The glutamine-glutamate metabolic axis in autoimmune rheumatic diseases: immunometabolic regulation and therapeutic potential

Autoimmune rheumatic diseases (AIRDs), such as rheumatoid arthritis and systemic lupus erythematosus, represent a heterogeneous group of chronic inflammatory disorders characterized by loss of self-tolerance and persistent immune activation. Growing evidence indicates that metabolic reprogramming is essential for immune cell activation and lineage commitment. Among these pathways, the glutamine-glutamate metabolic axis has emerged as an important immunometabolic regulatory network linking nutrient utilization and cellular metabolic remodeling to immune cell fate and function. Beyond supporting energy production and biosynthesis, this axis actively regulates immune cell activation, differentiation, and effector functions across multiple immune cell populations, including lymphocytes and monocytes/macrophages. Moreover, accumulating experimental and clinical evidence suggests that dysregulated glutamine-glutamate metabolism is associated with immune dysregulation and tissue injury in rheumatic diseases. This review comprehensively summarizes the roles of the glutamine-glutamate metabolic axis in regulating the fate and function of immune cells, and discusses its underlying mechanisms in the pathogenesis of rheumatic diseases. A deeper understanding of these immunometabolic mechanisms may facilitate the development of precision metabolism-based therapeutic strategies for AIRDs.