Gasdermin D plays a key role as a pyroptosis executor of non-alcoholic steatohepatitis in humans and mice
Abstract
Background & aims Gasdermin D (GSDMD)-executed programmed necrosis is involved in inflammation and controls interleukin (IL)-1β release. However, the role of GSDMD in non-alcoholic steatohepatitis (NASH) remains unclear. We investigated the role of GSDMD in the pathogenesis of steatohepatitis. Methods Human liver tissues from patients with non-alcoholic fatty liver disease (NAFLD) and control individuals were obtained to evaluate GSDMD expression. Gsdmd knockout (Gsdmd -/- ) mice, obese db/db mice and their wild-type (WT) littermates were fed with methionine-choline deficient (MCD) or control diet to induce steatohepatitis. The Gsdmd -/- and WT mice were also used in a high-fat diet (HFD)-induced NAFLD model. In addition, Alb-Cre mice were administered an adeno-associated virus (AAV) vector that expressed the gasdermin-N domain (AAV9-FLEX-GSDMD-N) and were fed with either MCD or control diet for 10 days. Results GSDMD and its pyroptosis-inducing fragment GSDMD-N were upregulated in liver tissues of human NAFLD/NASH. Importantly, hepatic GSDMD-N protein levels were significantly higher in human NASH and correlated with the NAFLD activity score and fibrosis. GSDMD-N remained a potential biomarker for the diagnosis of NASH. MCD-fed Gsdmd -/- mice exhibit decreased severity of steatosis and inflammation compared with WT littermates. GSDMD was associated with the secretion of pro-inflammatory cytokines (IL-1β, TNF-α, and MCP-1 [CCL2]) and persistent activation of the NF-ĸB signali…
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Hepatocytes begin to die by lytic forms of cell death including necroptosis, pyroptosis and ferroptosis, causing damage to surrounding tissue.
“Hepatocytes begin to die by lytic forms of cell death including necroptosis(202, 203), pyroptosis(204, 205) and ferroptosis(206), causing damage to surrounding tissue.”
From The liver as a central "hub" of the immune system: pathophysiological implications (2025) · cites this paper as [204]
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References 45 · Cited by 426
- Authors
- Xu, B., Jiang, M., Chu, Y., Wang, W., Chen, D., Li, X., Zhang, Z., Zhang, D., Fan, D., Nie, Y., Shao, F., Wu, K., & Liang, J.
- Affiliations
- National Clinical Research Center for Digestive Diseases (CN)
- People's Liberation Army Air Force (CN)
- National Institute of Biological Sciences, Beijing (CN)
- Corresponding author
- Wu, Kaichun
- Liang, Jie
- ORCID
- Venue
- Journal of Hepatology
- Publisher
- Elsevier BV
- Published
- 2018-04
- Volume
- 68
- Issue
- 4
- Pages
- 773-782
- ISSN
- 0168-8278 (ISSN-L)
- OpenAlex
- W2778492404
- Cited by
- 426
- References
- 45
- Citations by year
- 2026: 34 · 2025: 57 · 2024: 64 · 2023: 63 · 2022: 67 · 2021: 63 · 2020: 47 · 2019: 21 · 2018: 9
- FWCI
- 16.49
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Hepatology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (81421003, 81730016, 81322037, 81572302, 81772650)
- Independent Funds of the Key Laboratory (CBSKL2015Z12)
- Topics
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Keywords
- gasdermin D, pyroptosis, nonalcoholic steatohepatitis, non-alcoholic fatty liver disease, necroptosis, GSDMD-N, steatosis, liver inflammation, NF-κB signaling, SREBP-1c, lipogenesis, lipolysis, IL-1β, TNF-α, MCP-1, methionine-choline-deficient diet, high-fat diet
- MeSH terms
- Pyroptosis, Gasdermins, Animals, Cells, Cultured, Humans, Lipolysis, Liver, Male, Mice, Inbred C57BL, Neoplasm Proteins, Cytokines, NF-kappa B, Phosphate-Binding Proteins, Intracellular Signaling Peptides and Proteins, Apoptosis Regulatory Proteins, Mice, Diet, High-Fat, Non-alcoholic Fatty Liver Disease
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