NLRP1 is activated by palmitic acid and induced in human metabolic dysfunction-associated steatohepatitis

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent cause of liver disease worldwide. This progressive condition ranges from simple steatosis to a more advanced stage, known as metabolic dysfunction-associated steatohepatitis (MASH), which is characterized by inflammation, hepatocellular ballooning, and hepatic steatosis. Several studies have demonstrated the involvement of inflammasomes in MASH development. Recently, the NLRP1 inflammasome has gained attention as an important sensor in various human inflammatory conditions, though its role in metabolic diseases like MASLD remains unclear. In this study, we identified significantly higher mRNA and protein levels of NLRP1 in liver samples from patients with MASH compared to those with normal or steatotic livers. Furthermore, NLRP1 mRNA levels correlated with hepatic palmitic acid (PA) levels. We also showed that NLRP1 inflammasome expression is mediated by PA in both human HepG2 cells and human liver organoids. Importantly, we found that NLRP1 was activated by PA, but not by other saturated fatty acids like myristic acid, and that PA-induced NLRP1 activation was inhibited by oleic acid. These findings uncover a previously unknown role of the hepatic NLRP1 inflammasome in the human liver. However, further research is needed to fully understand the complex interactions between NLRP1, inflammation, and metabolic processes in the development of MASLD.