Molecular basis of breast cancer with comorbid depression and the mechanistic insights of Xiaoyaosan in treating breast cancer-associated depression

Depression and breast cancer (BC) have been found to have a shared genetic basis, multiple loci of effect, and a presumed causal relationship. The treatment of BC combined with depression poses significant challenges. This study aims to use bioinformatics and network pharmacology to explore the molecular basis of BC combined with depression and to elucidate the potential mechanisms of Xiaoyaosan (XYS) in treating this disease. The molecular background of BC complicated with depression was discovered via data mining and bioinformatics. The molecular mechanism of XYS in the treatment of BC with depression was investigated by network pharmacology. The binding affinity between targets and active compounds was evaluated by molecular docking. The impact of XYS on the gene and protein expression of matrix metallopeptidase 9 (MMP9) in microglial cells was assessed using RT-quantitative PCR and western blot analysis, respectively. Differential expression analysis was conducted to identify genes associated with BC, revealing that 2958 genes were involved, with 277 of these genes also being related to depression. XYS was found to contain 173 active compounds and 342 targets, with 44 of these targets being involved in regulating the progression of BC and depression. Enrichment analysis was performed to identify pathways associated with these targets, revealing that they were related to cell proliferation, catalytic activity, cell communication, and interleukin-18 signaling and LXR/RXR activation. Network analysis was conducted to identify key targets of Xiaoyaosan in treating BC combined with depression, with EGF, interleukin 6, epidermal growth factor receptor, and peroxisome proliferator activated receptor gamma being identified as important targets. Molecular docking was also performed to assess the binding affinity between key targets and active compounds, with puerarin showing the strongest affinity for MMP9. In microglial cells, XYS significantly enhances the gene and protein expression of MMP9. This study elucidated the pharmacological mechanism of co-treatment for BC patients complicated with depression and the pharmacological mechanism of XYS against BC plus depression.