The protective effects of selenium against NLRP3-mediated inflammation and pyroptosis: mechanisms and the potential health benefits

Selenium (Se) is an essential metalloid, possessing not only antioxidant but also anti-inflammatory effects. Recent studies have shown that the latter may be mediated by modulation of NLRP3 inflammasome activation, although the exact mechanisms have yet to be fully characterized. Therefore, the objective of this review is to discuss the molecular mechanisms by which Se modulates NLRP3 inflammasome activation and to examine the downstream effects on NLRP3-mediated inflammation and pyroptotic cell death. The selenoproteins S, O, M, W, and especially glutathione peroxidase (GPX) and thioredoxin reductase (TXNRD) are involved in regulation of the NLRP3 inflammasome machinery through modulation of redox homeostasis. In contrast, Se deficiency has been shown to aggravate NLRP3 inflammasome activation induced by lipopolysaccharide (LPS) treatment or exposure to organic pollutant bisphenol A (BPA). In addition to increased reactive oxygen species (ROS) generation, Se deficiency contributes to NLRP3-mediated inflammation and pyroptosis through modulation of non-coding RNA expression. In turn, Se supplementation mitigates NLRP3 inflammasome activation in liver, heart, kidneys, intestine, brain, and certain other tissues induced by LPS exposure, ischemia/reperfusion (I/R), and various xenobiotics including heavy metals and organic pollutants. This effect appears to be mediated by modulation of various components of Toll-like receptor (TLR)/nuclear factor κB (NF-κB)/NRLP3, nuclear factor erythroid 2-related factor 2 (Nrf2)/ROS/NLRP3, thioredoxin-interacting protein (TXNIP)/NLRP3 pathways, and several other mechanisms including modulation of gut microbiota with subsequent reduction of circulating LPS levels. Collectively, these findings demonstrate that the anti-inflammatory and cytoprotective effects of Se supplementation may be mediated by modulation of NLRP3 inflammasome activation. © 2025 Elsevier B.V., All rights reserved.