DHODH Blockade Induces Ferroptosis in Neuroblastoma by Modulating the Mevalonate Pathway

Area of Science:

• Oncology
• Biochemistry
• Metabolic Pathways

Background:

• Neuroblastoma, a common pediatric cancer, has limited treatment options, especially for high-risk cases.
• Dihydroorotate dehydrogenase (DHODH) is a validated cancer target, but existing inhibitors lack efficacy in neuroblastoma.
• Targeting DHODH offers a potential therapeutic avenue for aggressive pediatric tumors.

Purpose of the Study:

• To identify novel DHODH inhibitors for neuroblastoma treatment.
• To investigate the molecular mechanisms by which DHODH inhibition affects neuroblastoma growth.
• To explore the role of lipid metabolism and ferroptosis in DHODH-targeted neuroblastoma therapy.

Main Methods:

• Virtual screening to identify potential DHODH inhibitors.
• In vitro studies using neuroblastoma cell lines and patient-derived organoids.
• Tandem Mass Tag (TMT)-based quantitative proteomics (LC-MS/MS) to analyze proteomic changes.
• Analysis of lipid metabolism, including cholesterol and Squalene Epoxidase (SQLE) expression.

Main Results:

• Regorafenib was identified as a potent DHODH inhibitor, significantly reducing neuroblastoma cell and organoid growth.
• Proteomic analysis revealed DHODH inhibition-induced alterations in lipid metabolism, particularly the mevalonate pathway, correlating with ferroptosis.
• DHODH inhibition decreased cholesterol and cholesterol esters, disrupted lipid droplets, and reduced SQLE expression, while increasing nuclear SQLE.

Conclusions:

• DHODH blockade is a promising strategy to induce ferroptosis in neuroblastoma via lipid metabolism reprogramming.
• Regorafenib demonstrates efficacy against neuroblastoma by targeting DHODH and altering lipid homeostasis.
• This study establishes DHODH as a viable therapeutic target and highlights metabolic interventions for pediatric cancers.