Limited impact of NLRP3 inflammasome deficiency on diet-induced metabolic dysfunction-associated steatohepatitis in mice.

Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive form of metabolic dysfunction-associated steatotic liver disease (MASLD) and a growing cause of chronic liver disease worldwide. Although the NLRP3 inflammasome has been implicated in MASH pathogenesis, its contribution remains controversial across experimental models. We investigated whether systemic deletion of NLRP3 attenuates diet-induced MASH using a choline-deficient, l-amino acid-defined, high-fat diet (CDAHFD) model. Wild-type (WT) and NLRP3-knockout (KO) mice were fed either CDAHFD or a control diet. CDAHFD induced comparable hepatic steatosis, inflammation, fibrosis, and serum alanine aminotransferase elevation in both genotypes. Systemic and hepatic oxidative stress was also comparable between WT and NLRP3-KO mice. Total NAFLD activity scores did not differ between the two genotypes. Although hepatic Adgre1 expression showed a partial reduction in NLRP3-KO mice, pro-inflammatory cytokines and fibrosis-related genes were not significantly altered. These findings indicate that systemic NLRP3 deletion does not substantially attenuate CDAHFD-induced MASH. Together with recent reports using other diet-induced MASH models, our results support the concept that global NLRP3 deficiency alone is insufficient to prevent MASH progression and highlight the context-dependent role of inflammasome signaling in steatohepatitis.