High uric acid exacerbates nonalcoholic steatohepatitis through NLRP3 inflammasome and gasdermin D-mediated pyroptosis

Hyperuricemia is independently associated with an increased risk of nonalcoholic steatohepatitis (NASH), but the underlying mechanisms responsible for this association remain unclear. We first analyzed the association between intrahepatic UA levels and gasdermin D (GSDMD)-mediated pyroptosis in vivo and in vitro. We subsequently generated hepatic-specific glucose transporter 9 (GLUT9)-knockout mice and GSDMD knockout (GSDMD^-/-) mice to explore the role of intrahepatic UA in GSDMD-induced pyroptosis in NASH. We found that high intrahepatic UA levels were positively related to GSDMD-mediated pyroptosis in NASH mice. The inhibition of hepatic UA production by allopurinol alleviated hepatic inflammation and GSDMD-mediated pyroptosis in NASH mice. Hepatic-specific knockout of Glut9 significantly decreased intrahepatic UA levels, attenuated NOD-like receptor family pyrin domain containing 3 (NLRP3)-Caspase-1-GSDMD-mediated pyroptosis in hepatocytes, and ameliorated hepatic inflammation and fibrosis in different mouse models of NASH. Further experiments revealed that inhibiting the NLRP3/Caspase-1/GSDMD pathway obviously blocked UA-induced pyroptosis and inflammation in hepatocytes. Additionally, GSDMD deficiency markedly reversed hepatic inflammation and fibrosis in NASH mice. In conclusion, our results showed that high UA could induce NLRP3-Caspase1-GSDMD-mediated pyroptosis, thereby aggravating NASH in mice.