The NLRP3 inflammasome in metabolic dysfunction-associated steatotic liver disease: role and advances in therapeutic targeting

Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly termed non-alcoholic fatty liver disease (NAFLD), has become the most prevalent chronic liver disease worldwide. Its disease spectrum begins with simple steatosis, progresses through steatohepatitis (MASH, formerly NASH) and liver fibrosis, and can eventually advance to cirrhosis and even hepatocellular carcinoma. With deeper insight into its metabolic nature, the nomenclature of this disease has been updated from NAFLD to MASLD. During the transition from simple lipid accumulation to necroinflammation, excessive activation of innate immunity constitutes a decisive step, and the NLRP3 inflammasome serves as a central hub linking hepatic metabolic stress to sterile inflammation. The NLRP3 inflammasome is assembled from the sensor protein NLRP3, the adaptor protein ASC, and the effector protein pro-caspase-1, and is triggered by a two-signal model comprising priming and activation. In the metabolic microenvironment of MASLD, multiple danger signals-including free fatty acids, cholesterol crystals, reactive oxygen species, molecules released from damaged mitochondria, endoplasmic reticulum stress, and gut-derived lipopolysaccharide-can drive its activation in hepatocytes, Kupffer cells, hepatic stellate cells, and other cell types. Subsequently, caspase-1 catalyzes the maturation of IL-1β and IL-18 and cleaves gasdermin D to mediate hepatocyte pyroptosis, thereby amplifying liver inflammation, promoting stellate cell activation and extracellular matrix deposition, and contributing to inflammation-associated hepatocellular carcinoma. Given its pivotal position in this pathological network, targeting the NLRP3 inflammasome is considered a promising strategy to simultaneously curb inflammation and fibrosis. This narrative review examines the structure and activation mechanisms of the NLRP3 inflammasome and its roles in each stage of MASLD progression, summarizes current research on multi-level intervention strategies-represented by synthetic inhibitors, natural products, traditional Chinese medicine, and metabolic regulation-and analyzes current deficiencies in clinical translation, thereby providing a reference for future mechanistic studies and drug development.