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Inhibiting cholesterol synthesis halts rhabdomyosarcoma growth via ER stress and cell cycle arrest

Nebeyu Yosef Gizaw1, Kalle Kolari2, Pauliina Kallio3

  • 1Stem Cells and Metabolism Research Program, Research Programs Unit, Faculty of Medicine, University of Helsinki, 00014, Helsinki, Finland.

EMBO Molecular Medicine
|November 17, 2025
PubMed

Insights

Rhabdomyosarcoma cells exhibit a critical vulnerability in cholesterol production. Inhibiting this pathway halts cancer growth and triggers cell death, offering a novel therapeutic strategy for this pediatric sarcoma.

Area of Science:

  • Oncology
  • Metabolic Pathways
  • Molecular Biology

Background:

  • Rhabdomyosarcoma (RMS) is a common pediatric soft tissue sarcoma with poor prognoses in high-risk and relapsed cases.
  • Identifying unique metabolic vulnerabilities is crucial for developing effective RMS therapies.

Purpose of the Study:

  • To investigate the role of cholesterol biosynthesis as a metabolic vulnerability in Rhabdomyosarcoma.
  • To elucidate the regulatory mechanisms and therapeutic potential of targeting cholesterol metabolism in RMS.

Main Methods:

  • Investigated the role of transcription factor PROX1 in regulating cholesterol biosynthesis genes.
  • Utilized genetic and pharmacological inhibition of cholesterol biosynthesis in RMS cells.
  • Analyzed cell proliferation, cell cycle progression, and apoptosis induction (ER stress, PERK-ATF4-CHOP axis).
  • Assessed rescue effects of exogenous LDL cholesterol.
  • Performed clinical and single-cell RNA-seq analyses on RMS patient samples.

Main Results:

  • De novo cholesterol biosynthesis is a critical metabolic vulnerability in RMS, regulated by PROX1.
  • Inhibition of cholesterol biosynthesis impaired RMS cell proliferation, arrested cell cycle, and induced apoptosis via ER stress.
  • RMS cells showed a unique reliance on endogenous cholesterol production, unlike normal cells.
  • High expression of cholesterol biosynthesis genes correlated with poor survival and cell cycle signatures in RMS.

Conclusions:

  • Cholesterol biosynthesis is a key driver of proliferation and ER stress response in Rhabdomyosarcoma.
  • Targeting endogenous cholesterol production represents a promising, non-redundant therapeutic strategy for RMS.
  • PROX1-mediated regulation of cholesterol metabolism is a significant finding for RMS research.
Keywords:
Drug RepurposingMevalonate PathwayPediatric CancerSarcomaStatins

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