# NOTCH3 Drives Fatty Acid Oxidation and Ferroptosis Resistance in Aggressive Meningiomas

## TL;DR

This study shows that NOTCH3 promotes fatty acid metabolism and protects aggressive meningioma cells from a type of cell death called ferroptosis.

## Contribution

The paper reveals a novel metabolic role of NOTCH3 in meningiomas, linking it to fatty acid oxidation and ferroptosis resistance.

## Key findings

- NOTCH3 drives a metabolic shift toward fatty acid oxidation in meningioma cells.
- NOTCH3 overexpression increases resistance to ferroptosis and enhances mitochondrial respiration.
- CD36 expression correlates with NOTCH3 activity and supports fatty acid uptake in these tumors.

## Abstract

NOTCH3 is increasingly implicated for its oncogenic role in many malignancies, including meningiomas. While prior work has linked NOTCH3 expression to higher-grade meningiomas and treatment resistance, the metabolic phenotype of NOTCH3 activation remains unexplored in meningioma.

We performed single-cell RNA sequencing on NOTCH3 + human meningioma cell lines. Using the CH157-MN meningioma cell model, we overexpressed NOTCH3 intracellular domain (ICD) and performed untargeted metabolomic, lipidomic, and bulk RNA sequencing analyses as well as functional metabolic assays.

We show that NOTCH3 mediates a metabolic shift towards fatty acid oxidation (FAO), depleting lipid availability and conferring resistance to ferroptosis. Single-cell RNA sequencing revealed a correlation with CD36, a key fatty acid transporter. Furthermore, patient-derived primary meningioma lines stratified by NOTCH3 expression confirmed higher CD36 expression and increased maximal mitochondrial respiration in NOTCH3-high cells in the presence of palmitate, supporting enhanced FAO. NOTCH3 ICD overexpression (OE) exhibited depletion of fatty acid pools, alongside transcriptional upregulation of canonical FAO genes. Functional mitochondrial assays confirmed elevated oxidative respiration in the presence of palmitate compared with controls. Additionally, NOTCH3 OE cells exhibit increased resistance to RSL3-induced ferroptosis, a phenotype that was reversed with CPT1.

These data establish a link between NOTCH3 signaling, lipid metabolic reprogramming, and ferroptosis evasion in aggressive meningioma cells. This metabolic shift may contribute to the malignant behavior observed in NOTCH3 + meningiomas, offering new insight into the biochemical vulnerabilities of these tumors.