GLP-1 Receptor Agonists and DPP-4 Inhibitors Suppress NLRP3 Inflammasome via AMPK/SIRT1, Nrf2, and Mitophagy

Beyond their established roles in glycemic control and weight management, Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and dipeptidyl peptidase-4 inhibitors (DPP-4i) exhibit wide-ranging pleiotropic effects. A critical underlying mechanism for these benefits is their ability to inhibit the NLRP3 inflammasome, a central mediator of sterile inflammation. Dysregulated NLRP3 activation is implicated in numerous chronic diseases, including metabolic dysfunction-associated steatotic liver disease (MASLD), cardiovascular disease, kidney disease, and neurodegenerative disorders. Understanding this common pathway offers new therapeutic avenues for targeting inflammation across diverse organ systems.

This comprehensive review synthesized evidence from numerous preclinical and clinical studies, focusing on the mechanistic links between GLP-1RAs and DPP-4 inhibitors and the NLRP3 inflammasome. Researchers analyzed how GLP-1 signaling modulates specific intracellular pathways, including AMPK/SIRT1, Nrf2, and mitophagy, to suppress NLRP3 activation and its upstream regulator NF-κB. The review also discussed the comparative potential of different GLP-1-based therapies and emerging strategies like multi-agonists and combination approaches with direct NLRP3 inhibitors, providing a broad overview of their anti-inflammatory actions.

The review established that GLP-1 signaling consistently inhibits the NLRP3 inflammasome across various tissues, serving as a central mechanism for the pleiotropic effects of GLP-1RAs and DPP-4i. This suppression occurs through the activation of key cellular pathways: AMPK/SIRT1, Nrf2, and mitophagy. These pathways collectively reduce NLRP3 activation and its upstream regulator, NF-κB, thereby mitigating sterile inflammation. The beneficial effects of NLRP3 modulation were observed across multiple organ systems. These include improved outcomes in metabolic disorders, cardiovascular disease, renal dysfunction, pulmonary conditions, and neurological pathologies. The review highlighted that different GLP-1-based therapies possess varying potentials in modulating the NLRP3 pathway, suggesting opportunities for optimized therapeutic strategies. Emerging multi-agonists and combinations with direct NLRP3 inhibitors were also identified as promising future directions.

Collectively, these findings underscore that GLP-1RAs and DPP-4i function not only as antidiabetic agents but also as potent metabolic anti-inflammatory drugs, capable of targeting sterile inflammation across diverse disease states.