active components and related targets. Main active components were further verified by ultra-high-performance liquid chromatography-high-resolution mass spectrometry (UPLC-HRMS). Protein–protein interaction and enrichment analyses were taken to predict potential hub targets and related pathways. Molecule docking was used to understand the interactions between main compounds and hub targets. In addition, an animal model of breast cancer combined with depression was established to evaluate the intervention effect of FXDH and verify the pathways screened by network pharmacology. Results: 174 active components of FXDH and 163 intersection targets of FXDH, breast cancer, and depression were identified. Quercetin, methyl ferulate, luteolin, ferulaldehyde, wogonin, and diincarvilone were identified as the principal active components of FXDH. Protein–protein interaction and KEGG enrichment analyses revealed that the phosphoinositide-3-kinase–protein kinase B (PI3K/AKT) and Janus kinase/signal transducer and activator of transcription (JAK2/STAT3) signaling pathways played a crucial role in mediating the efficacy of FXDH for inhibiting breast cancer progression induced by depression. In addition, in vivo experiments revealed that FXDH ameliorated depression-like behavior in mice and inhibited excessive tumor growth in mice with breast cancer and depression. FXDH treatment downregulated the expression of epinephrine, PI3K, AKT, STAT3, and JAK2 compared with the control treatment (p < 0.05). Molecular docking verified the relationship between the six primary components of FXDH and the three most important targets, including phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), AKT, and STAT3. Conclusion: This study provides a scientific basis to support the clinical application of FXDH for improving depression-like behavior and inhibiting breast cancer progression promoted by chronic stress. The therapeutic effects FXDH may be closely related to the PI3K/AKT and JAK2/STAT3 pathways. This finding helps better understand the regulatory mechanisms underlying the efficacy of FXDH.