DHODH Blockade Induces Ferroptosis in Neuroblastoma by Modulating the Mevalonate Pathway
Journal
Molecular and Cellular Proteomics
Journal Volume
24
Journal Issue
7
ISSN
15359476
Date Issued
2025-07
Author(s)
Shir, Jui-Chia
Chen, Pin-Yu
Kuo, Chuan-Hao
Hsieh, Chiao-Hui
Chang, Hsin-Yi
Lee, Hong-Chih
Huang, Chen-Hao
Huang, Hsuan-Cheng
Abstract
Neuroblastoma is the most common heterogeneous solid tumor in children, and current treatment options remain limited, especially for high-risk patients. Previous studies have identified dihydroorotate dehydrogenase (DHODH), a key enzyme in pyrimidine synthesis, as a potential therapeutic target in cancer. However, none of the existing FDA-approved DHODH inhibitors have shown effective inhibition of neuroblastoma cell growth. To address this challenge, we employed virtual screening to discover potential DHODH-targeting drugs, identifying Regorafenib as a promising candidate. Regorafenib significantly inhibited neuroblastoma growth in both neuroblastoma cells and patient-derived organoids. To unravel the underlying molecular mechanisms, we conducted Tandem Mass Tag (TMT)-based quantitative proteomics using LC-MS/MS. Our proteomic profiling revealed substantial regulation of lipid metabolism proteins, specifically those in the mevalonate pathway, correlating with ferroptosis induction. Further analysis showed that DHODH inhibition led to a reduction in total cholesterol, cholesterol esters, disrupted lipid droplet formation, and significantly decreased the expression of Squalene Epoxidase (SQLE), a key enzyme in lipid metabolism. Notably, we also observed an increase in nuclear SQLE expression following DHODH inhibition. In summary, our study highlights DHODH blockade as a novel approach to induce ferroptosis through lipid metabolism reprogramming, underscoring DHODH as a viable therapeutic target for neuroblastoma treatment. These insights open new avenues for metabolism-based interventions in aggressive pediatric cancers.
SDGs
Publisher
American Society for Biochemistry and Molecular Biology Inc.
Description
Article number: 101014
Type
journal article