Regulation of inflammation by Chaihu-Shugan-San: Targeting the IL-17/ NF-κB pathway to combat breast cancer-related depression

Background Breast cancer-related depression (BCRD) is one of the severest comorbidities, affecting the quality of life and the treatment efficacy in BC patients. Chaihu-Shugan-San (CSS), a traditional Chinese medicine presents a potential therapeutic method in BCRD. Purpose The main purpose of the research was to investigate the effects of CSS on BCRD in a mouse model and to elucidate its mechanisms, particularly its impact on microglial polarization through the IL-17/ NF-κB pathway. Methods A mouse BCRD model was constructed and treated with CSS. Behavioral testing, biochemical parameters, H&E staining, and small animal imaging were used to assess the depressive-like behaviors and tumor growth in mice. RNA sequencing analysis was performed, and the data were authenticated by Western blot as well as quantitative qRT-PCR to explore the mechanisms of CSS treatment in BCRD. The BV2 microglia were stimulated with LPS in vitro and intervened by IL-17 protein, IL-17 antagonist, IMD-0354, and CSS. In addition, western blot was utilized to confirm the expression of IL-17/ NF-κB pathway-related factors. Molecular docking technique and UPLC-Q-TOF/MS were used to find out the key active components of CSS. Results CSS treatment significantly improved depression-like behaviors and retarded tumor growth in mice. Through RNA sequencing analysis, it was indicated that the improvement of BCRD by CSS was highly associated with the regulation of the IL-17/ NF-κB pathway. Western blot and qRT-PCR outcomes suggested that CSS inhibited the IL-17/ NF-κB pathway, facilitating the transformation from pro-inflammatory M1 microglial phenotype to anti-inflammatory M2 phenotype, contributing to the reduction of neuroinflammation. In vitro experiments demonstrated that CSS modulated the immune reaction through the induction of phenotypic transformation of microglia from M1 toward M2 phenotype, hence reducing neuroinflammation. Notably, this therapeutic effect of CSS was highly similar to the effects of IL-17 antagonists, thus suggesting that CSS alleviates the symptoms of BCRD by targeting IL-17. Molecular docking revealed that the major bioactive compounds in CSS were Saikosaponin A, Saikosaponin C, and Saikosaponin D. Conclusion This study systematically demonstrates that CSS ameliorates BCRD by suppressing the IL-17/ NF-κB pathway as well as modulating microglial polarization and elucidates the dual function of IL-17. These results point to a new multi-target intervention strategy for BCRD treatment and fully reflect the holistic effects of CSS by its multi-component as well as multi-target actions.