Caspase-11–Mediated Hepatocytic Pyroptosis Promotes the Progression of Nonalcoholic Steatohepatitis

BACKGROUND: Nonalcoholic steatohepatitis (NASH) is an inflammatory disease with severe outcomes. Hepatocyte death, including apoptosis, necrosis, and pyroptosis, has been implicated in pathophysiology of NASH. Pyroptosis is mediated by inflammasome activation pathways including caspase-1–mediated canonical signaling pathway and caspase-11–mediated noncanonical signaling pathway. Until now, the precise role of caspase-11 in NASH remains unknown. In the present study, the potential roles of caspase-11 in NASH were explored. METHODS: We established methionine- and choline-deficient diet (MCD)–induced NASH mice model using wild-type caspase-11–deficient mice. The expression of caspase-11, liver injury, fibrosis, inflammation, and activation of gasdermin D and interleukin-1β were evaluated. RESULTS: Upregulated caspase-11 was detected in liver of mice with NASH. MCD-treated caspase-11–deficient mice had significantly decreased liver injury, fibrosis, and inflammation. The activation of gasdermin D and interleukin-1β was inhibited in caspase-11–deficient mice after MCD treatment. Overexpression of caspase-11 promoted steatohepatitis. CONCLUSIONS: Caspase-11–mediated hepatocytic pyroptosis promotes the progression of NASH.