Glutamine metabolism in health and disease

Abstract Glutamine is the most abundant free amino acid in the body. It plays a central role in cellular metabolism, connecting synthetic and catabolic pathways, and maintaining life activities under physiological and pathological conditions. This review systematically explores the dual role of glutamine metabolism in health and disease. Glutamine is not only the main energy and nitrogen source for rapidly proliferating cells, such as immune cells, intestinal epithelial cells, and cancer cells but also participates in several key biological processes, such as nucleotide synthesis, REDOX balance, and immune regulation. Glutamine metabolism is often abnormally activated or disrupted in disease states, such as “glutamine addiction” in cancer and excitotoxicity and mitochondrial dysfunction in neurodegenerative diseases. Disorders of glutamine metabolism are also present in metabolic diseases (such as diabetes and MAFLD) and cardiovascular diseases. In addition, gut microbes regulate host glutamine metabolism through metabolites and signaling pathways, further affecting the disease process. Therapeutic strategies to target glutamine metabolism include inhibition of key enzymes or transporters, as well as exogenous glutamine supplementation. However, the effects of these strategies are context-dependent and need to be applied individually according to the specific pathological status of patients. Future research should focus on tissue-specific metabolic profiling, integrated multiomics analysis, and the development of combined treatment strategies to fully realize the potential of glutamine metabolism in disease treatment.