The research progress on the role of glucose-6-phosphate dehydrogenase in immune regulation

Glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme of the pentose phosphate pathway (PPP), plays a pivotal role in immune regulation by regulating metabolic reprogramming and redox homeostasis of immune cells. It mediates the production of nicotinamide adenine dinucleotide phosphate (NADPH) and ribose-5-phosphate (R5P), which are essential for the activation, proliferation, and effector function of T lymphocytes, B lymphocytes, macrophages, and neutrophils-specifically promoting T/B cell-mediated adaptive immunity and macrophage/neutrophil-mediated innate immune responses. Abnormal G6PD activity (deficiency or overexpression) is closely associated with the pathogenesis of immune-related diseases: G6PD deficiency increases susceptibility to autoimmune diseases (e.g., rheumatoid arthritis, systemic lupus erythematosus) and infectious diseases (e.g., hepatitis, malaria, COVID-19) by inducing oxidative stress and immune cell dysfunction; in tumor immunity, G6PD dualistically promotes tumor cell proliferation while regulating anti-tumor immunity via modulating cytoxic D8⁺ T cell exhaustion and macrophage polarization. Additionally, G6PD-targeted immunotherapies, including small-molecule inhibitors and gene therapy, have shown promising preclinical potential for treating immune-related diseases. These findings highlight G6PD as a key metabolic-immune hub, providing critical theoretical basis for understanding immune regulation mechanisms and developing novel diagnostic and therapeutic strategies for autoimmune diseases, infectious diseases, and tumors.