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Updated: Jul 1, 2025
Author Spotlight: Tracing the Ferroptotic Signatures and Cell Death Dynamics in Medulloblastoma for Advanced Therapeutics
Published on: March 15, 2024
Enzyme-Mediated Bioorthogonal Cascade Catalytic Reaction for Metabolism Intervention and Enhanced Ferroptosis on
Qi Wang1, Xiangze Li1, Zhiyao Cao1
1Department of General Surgery, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, P. R. China.
Abstract:
It remains a tremendous challenge to explore effective therapeutic modalities against neuroblastoma, a lethal cancer of the sympathetic nervous system with poor prognosis and disappointing treatment outcomes. Considering the limitations of conventional treatment modalities and the intrinsic vulnerability of neuroblastoma, we herein develop a pioneering sequential catalytic therapeutic system that utilizes lactate oxidase (LOx)/horseradish peroxidase (HRP)-loaded amorphous zinc metal-organic framework, named LOx/HRP-aZIF, in combination with a 3-indole-acetic acid (IAA) prodrug. On the basis of abnormal lactate accumulation that occurs in the tumor microenvironment, the cascade reaction of LOx and HRP consumes endogenous glutathione and a reduced form of nicotinamide adenine dinucleotide to achieve the first stage of killing cancer cells via antioxidative incapacitation and electron transport chain interference. Furthermore, the generation of reactive oxygen species induced by HRP and IAA through bioorthogonal catalysis promotes ferritin degradation and lipid peroxidation, ultimately provoking self-enhanced ferroptosis with positive feedback by initiating an endogenous Fenton reaction. This work highlights the superiority of the natural enzyme-dependent cascade and bioorthogonal catalytic reaction, offering a paradigm for synergistically enzyme-based metabolism-ferroptosis anticancer therapy.
Insights
This study introduces a novel sequential catalytic therapy for neuroblastoma, using enzymes and a prodrug to trigger self-enhanced ferroptosis. This approach targets cancer metabolism and induces cell death, offering a promising new treatment strategy.
Area of Science:
- Biochemistry
- Oncology
- Materials Science
Background:
- Neuroblastoma is a lethal pediatric cancer with poor treatment outcomes.
- Conventional therapies face limitations, necessitating innovative treatment strategies.
Purpose of the Study:
- To develop a pioneering sequential catalytic therapeutic system for neuroblastoma treatment.
- To leverage tumor microenvironment abnormalities for targeted cancer therapy.
Main Methods:
- Utilized lactate oxidase (LOx)/horseradish peroxidase (HRP)-loaded amorphous zinc metal-organic framework (LOx/HRP-aZIF).
- Combined LOx/HRP-aZIF with a 3-indole-acetic acid (IAA) prodrug for synergistic effects.
- Exploited abnormal lactate accumulation in the tumor microenvironment to initiate cascade reactions.
Main Results:
- The cascade reaction consumed endogenous glutathione and reduced nicotinamide adenine dinucleotide, leading to cancer cell death via antioxidative incapacitation and electron transport chain interference.
- HRP and IAA generated reactive oxygen species, promoting ferritin degradation and lipid peroxidation.
- Achieved self-enhanced ferroptosis through an endogenous Fenton reaction, demonstrating a positive feedback loop for cancer cell elimination.
Conclusions:
- The developed system offers a superior, enzyme-dependent cascade and bioorthogonal catalytic reaction for neuroblastoma therapy.
- This approach provides a novel paradigm for synergistic enzyme-based metabolism-ferroptosis anticancer therapy.
- Highlights the potential of combining metabolic targeting with ferroptosis induction for enhanced therapeutic efficacy.
