Pyroptosis: An inflammatory link between NAFLD and NASH with potential therapeutic implications

Non-alcoholic fatty liver disease (NAFLD) represents a major health problem worldwide because of its high and rising prevalence, its association with cardiovascular disease, and its link with an increased risk of developing cirrhosis and hepatocellular carcinoma (HCC). NAFLD is classified into different degrees, from simple steatosis (overall 20–30% prevalence), which is considered "benign", to steatohepatitis (NASH: 2–5% prevalence) and fibrosis.1,2 The major risk factors of NAFLD include metabolic syndrome (i.e. obesity, diabetes, hypercholesterolemia and hypertriglyceridemia), sedentary lifestyle, genetic predispositions (e.g. PNPLA3 p.I148M, TM6SF2 p.E167K and MBOAT7 rs641738) and environmental factors (e.g. Western diet).1–3 Indeed, the prevalence of NAFLD/NASH in patients with obesity and/or diabetes increases dramatically.2 The differential diagnosis of NAFLD and NASH is currently available with accurate non-invasive methods based on serum metabolomics and/or imaging approaches,4,5 and the determination and monitoring of liver fat concentration is also possible by magnetic resonance imaging.6 However, the precise determination of hepatocyte ballooning, inflammation and fibrosis still requires histological characterization by liver biopsy. The EASL–EASD–EASO clinical practice guidelines7 recommend a Mediterranean diet and weight loss (7–10%) to obese patients, which have been shown to significantly improve the NAFLD activity score (NAS score).8 However, since lifestyle modifications are often not completely successful, current research is aimed at unravelling the molecular mechanisms that trigger the development and progression of NAFLD. Such advances will aid the ultimate goal of providing new potential targets for pharmacological therapy, as well as discovering biomarkers for prognosis and response to therapy.