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Vesicle-mediated mitochondrial clearance presents an actionable metabolic vulnerability in triple-negative breast

Jody Vykoukal1, Yihui Chen1, Mingxin Zuo1

  • 1Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Cell Reports. Medicine
|December 17, 2025
PubMed

Insights

Triple-negative breast cancer cells survive by salvaging sphingomyelin and clearing mitochondrial damage via extracellular vesicles. Inhibiting this pathway with eliglustat triggers cell death and slows tumor growth.

Area of Science:

  • Oncology
  • Molecular Biology
  • Metabolic Research

Background:

  • Selective mitochondrial autophagy, or mitophagy, promotes cancer cell survival and progression, particularly in triple-negative breast cancer (TNBC).
  • Understanding metabolic adaptations supporting mitochondrial quality control is crucial for developing novel TNBC therapies.

Purpose of the Study:

  • To investigate metabolic adaptations enabling mitochondrial quality control in TNBC.
  • To identify and target a novel onco-metabolic pathway involving sphingolipid metabolism.

Main Methods:

  • Integrated multi-omics analysis combined with functional experimental validation.
  • Investigation of extracellular sphingomyelin salvaging and extracellular vesicle-mediated mitochondrial clearance.
  • Pharmacological targeting using eliglustat, a glucosylceramide synthase inhibitor.

Main Results:

  • A novel mitochondrial quality control mechanism complementary to mitophagy was identified, involving heightened extracellular sphingomyelin salvaging in TNBC.
  • Extracellular vesicle-mediated clearance of mitochondrial damage was observed.
  • Eliglustat treatment induced ceramide-mediated compensatory mitophagy, leading to cancer cell death in vitro.
  • Eliglustat attenuated tumor growth and prolonged survival in preclinical TNBC models (syngeneic and xenograft).

Conclusions:

  • Aberrant sphingolipid metabolism represents an actionable metabolic vulnerability in TNBC.
  • Targeting this pathway with eliglustat offers a promising therapeutic strategy for TNBC.
Keywords:
autophagyeliglustatextracellular vesiclesglucosylceramide synthasemitochondriasphingolipidstriple-negative breast cancer

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