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Nobiletin and polydatin synergistically alleviate triple-negative breast cancer liver metastasis via suppressing ECM1a-mediated fatty acid biosynthesis

Acta Pharmacologica Sinica (2025)Cite this article

Abstract

Breast cancer liver metastasis (BCLM) is characterized by high incidence and poor prognosis, lacking effective therapeutic strategies. Recent evidence suggests that lipid metabolic reprogramming plays an important role in the initiation and development of BC metastasis. In clinical practice of traditional Chinese medicine, Citri Reticulatae Pericarpium-Reynoutria japonica Houtt. (CR) herb pair is used for the treatment of BCLM. In this study, we explored the active ingredients of CR herb pair and underlying mechanisms against BCLM. By RNA sequencing analysis, we showed that extracellular matrix protein 1 isoform a (ECM1a), a secreted multifunctional glycoprotein, was a vital link between liver-metastatic potential and fatty acid (FA)-biosynthesis program in triple-negative breast cancer (TNBC) cells. Through integrative screening approaches, nobiletin and polydatin were identified as the core active ingredients of the CR herb pair. As an ECM1a inhibitor, nobiletin+polydatin combination exerted superior synergistic inhibitory effects on TNBC cells and liver-metastatic xenograft models. We further revealed that nobiletin+polydatin combination impaired ECM1a-mediated tumor FA-biosynthesis program by downregulating PI3K/AKT/mTOR/SREBPs signaling. These results support nobiletin+polydatin combination as a novel and promising therapeutic option for BCLM and highlight the role of ECM1a as the targetable master regulator of lipid metabolism in BCLM.

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Fig. 1: ECM1a is a potential driver of FA synthesis in TNBC liver metastasis.
Fig. 2: Identification of the absorbed prototype compounds of CR herb pair in mouse plasma.
Fig. 3: Screening of core active ingredients targeting ECM1 in CR herb pair.
Fig. 4: Nob + PD combination synergistically inhibits proliferation, migration, invasion and EMT properties in TNBC cells.
Fig. 5: Nob + PD combination synergistically alleviates liver metastasis in TNBC mice.
Fig. 6: Nob + PD combination synergistically suppresses FA biosynthesis in vitro and in vivo.
Fig. 7: Nob + PD combination synergistically reverses FA-induced TNBC liver metastasis in vitro and in vivo.
Fig. 8: Nob + PD combination synergistically downregulates FA synthesis in TNBC cells via suppressing ECM1a/PI3K/AKT/mTOR pathway.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (Grant numbers: 82574635 and 82174016).

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Authors and Affiliations

  1. Institute of Chinese Traditional Surgery, Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China

    Jue Wang, Wei-wei Liu, Qiong-lian Huang, Han-juan Ning & Xiang-hui Han

  2. Department of Liver Disease, Shanghai Yueyang Integrated Traditional Chinese Medicine and Western Medicine Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 200080, China

    Jian-yi Wang

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Contributions

JW conducted the main experiments and data analysis. WWL contributed to the data interpretation and figure preparation. HJN and QLH carried out the experiments in molecular biology. JYW and XHH designed this research and wrote the manuscript. All authors approved the final manuscript.

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Correspondence to Jian-yi Wang or Xiang-hui Han.

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Wang, J., Liu, Ww., Huang, Ql. et al. Nobiletin and polydatin synergistically alleviate triple-negative breast cancer liver metastasis via suppressing ECM1a-mediated fatty acid biosynthesis. Acta Pharmacol Sin (2025). https://doi.org/10.1038/s41401-025-01669-6

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