Dual targeting of lipogenesis and PUFAs homeostasis by compound kushen injection suppresses breast cancer bone metastasis

Background

Bone metastasis is a major cause of mortality in patients with advanced breast cancer, yet effective therapies remain limited. Compound Kushen Injection (CKI), a standardized Traditional Chinese Medicine (TCM) formulation, has demonstrated clinical efficacy in relieving cancer-related pain and improving quality of life in patients with bone metastases. However, the effects of CKI on breast cancer bone metastasis and its action mechanisms remain to be elucidated.

Purpose

This study aims to determine the effect of CKI on breast cancer bone metastasis and explore its underlying molecular mechanisms.

Methods

In vitro, human breast cancer (MDA-MB-231) and bone-metastatic (MDA-BoM-1833) cell lines were used to assess the cytotoxic, anti-proliferative, and anti-migratory effects of CKI via MTT, colony formation, Transwell, wound healing, and flow cytometry. Two mouse models of breast cancer bone metastasis were established via left ventricular and tibial injection. Tumor progression was monitored by in vivo imaging, and therapeutic outcomes were evaluated using micro-CT, histopathology, and survival analysis. Multi-omics approaches—including metabolomics, transcriptomics, and proteomics—combined with network pharmacology, were used to identify CKI targets and pathways. Key findings were validated by qRT-PCR, Western blotting, lipid staining, ROS analysis, and mitochondrial function assays.

Results

CKI exhibits selective cytotoxicity against bone-tropic breast cancer cells and significantly reduces tumor burden in both intracardiac and intratibial metastatic mouse models, while maintaining a favorable safety profile. Metabolomics reveals that CKI treatment leads to the accumulation of polyunsaturated fatty acids (PUFAs). Multi-omics integration uncovers CKI-mediated inhibition of the HIF-1α/SREBP1 axis, suppressing de novo lipogenesis (DNL), and downregulation of the PPARα/SLC47A1 pathway, impairing fatty acid oxidation and lipid efflux. This dual blockade results in intracellular PUFAs accumulation and elevated lipid peroxidation, triggering mitochondrial dysfunction and oxidative stress-induced cell death.

Conclusion

CKI, a clinically approved traditional Chinese medicine, as a potent metabolic disruptor that impairs breast cancer bone metastasis through coordinated reprogramming of lipid metabolism and preservation of bone integrity.