NLRP3 Inflammasome Activation in Liver Disorders: From Molecular Pathways to Therapeutic Strategies

The NOD-like receptor protein 3 (NLRP3) inflammasome, a cytosolic multi-protein complex, detects danger signals released by injured cells and pathogens. It plays a critical role in the pathogenesis of various acute and chronic liver diseases. NLRP3 activation triggers caspase-1-mediated processing and secretion of pro-inflammatory cytokines interleukin (IL)-1β and IL-18. Unlike other inflammatory pathways, NLRP3 activation requires two signals, ensuring a tight control over inflammation. Caspase-1 activation further amplifies the response by cleaving IL-1β, a potent pro-inflammatory mediator. Extensive research suggests the NLRP3 inflammasome contributes significantly to hepatocyte injury, immune cell activation, and the perpetuation of inflammatory responses in various human and experimental liver disease models. This review comprehensively examines NLRP3 inflammasome activation and its functional consequences in the context of liver injury and disease progression, including conditions such as alcoholic liver disease (ALD), metabolic dysfunction-associated fatty liver disease (MAFLD), viral hepatitis, hepatic fibrosis, and drug-induced liver injury (DILI). We specifically highlight emerging therapeutic strategies targeting NLRP3 inflammasome that show translational promise in attenuating liver inflammation and fibrosis. This review provides a theoretical framework and reference for the development of novel therapeutics targeting the NLRP3 inflammasome in liver injury and chronic liver diseases.