Immunometabolism and GLP-1 Signaling in Rheumatic Diseases: Molecular Mechanisms, Clinical Implications, and Therapeutic Perspectives

Abstract

BackgroundRheumatic diseases are increasingly recognized as disorders driven by both immune dysregulation and profound metabolic alterations. Glucagon-like peptide-1 receptor agonists (GLP-1RAs), initially developed for obesity and type 2 diabetes, have demonstrated pleiotropic effects extending beyond metabolic control. However, the relationship between immunometabolism and GLP-1 signaling in rheumatic diseases remains incompletely understood. AimTo summarize current evidence on the interplay between immunometabolic pathways and GLP-1 signaling in rheumatic diseases. Material and methodsA narrative review of studies published between 2010 and 2026 was conducted using the PubMed, Scopus, and Web of Science databases. ResultsDysregulated glycolysis, mitochondrial dysfunction, altered lipid metabolism, and hypoxia-driven signaling contribute to chronic inflammation and tissue damage in rheumatic diseases. Key pathways involving AMP-activated protein kinase, mammalian target of rapamycin, hypoxia-inducible factor-1α, and the NLRP3 inflammasome link metabolism to immune activation. Beyond their glucose-lowering effects, GLP-1RAs modulate immune responses, attenuate inflammation, and improve cardiometabolic outcomes. Emerging evidence suggests potential benefits in rheumatoid arthritis, osteoarthritis, psoriasis, and other immune-mediated disorders. ConclusionsImmunometabolism represents a promising therapeutic frontier in rheumatology, positioning GLP-1 signaling at the intersection of metabolism and immune homeostasis. Further mechanistic studies and clinical trials are needed to define the therapeutic role of GLP-1RAs in rheumatic diseases.