Targeting the P2X7–NLRP3 Inflammasome Axis in Obesity: Circadian Regulation of Metabolic Inflammation and Disease Progression

Abstract

Obesity has become a significant public health issue in both industrialized and developing nations, growing substantially over recent decades. Emerging evidence supports a central role for the purinergic P2X7 receptor along with the NLRP3 inflammasome as intermediary mediators linking metabolic stress and inflammatory activation. The P2X7 receptor is activated by extracellular ATP, which leads to the increase of reactive oxygen species (ROS) through potassium efflux and mitochondrial malfunction. These events, itself, causes the NLRP3 inflammasome to assemble and secrete pro-inflammatory cytokines like IL-1β and IL-18. Newer studies have recently uncovered that maturating Immune and metabolic pathways can affect the circadian rhythms, whereas the disruption of clock genes potentiates P2X7–NLRP3 signalling thereby accelerating obesity-associated inflammation and disease development. This study signifies the mechanisms underlying circadian regulation of the P2X7–NLRP3 axis, its tissue-specific roles in obesity, and available preclinical and clinical evidence. We further review innovative therapeutics like inflammatory inhibiting targets including inflammasome inhibitors, P2X7 antagonists and chronotherapeutic strategies targeting the obesity as novel therapeutic opportunities.