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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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NADK Governs Ferroptosis Susceptibility by Orchestrating NADPH Homeostasis
Xinyi Chen1, Yingying Zhang1, Dandan Song1
1School of Public Health and Nursing, Hangzhou Normal University, Hangzhou 311121, China.
Antioxidants (Basel, Switzerland)
|December 30, 2025
Summary
NAD kinase (NADK) regulates ferroptosis, a cell death pathway. It fuels antioxidant defenses by producing NADPH, crucial for protecting cells against iron-dependent lipid peroxidation and oxidative stress.
Area of Science:
- Cell Biology
- Biochemistry
- Metabolism
Background:
- Ferroptosis is an iron-dependent cell death pathway regulated by antioxidant systems, notably the glutathione (GSH)-glutathione peroxidase 4 (GPX4) axis.
- NAD kinase (NADK) is the primary cytoplasmic enzyme responsible for converting NAD+ to NADP+, which is essential for NADPH-dependent antioxidant defenses.
- The precise role of NADK in ferroptosis regulation has not been fully elucidated.
Purpose of the Study:
- To investigate the role of NAD kinase (NADK) in the regulation of ferroptosis.
- To determine how NADK activity impacts cellular redox balance and susceptibility to ferroptosis.
- To explore the metabolic interactions of NADK with other key enzymes and metabolites involved in ferroptosis.
Main Methods:
- Utilized ferroptosis-sensitive HT1080 cells for experiments.
- Employed pharmacological inhibition (thioNAM), siRNA-mediated knockdown, and plasmid-driven overexpression of NADK.
- Assessed cell viability, redox metabolites (NADPH, GSH), oxidative stress markers (ROS, MDA), and protein expression.
- Investigated metabolic interactions using nicotinamide mononucleotide (NMN), glucose-6-phosphate dehydrogenase (G6PD), and malic enzyme 1 (ME1).
Main Results:
- Pharmacological inhibition or knockdown of NADK depleted NADP(H) levels, sensitized cells to ferroptosis, and increased lipid peroxidation.
- Overexpression of NADK restored NADPH and GSH levels, conferring resistance to ferroptosis.
- NADK was critical for G6PD- and ME1-mediated NADPH production, ferroptosis resistance, and the ferroptosis-rescuing effects of NMN.
Conclusions:
- NAD kinase (NADK) plays a crucial role in ferroptosis regulation by maintaining redox homeostasis through NADPH synthesis.
- NADK acts as a metabolic hub, linking NAD+ salvage pathways (e.g., NMN) to NADPH production via G6PD and ME1.
- Targeting NADK presents a potential therapeutic strategy for diseases associated with ferroptosis.
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