IDDF2024-ABS-0226 High uric acid aggravates nonalcoholic steatohepatitis through trigging NLRP3-GSDMD-mediated pyroptosis

<h3>Background</h3> Hyperuricemia is independently associated with an increased risk of nonalcoholic steatohepatitis (NASH), while the mechanisms responsible for this association remain unclear. This study aimed to investigate the effects and underlying mechanisms of uric acid on hepatocyte pyroptosis and its association with the regulation of NASH. <h3>Methods</h3> We first analyzed the association between intrahepatic uric acid contents and gasdermin D (GSDMD)-mediated pyroptosis<i> in vivo</i> and <i>in vitro</i>. Then, we generated glucose transporter 9 (GLUT9) hepatic-specific knockout mice and GSDMD^-/- mice to explore the role of intrahepatic uric acid and GSDMD-induced pyroptosis in NASH. <h3>Results</h3> We found that high intrahepatic uric acid contents were positively related to GSDMD-mediated pyroptosis in NASH mice (IDDF2024-ABS-0226 Figure 1. Intrahepatic uric acid is associated with NLRP3 GSDMD-mediated pyroptosis in NASH). Inhibiting hepatic uric acid production by allopurinol alleviated hepatic inflammation and GSDMD-mediated pyroptosis in NASH mice (IDDF2024-ABS-0226 Figure 2. Inhibiting uric acid production reduced inflammation in NASH mice by improving hepatocyte pyroptosis). Liver-specific knockout of GLUT9 significantly decreased intrahepatic uric acid contents, attenuated NOD-like receptor family pyrin domain containing 3 (NLRP3)-caspase1-GSDMD-mediated pyroptosis in hepatocytes, and ameliorated hepatic inflammation and fibrosis in different mouse models of NASH (IDDF2024-ABS-0226 Figure 3. Hepatic specific GLUT9 knockout ameliorated NASH by inhibiting UA uptake). Further experiments showed that inhibiting NLRP3/Caspase1/GSDMD pathway obviously blocked uric acid-induced pyroptosis and inflammation in hepatocytes. Moreover, GSDMD deficiency markedly reversed hepatic inflammation and fibrosis in NASH mice (IDDF2024-ABS-0226 Figure 4. GSDMD deletion reversed UA-induced hepatic inflammation and fibrosis in NASH mice) <h3>Conclusions</h3> Our study showed that high uric acid could induce NLRP3-Caspase1-GSDMD-mediated pyroptosis and thereby aggravate NASH in mice.