Glutamine Metabolism in Health and Diseases.

Glutamine, the most abundant nonessential amino acid in the blood and tissues, plays essential roles in cellular proliferation, immune regulation, acid-base homeostasis, and metabolic balance. Although traditionally classified as a nonessential amino acid, glutamine becomes conditionally essential under pathological conditions and physiological stress due to its critical role in supporting cellular adaptation. Under diverse pathological states, glutamine metabolism undergoes extensive reprogramming, and cancer cells exhibit a particularly high dependence on glutamine to sustain proliferation, redox balance, and biosynthetic demands. In this review, we summarize the multifaceted functions of glutamine metabolism in physiological and pathological processes. We first discuss the fundamental pathways of glutamine synthesis, transport, and utilization, followed by an overview of its regulatory roles in cellular responses to oxidative, nutritional, thermal, mechanical, DNA damage, and osmotic stresses. We further highlight the involvement of glutamine metabolism in cancer progression, immune regulation, metabolic plasticity, and therapeutic resistance. Finally, we summarize emerging glutamine-targeted therapeutic strategies, including metabolic inhibitors, combination therapies, and advanced technologies for metabolic imaging and single-cell analysis. This review provides a comprehensive perspective on glutamine metabolism and highlights its potential as a therapeutic target for cancer and other metabolic disorders.