NADK Governs Ferroptosis Susceptibility by Orchestrating NADPH Homeostasis.

ABSTRACT: Ferroptosis, a regulated cell death pathway driven by iron-dependent lipid peroxidation, is modulated by cellular antioxidant systems, particularly the glutathione (GSH)-glutathione peroxidase 4 (GPX4) axis. NAD kinase (NADK), the only enzyme converting NAD⁺ to NADP⁺ located in cytoplasm, fuels NADPH-dependent antioxidant defenses. However, its role in ferroptosis regulation remains not fully explored. Using ferroptosis-sensitive HT1080 cells, we employed pharmacological inhibition (thioNAM), siRNA-mediated knockdown, and plasmid-driven overexpression of NADK to dissect its impact on ferroptosis. Complementary interventions with nicotinamide mononucleotide (NMN), glucose-6-phosphate dehydrogenase (G6PD) and malic enzyme 1 (ME1) were used to map metabolic interactions.

SUBMITTER: Chen X 

PROVIDER: S-EPMC12730079 | biostudies-literature | 2025 Nov

REPOSITORIES: biostudies-literature