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Background <p>Triple-negative breast cancer (TNBC) is characterized by aggressive metastatic behavior and limited therapeutic options. Although metabolic reprogramming is increasingly recognized as a hallmark of TNBC, the mechanisms by which specific metabolic enzymes and intermediates drive metastasis remain poorly defined.</p> Methods <p>We performed untargeted metabolomic profiling on TNBC tumors and matched normal tissues to identify dysregulated metabolic pathways. Functional assays, chemoproteomic succination profiling, molecular interaction analyses, and in vivo cancer metastasis models were used to define the mechanistic and biological consequences of altered metabolism. In <i>vitro</i> experiments validated the effects of N-acetylcysteine (NAC) in TNBC cell lines.</p> Results <p>Metabolomic analyses revealed aberrant activation of the alanine–aspartate–glutamate axis and upregulation of adenylosuccinate lyase (ADSL) in TNBC. ADSL promoted tumor cell proliferation and metastasis by generating fumarate, which accumulated primarily through covalent protein succination. Chemoproteomic profiling identified the cell polarity regulator SCRIB as a critical fumarate target. Fumarate-mediated succination of SCRIB impaired its membrane localization, promoted epithelial–mesenchymal transition, and facilitated aberrant interaction with the mTORC2 component RICTOR, leading to activation of AKT/mTOR signaling. Genetic disruption of SCRIB succination abrogated these effects. Importantly, pharmacological perturbation of fumarate using NAC reduced SCRIB succination and attenuated the malignant phenotypes of TNBC cells in vitro.</p> Conclusions <p>These findings identify an ADSL-fumarate-SCRIB signaling axis that links metabolic reprogramming to the loss of cell polarity and activation of pro-metastatic signaling in TNBC. Targeting fumarate-mediated protein succination represents a previously unrecognized and experimental vulnerability in TNBC.</p>

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ADSL drives fumarate mediated scrib-rictor complex formation to promote metastasis dissemination in triple-negative breast cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月20日

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  • Yidan Fan,
  • Xiaofang He,
  • Wei Deng,
  • Jianxiang Sun,
  • Jinkun Qin,
  • Yutian Zou,
  • Xudong Zhu,
  • Xiaoming Xie,
  • Hailin Tang,
  • Ping Yu,
  • Weiyu Bao,
  • Feng Ye

摘要

Background

Triple-negative breast cancer (TNBC) is characterized by aggressive metastatic behavior and limited therapeutic options. Although metabolic reprogramming is increasingly recognized as a hallmark of TNBC, the mechanisms by which specific metabolic enzymes and intermediates drive metastasis remain poorly defined.

Methods

We performed untargeted metabolomic profiling on TNBC tumors and matched normal tissues to identify dysregulated metabolic pathways. Functional assays, chemoproteomic succination profiling, molecular interaction analyses, and in vivo cancer metastasis models were used to define the mechanistic and biological consequences of altered metabolism. In vitro experiments validated the effects of N-acetylcysteine (NAC) in TNBC cell lines.

Results

Metabolomic analyses revealed aberrant activation of the alanine–aspartate–glutamate axis and upregulation of adenylosuccinate lyase (ADSL) in TNBC. ADSL promoted tumor cell proliferation and metastasis by generating fumarate, which accumulated primarily through covalent protein succination. Chemoproteomic profiling identified the cell polarity regulator SCRIB as a critical fumarate target. Fumarate-mediated succination of SCRIB impaired its membrane localization, promoted epithelial–mesenchymal transition, and facilitated aberrant interaction with the mTORC2 component RICTOR, leading to activation of AKT/mTOR signaling. Genetic disruption of SCRIB succination abrogated these effects. Importantly, pharmacological perturbation of fumarate using NAC reduced SCRIB succination and attenuated the malignant phenotypes of TNBC cells in vitro.

Conclusions

These findings identify an ADSL-fumarate-SCRIB signaling axis that links metabolic reprogramming to the loss of cell polarity and activation of pro-metastatic signaling in TNBC. Targeting fumarate-mediated protein succination represents a previously unrecognized and experimental vulnerability in TNBC.