Enhancing NADPH to restore redox homeostasis and lysosomal function in G6PD-deficient microglia

Microglia, the immune cells of the central nervous system (CNS), play key roles in neurogenesis, myelination, synaptic transmission, immune surveillance, and neuroinflammation. Inflammatory responses in microglia can lead to oxidative stress and neurodegeneration, contributing to diseases like Parkinson's and Alzheimer's. The enzyme glucose-6-phosphate dehydrogenase (G6PD) is essential for producing nicotinamide adenine dinucleotide phosphate hydrogen (NADPH), which neutralizes oxidative stress. G6PD deficiency has been linked to several disorders, including neurological conditions. Our study shows that G6PD deficiency in microglia reduces NADPH levels, disrupting redox balance and lysosomal function. To address this, we explored alternative metabolic pathways by targeting enzymes like isocitrate dehydrogenase 1 (IDH1) and malic enzyme 1 (ME1), both crucial for NADPH production. Supplementing metabolites such as citric and malic acid improved NADPH levels, while small molecules like dieckol and resveratrol enhanced IDH1 and ME1 expression. The combination of these approaches restored redox homeostasis and lysosomal function, offering potential therapeutic strategies for G6PD deficiency.