A positive feedback loop between RIP3 and JNK controls non‐alcoholic steatohepatitis
Open accessAbstract
Non‐alcoholic fatty liver disease (NAFLD) represents the most common liver disease in Western countries and often progresses to non‐alcoholic steatohepatitis (NASH) leading ultimately to liver fibrosis and liver cancer. The occurrence of hepatocyte cell death—so far characterized as hepatocyte apoptosis—represents a fundamental step from benign steatosis toward progressive steatohepatitis. In contrast, the function of RIP3‐dependent “necroptosis” in NASH and NASH‐induced fibrosis is currently unknown. We show that RIP3 is upregulated in human NASH and in a dietary mouse model of steatohepatitis. RIP3 mediates liver injury, inflammation, induction of hepatic progenitor cells/activated cholangiocytes, and liver fibrosis through a pathway suppressed by Caspase‐8. This function of RIP3 is mediated by a positive feedback loop involving activation of Jun‐(N)‐terminal Kinase (JNK). Furthermore, RIP3‐dependent JNK activation promotes the release of pro‐inflammatory mediators like MCP‐1, thereby attracting macrophages to the injured liver and further augmenting RIP3‐dependent signaling, cell death, and liver fibrosis. Thus, RIP3‐dependent necroptosis controls NASH‐induced liver fibrosis. This pathway might represent a novel and specific target for pharmacological strategies in patients with NASH.
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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 [203]
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- Authors
- Gautheron, J., Vucur, M., Reisinger, F., Cardenas, D. V., Roderburg, C., Koppe, C., Kreggenwinkel, K., Schneider, A. T., Bartneck, M., Neumann, U. P., Canbay, A., Reeves, H. L., Luedde, M., Tacke, F., Trautwein, C., Heikenwalder, M., & Luedde, T.
- Affiliations
- Universitätsklinikum Aachen (DE)
- Helmholtz Munich (DE)
- Essen University Hospital (DE)
- Newcastle upon Tyne Hospitals NHS Foundation Trust (GB)
- University Hospital Schleswig-Holstein (DE)
- Corresponding author
- Luedde, Tom
- ORCID
- Venue
- EMBO Molecular Medicine
- Published
- 2014-06-24
- Volume
- 6
- Issue
- 8
- Pages
- 1062-1074
- ISSN
- 1757-4676 (ISSN-L)
- 1757-4684
- PMC
- PMC4154133
- OpenAlex
- W2170005129
- Cited by
- 314
- References
- 8
- Citations by year
- 2026: 12 · 2025: 16 · 2024: 28 · 2023: 36 · 2022: 30 · 2021: 23 · 2020: 31 · 2019: 28 · 2018: 34 · 2017: 26 · 2016: 21 · 2015: 23 · 2014: 5
- FWCI
- 18.88
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- EMBO Molecular Medicine (publishedVersion, other-oa)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion)
- Site cant be reached (submittedVersion, cc-by)
- RWTH Publications (RWTH Aachen) (submittedVersion, other-oa)
- RWTH Publications (RWTH Aachen)
- Newcastle University ePrints (Newcastle Univesity) (cc-by)
- Funders
- German‐Research‐Foundation (SFB‐TRR57 / P06, SFB‐TR36)
- German Cancer Aid
- Deutsche Krebshilfe (110043)
- ERC (ERC‐2007‐Stg/208237‐Luedde‐Med3‐Aachen)
- EMBO Young Investigator Program
- Ernst‐Jung‐Foundation/Hamburg
- Interdisciplinary‐Centre‐for‐Clinical‐Research
- medical faculty of the RWTH Aachen
- Helmholtz Foundation
- Hofschneider Foundation
- Deutsche Stiftung Herzforschung (12/12)
- Topics
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- RIPK3, JNK, necroptosis, nonalcoholic steatohepatitis, liver fibrosis, caspase-8, positive feedback loop, hepatocyte death, MCP-1, macrophage recruitment, liver inflammation, hepatic progenitor cells, cholangiocytes, non-alcoholic fatty liver disease
- MeSH terms
- Animals, Disease Models, Animal, Gene Expression Regulation, Humans, Liver, Chemokine CCL2, MAP Kinase Kinase 4, Mice, Receptor-Interacting Protein Serine-Threonine Kinases, Non-alcoholic Fatty Liver Disease
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