From the Editor’s desk....: April 2018

Abstract

There is a clear need to identify molecular mechanisms of non-alcoholic steatohepatitis (NASH) to develop novel targeted therapies. Pyroptosis is a highly inflammatory form of programmed cell death. Gasdermin D (GSDMD)-executed programmed necrosis is involved in inflammation and controls interleukin (IL)-1β release. In this issue of the Journal, Xu et al. studied its role in human and experimental NASH. GSDMD and its pyroptosis-inducing fragment GSDMD-N were upregulated in liver tissues of human NASH and correlated with disease severity. Gsdmd−/− mice with experimental NASH exhibit decreased severity of steatosis and inflammation. GSDMD expression was associated with the secretion of pro-inflammatory cytokines and persistent activation of the NF-κB signaling pathway. Reduced steatosis in Gsdmd−/− mice was due to decreased expression of the lipogenic gene Srebp-1c and upregulated expression of lipolytic genes. This translational study reveals that GSDMD plays a key role as a pyroptosis executor in the pathogenesis of steatohepatitis by controlling cytokine secretion and lipogenesis.