NLRP3 Inflammasome in Liver Diseases: From Molecular Pathogenesis to Emerging Therapeutic Strategies
TL;DR
The molecular mechanisms underlying NLRP3 inflammasome activation in liver diseases are summarized, its contribution to hepatic inflammation and fibrosis is discussed, and emerging therapeutic strategies targeting this pathway are explored.
Abstract
Liver diseases represent a major global health burden, with chronic inflammation, immune dysregulation, and progressive fibrosis contributing to disease progression and complications. Recent advances in hepatology have highlighted the critical role of innate immune pathways in hepatic injury, particularly the NLRP3 (NOD-, LRR-, and pyrin domain-containing protein 3) inflammasome. As a central regulator of inflammatory responses, the NLRP3 inflammasome senses cellular stress signals, including reactive oxygen species, mitochondrial dysfunction, extracellular ATP, and pathogen-associated molecular patterns. Upon activation, it promotes caspase-1 activation and subsequent maturation of pro-inflammatory cytokines, including interleukin (IL)-1β and IL-18, leading to pyroptotic cell death and amplification of hepatic inflammation. Emerging evidence demonstrates that dysregulated NLRP3 activation contributes to the pathogenesis of multiple liver diseases, including metabolic dysfunction-associated steatotic liver disease (MASLD), metabolic dysfunction-associated steatohepatitis (MASH), alcohol-associated liver disease, viral hepatitis, liver fibrosis, and hepatocellular carcinoma. In MASLD/MASH, metabolic stress, lipotoxicity, and oxidative injury activate NLRP3 signaling, promoting hepatocyte damage, macrophage activation, and hepatic stellate cell-mediated fibrosis. Similarly, alcohol-induced gut-derived endotoxemia and oxidative stress stimulate NLRP3 activation, contributing to inflammatory liver injury. Given its central role in hepatic inflammation and fibrosis, the NLRP3 inflammasome has emerged as a promising therapeutic target. Experimental studies investigating direct NLRP3 inhibitors, IL-1 pathway blockade, caspase-1 inhibition, metabolic therapies, and lifestyle interventions suggest potential benefits in reducing liver inflammation and disease progression. However, challenges remain regarding clinical translation, long-term safety, and selective modulation of immune responses. This review summarizes the molecular mechanisms underlying NLRP3 inflammasome activation in liver diseases, discusses its contribution to hepatic inflammation and fibrosis, and explores emerging therapeutic strategies targeting this pathway. Understanding NLRP3-mediated immune regulation may provide new opportunities for precision-based treatments in chronic liver disease.