The prevalence of nonalcoholic fatty liver disease (NAFLD) is high and increasing throughout the world. The intense sterile inflammation stemming from steatosis plays a significant role in the development of NAFLD, but the mechanism is unclear. We found that the NLRC4 inflammasome was activated in an in vitro cell model of NAFLD, and that the secretion of inflammatory factors IL-18, IL-1 beta, and tumor necrosis factor alpha (TNF-alpha) increased during this process and pyroptosis is triggered. In this study, we used NLRC4-targeting siRNA and an NLRC4-encoding plasmid to demonstrate that the increases in IL-18 and IL-1 beta are mainly attributable to the activation of the NLR family CARD domain-containing protein 4 (NLRC4) inflammasome, which stimulates cellular pyroptosis. NLRC4 inflammasome activation is regulated by TNF-alpha and accompanies the translocation of NLRC4 from the cytoplasm into the mitochondria, but the specific mechanism is unclear. In summary, the increase in TNF-alpha during NAFLD promotes the activation of the NLRC4 inflammasome, which increases the production of IL-18 and IL-1 beta and triggers pyroptosis. These exacerbate inflammation and promote disease development. (C) 2019 Elsevier Inc. All rights reserved.