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Updated: Jan 6, 2026

Author Spotlight: Tracing the Ferroptotic Signatures and Cell Death Dynamics in Medulloblastoma for Advanced Therapeutics
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Author Spotlight: Tracing the Ferroptotic Signatures and Cell Death Dynamics in Medulloblastoma for Advanced Therapeutics

Published on: March 15, 2024

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NOTCH3 drives fatty acid oxidation and ferroptosis resistance in aggressive meningiomas

Nishanth S Sadagopan1,2, Mateo Gomez1,2, Shashwat Tripathi1,2

  • 1Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.

Journal of Neuro-Oncology
|September 9, 2025
PubMed
Abstract

Insights

NOTCH3 signaling drives aggressive meningioma by promoting fatty acid oxidation, depleting lipids, and conferring resistance to ferroptosis. This metabolic reprogramming highlights potential therapeutic vulnerabilities in NOTCH3-positive tumors.

Area of Science:

  • Oncology
  • Cancer Metabolism
  • Molecular Biology

Background:

  • NOTCH3 signaling is implicated in various cancers, including meningiomas.
  • Prior research links NOTCH3 expression to higher-grade meningiomas and treatment resistance.
  • The metabolic phenotype associated with NOTCH3 activation in meningioma remains largely unexplored.

Purpose of the Study:

  • To investigate the metabolic consequences of NOTCH3 activation in meningioma.
  • To explore the role of NOTCH3 in lipid metabolism and ferroptosis evasion.
  • To identify potential therapeutic targets based on NOTCH3-mediated metabolic alterations.

Main Methods:

  • Single-cell RNA sequencing of NOTCH3-positive meningioma cell lines.
  • Overexpression of NOTCH3 intracellular domain (ICD) in the CH157-MN cell model.
  • Untargeted metabolomic, lipidomic, bulk RNA sequencing, and functional metabolic assays.

Main Results:

  • NOTCH3 activation promotes fatty acid oxidation (FAO), depleting lipid pools and increasing resistance to ferroptosis.
  • NOTCH3 expression correlates with CD36, a fatty acid transporter, and enhanced mitochondrial respiration.
  • Overexpression of NOTCH3 ICD leads to upregulation of FAO genes and resistance to ferroptosis, reversible with CPT1 inhibition.

Conclusions:

  • NOTCH3 signaling is linked to lipid metabolic reprogramming and ferroptosis evasion in aggressive meningioma.
  • This metabolic shift contributes to the malignant behavior of NOTCH3-positive meningiomas.
  • The findings offer novel insights into the biochemical vulnerabilities of meningioma, suggesting potential therapeutic strategies targeting NOTCH3-driven metabolism.
Keywords:
NOTCH3Fatty acid oxidationFerroptosisMeningioma metabolismTumor microenvironment

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