The generation of reducing equivalent NADPH via glucose-6-phosphate dehydrogenase (G6PD) is critical for the maintenance of redox homeostasis and reductive biosynthesis in cells. NADPH also plays key roles in cellular processes mediated by redox signaling. Insufficient G6PD activity predisposes cells to growth retardation and demise. Severely lacking G6PD impairs embryonic development and delays organismal growth. Altered G6PD activity is associated with pathophysiology, such as autophagy, insulin resistance, infection, inflammation, as well as diabetes and hypertension. Aberrant activation of G6PD leads to enhanced cell proliferation and adaptation in many types of cancers. The present review aims to update the existing knowledge concerning G6PD and emphasizes how G6PD modulates redox signaling and affects cell survival and demise, particularly in diseases such as cancer. Exploiting G6PD as a potential drug target against cancer is also discussed.

Metabolic hubs play a major role in the initiation and development of cancer. Oncogenic signaling pathways drive metabolic reprogramming and alter redox homeostasis. G6PD has potential oncogenic activity and it plays a pivotal role in cell proliferation, survival and stress responses. Aberrant activation of G6PD via metabolic reprogramming alters NADPH levels, leading to an antioxidant or a pro-oxidant environment which can either enhance DNA oxidative damage and genomic instability or initiate oncogenic signaling. Nutrient deprivation can rewire metabolism, which leads to mutations that determine a cancer cell's fate. Deregulated G6PD status and oxidative stress form a vicious cycle, which paves the way for cancer progression. This review aims to update and focus the potential role of G6PD in metabolic reprogramming and redox signaling in cancer.

The intestinal epithelium forms a physical barrier assembled by intercellular junctions, preventing luminal pathogens and toxins from crossing it. The integrity of tight junctions is critical for maintaining intestinal health as the breakdown of tight junction proteins leads to various disorders. Redox reactions are closely associated with energy metabolism. Understanding the regulation of tight junctions by cellular metabolism and redox status in cells may lead to the identification of potential targets for therapeutic interventions. In vitro and in vivo models have been utilized in investigating intestinal barrier dysfunction and in particular the free-living soil nematode, Caenorhabditis elegans, may be an important alternative to mammalian models because of its convenience of culture, transparent body for microscopy, short generation time, invariant cell lineage and tractable genetics.

The COVID-19 pandemic has so far affected more than 45 million people and has caused over 1 million deaths worldwide. Infection with SARS-CoV-2, the pathogenic agent, which is associated with an imbalanced redox status, causes hyperinflammation and a cytokine storm, leading to cell death. Glucose-6-phosphate dehydrogenase (G6PD) deficient individuals may experience a hemolytic crisis after being exposed to oxidants or infection. Individuals with G6PD deficiency are more susceptible to coronavirus infection than individuals with normally functioning G6PD. An altered immune response to viral infections is found in individuals with G6PD deficiency. Evidence indicates that G6PD deficiency is a predisposing factor of COVID-19.

Normal embryogenesis requires complex regulation and precision, which depends on multiple mechanistic details. Defective embryogenesis can occur by various mechanisms. Maintaining redox homeostasis is of importance during embryogenesis. NADPH, as produced from the action of glucose-6-phosphate dehydrogenase (G6PD), has an important role in redox homeostasis, serving as a cofactor for glutathione reductase in the recycling of glutathione from oxidized glutathione and for NADPH oxidases and nitric oxide synthases in the generation of reactive oxygen (ROS) and nitrogen species (RNS). Oxidative stress differentially influences cell fate and embryogenesis. While low levels of stress (eustress) by ROS and RNS promote cell growth and differentiation, supra-physiological concentrations of ROS and RNS can lead to cell demise and embryonic lethality. G6PD-deficient cells and organisms have been used as models in embryogenesis for determining the role of redox signaling in regulating cell proliferation, differentiation and migration. Embryogenesis is also modulated by anti-oxidant enzymes, transcription factors, microRNAs, growth factors and signaling pathways, which are dependent on redox regulation. Crosstalk among transcription factors, microRNAs and redox signaling is essential for embryogenesis.

Capsular polysaccharide (CPS) is a crucial virulence factor for Klebsiella pneumoniae infection. We demonstrated an association of CPS production with two phosphoenolpyruvate:carbohydrate phosphotransferase systems (PTSs). Deficiency of crr, encoding enzyme IIA of PTS, in K. pneumoniae enhanced the transcriptional activities of galF, wzi and gnd, which are in the cps gene cluster, leading to high CPS production. A crr mutant exhibited a higher survival rate in 1% hydrogen peroxide than the wild-type. The crr mutant showed less sensitivity to engulfment by macrophage (RAW 264.7) than the wild-type by observing the intracellular bacteria using confocal laser scanning microscopy (CLSM) and by calculating the colony-forming units (CFU) of intracellular bacteria. After long-term incubation, the survival rate of the intracellular crr mutant was higher than that of the wild-type. Deficiency of crr enhanced the transcriptional activities of etcABC which encodes another putative enzyme II complex of a PTS. Deletion of etcABC in the crr mutant reduced CPS production and the transcriptional activities of galF compared to those of the crr mutant. These results indicated that one PTS component, Crr, represses CPS production by repressing another PTS component, EtcABC, in K. pneumoniae. In addition, PTS plays a role in bacterial resistance to macrophage phagocytosis.