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Secoemestrin C exerts rapid and prominent anti-breast cancer effect in triple-negative breast cancer by inducing SLX4 and YAP degradation

Acta Pharmacologica Sinica (2026)Cite this article

Abstract

Mitochondrial DNA (mtDNA) mutations are the most common cause in aberrant mitochondrion-leading cancer, exploration of direct targeting mutated mtDNA still remains incomplete. Secoemestrin C (Sec C) is epitetrathiodioxopiperazine derived from the endophytic fungus, which exhibited a rapid and prominent anti-breast cancer effect in triple-negative breast cancer (TNBC). In this study we investigated the anticancer mechanism of Sec C, especially its effect on TNBC cells. We showed that Sec C potently inhibited the viability of both TNBC (MDA-MB-231, HS578T, BT-549) and non-TNBC (MCF-7, T47D, SK-BR-3) cells in vitro with IC50 values of 1−2 μM. In MDA-MB-231 cells, treatment with Sec C (2 μM) induced DNA breakage and subsequent apoptosis. Furthermore, treatment with Sec C (2 μM) caused mtDNA damage, mitochondrial ubiquitination and subsequent mitophagy in MDA-MB-231 and MCF-7 cells. RNA-seq analysis revealed that Sec C mitigated YAP level in time and dose-dependent manner either in MDA-MB-231 and MCF-7 cells. By re-analyzing the Sec C-responsive gene network proteins, we identified SLX4 as an oncogene promoting breast cancer development, potentially by stabilizing mtDNA to suppress pathologic mitochondrion mitophagy. Specifically, Sec C initiated MDA-MB-231 cells to yield ROS that induced SLX4 ubiquitination and degradation, leading to mtDNA damage and exacerbated mitophagy and promoted YAP degradation bypassing YAP-driven DNA repair pathways. This study not only demonstrates that Sec C is a rapid and prominent anti-breast cancer drug for TNBC, but also reveals SLX4 as a novel mtDNA stabilizer supporting breast cancer progression, positioning it as both a prognostic biomarker and therapeutic target.

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Fig. 1: Sec C exhibits potent anti-breast cancer activity in both TNBC and non-TNBC breast cancer cells.
Fig. 2: DNA breakage and subsequent apoptosis are induced by Sec C.
Fig. 3: Sec C leads to mitochondrial ubiquitination and subsequent mitophagy either in TNBC or in non-TNBC breast cancer cells.
Fig. 4: Mitochondrial DNA damage contributes to mitophagy.
Fig. 5: Activated YAP plays decisive role in Sec C-triggered DNA breakage-mediated apoptosis.
Fig. 6: SLX4-sustained mitochondrial DNA repair antagonizes mitophagy induced by Sec C.
Fig. 7: ROS-induced ubiquitination degradation of YAP and SLX4 dominates the downregulation YAP and SLX4 and anti-breast cancer effect of Sec C.
Fig. 8: Schematic diagram.

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Acknowledgements

This work was supported by Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (2021-I2M-1-030, 2023-I2M-2-001); and Beijing Natural Science Foundation (7254505).

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  1. These authors contributed equally: Xiao-jun Zhao, Yang Xu

Authors and Affiliations

  1. State Key Laboratory of Respiratory Health and Multimorbidity, Key Laboratory of Antibiotic Bioengineering, Ministry of Health, Laboratory of Oncology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China

    Xiao-jun Zhao, Cong-hui Zhang, Cong Zhao, Li Liu, Meng-yan Wang, Zi-xiang Gao, Rong-guang Shao & Wu-li Zhao

  2. Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China

    Yang Xu, Xiao-wei Wang & Yong-sheng Che

  3. Department of Breast Surgical Oncology, Cancer Institute and Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100021, China

    Li-qiang Qi

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Contributions

WLZ, YX and YSC contributed to the experimental design; WLZ and LQQ contributed to data acquisition and analysis; XJZ and CHZ carried out the immunoassays, Western blot assays, and other key experiments; XWW, MYW and LL reviewed the manuscript; CZ and ZXG assisted in data analysis; WLZ and RGS obtained the funding; WLZ and XJZ wrote the manuscript.

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Correspondence to Li-qiang Qi, Yong-sheng Che or Wu-li Zhao.

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Zhao, Xj., Xu, Y., Zhang, Ch. et al. Secoemestrin C exerts rapid and prominent anti-breast cancer effect in triple-negative breast cancer by inducing SLX4 and YAP degradation. Acta Pharmacol Sin (2026). https://doi.org/10.1038/s41401-025-01730-4

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