NLRP3 inflammasome as a central target for the pleiotropic effects of GLP-1 receptor agonists

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and dipeptidyl peptidase-4 inhibitors (DPP-4i) exert pleiotropic effects that extend beyond glycemic control, including benefits on body weight, cardiovascular disease, and kidney disease. A common mechanism underlying these effects is their ability to inhibit the NLRP3 inflammasome, a key regulator of sterile inflammation implicated in a variety of diseases. This review synthesizes evidence from preclinical and clinical studies highlighting NLRP3 inflammasome modulation as a major mechanism of action of these drugs. In particular, we discuss how GLP-1 signaling activates AMPK/SIRT1, Nrf2, and mitophagy pathways, which in turn suppress NLRP3 activation and its upstream regulator nuclear factor-κB (NF-κB). We further summarize evidence demonstrating beneficial effects across multiple organ systems, including metabolic, cardiovascular, renal, pulmonary, and neurological tissues, where modulation of the NLRP3 pathway appears to play an important role. In addition, we discuss the comparative potential of different GLP-1-based therapies and emerging therapeutic strategies such as multi-agonists and combination approaches with direct NLRP3 inhibitors. Collectively, these findings support a growing view that GLP-1-based therapies function not only as antidiabetic agents but also as metabolic anti-inflammatory drugs capable of targeting sterile inflammation across diverse diseases.