Disrupted Redox Homeostasis: G6PD Deficiency, Mechanisms of Cell Death, and Drug Discovery

The regulation of NADPH metabolism is a key determinant of redox homeostasis, oxidative stress responses, and regulated cell death, making it a rich source of pharmacologically actionable targets. Enzymes involved in NADPH regeneration, including glucose-6-phosphate dehydrogenase (G6PD), 6-phosphogluconate dehydrogenase, malic enzyme, and isocitrate dehydrogenase, maintain antioxidant defense and cellular survival, and their dysregulation is increasingly the focus of drug discovery efforts aimed at correcting or exploiting these vulnerabilities for therapeutic gain.

Recent advances have identified NADPH-dependent pathways as central drivers of ferroptosis, apoptosis, necroptosis, parthanatos, and eryptosis, opening new avenues for experimental pharmacology. Depletion of intracellular NADPH disrupts glutathione metabolism, impairs glutathione peroxidase 4 activity, promotes lipid peroxidation, and triggers ferroptotic cell death, a pathway now under active investigation for small-molecule intervention. NADPH oxidase-mediated reactive oxygen species production is likewise a druggable signaling node in inflammation and immune defense. Enzyme activity changes linked to NADPH metabolism contribute to cancer, neurodevelopmental disorders, epilepsy, developmental delay, and cardiometabolic dysfunction, and G6PD overexpression has emerged as a validated driver of chemoresistance, with G6PD inhibition now an active strategy to restore drug sensitivity in refractory tumors.

This Research Topic builds on our previous collection, The Culprit Behind Some Diseases: Overexpression/Hyperactivity of G6PD, which established G6PD as a high-priority drug target in NADPH-dependent diseases including cancer, obesity, and diabetes. This collection extends that work with a sharper pharmacological lens: broadening scope to the full network of NADPH-regenerating enzymes, incorporating G6PD deficiency alongside overexpression, and positioning regulated cell death, particularly ferroptosis, as a mechanistic framework for identifying and validating new drug targets.

The goal of this Research Topic is to advance experimental pharmacology and drug discovery efforts targeting NADPH metabolism, oxidative stress responses, and regulated cell death pathways. We aim to showcase small-molecule and biologic approaches targeting NADPH-generating enzymes across ferroptosis, apoptosis, necroptosis, parthanatos, and eryptosis; preclinical and translational studies validating these enzymes as drug targets; and pharmacological strategies addressing cancer, neurodevelopmental disorders, epilepsy, and cardiometabolic dysfunction. We particularly encourage submissions on target validation, compound screening, mechanism-of-action studies, and translational or clinical-stage therapeutic development related to NADPH homeostasis.

We welcome articles addressing, but not limited to, the following themes:
• Drug discovery and target validation strategies for NADPH-regenerating enzymes (G6PD, malic enzyme, isocitrate dehydrogenase) in oxidative stress and cell death
• Small-molecule and biologic modulators of ferroptosis, necroptosis, parthanatos, apoptosis, and eryptosis via NADPH-dependent pathways
• Pharmacological exploitation of the GSH–GPX4 axis and lipid peroxidation as a therapeutic vulnerability
• G6PD inhibitors and activators: mechanism of action, chemoresistance reversal, and preclinical development in cancer
• Experimental pharmacological approaches to correcting NADPH-generating enzyme deficiencies in neurodevelopmental disorders, epilepsy, and cardiometabolic dysfunction
• NADPH oxidase (NOX) inhibitors as anti-inflammatory and immunomodulatory therapeutics
• Translational and preclinical models for evaluating redox-targeted therapeutics