FIGURE 1.

Activation of the NLRP3 inflammasome. Priming and activation of the NLRP3 inflammasome involve two steps. First, inflammasome activation is triggered by priming signals, including various DAMPs and PAMPs, which can lead to NF-κB-mediated upregulation and expression of NLRP3, pro-IL-18, and pro-IL-1β. The second step is inflammasome formation, which is triggered by specific stimuli; the stimuli involved are diverse and depend on cellular stresses during NAFLD/NASH, and include extracellular ATP, mitochondrial ROS, mtDNA, cholesterol crystals, uric acid, cardiolipin, PFOA, ER stress, and impaired mitophagy. NLRP3 inflammasome stimulation can lead to self-cleavage of pro-caspase-1 to generate the active form, caspase-1, which subsequently cleaves pro-IL-18 and pro-IL-1β to generate their mature forms, L-18 and IL-1β, for secretion. Activated caspase-1 can also induce GSDMD-mediated pyroptosis. Finally, NLPR3 inflammasome activation can instigate a series of serious conditions, ranging from benign NAFLD to fibrosis, and ultimately cirrhosis and hepatocellular carcinoma.