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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.
Richard Moreau at Centre de Recherche sur l’Inflammation (CRI), INSERM, Université Paris Diderot, Paris, France; DHU UNITY, Service d’Hépatologie, Hôpital Beaujon, Assistance Publique-Hôpitaux de Paris, Clichy, France; Laboratoire d’Excellence (Labex) Inflamex, COMUE Sorbonne Paris Cité, Paris, France. Ramon Bataller at Division of Gastroenterology, Hepatology and Nutrition University of Pittsburgh Medical Center, Pittsburgh, PA, USA. Thomas Berg at Section Hepatology, Clinic for Gastroenterology and Rheumatology, University Hospital Leipzig, Leipzig, Germany. Jessica Zucman-Rossi at Inserm UMR-674; Génomique Fonctionnelle des Tumeurs Solides; IUH; Paris, France; Université Paris Descartes; Labex Immuno-oncology; Faculté de Médecine; Sorbonne Paris Cité; Paris, France. Rajiv Jalan at Liver Failure Group, Institute for Liver and Digestive Health, University College London, Royal Free Hospital, UK.
