ArticleMolecular cancer research : MCR2023
Absence of Either Ripk3 or Mlkl Reduces Incidence of Hepatocellular Carcinoma Independent of Liver Fibrosis.
Article in Molecular cancer research : MCR, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 25 citations in OpenAlex.
- A Non-Canonical Role for Hepatocyte MLKL in Promoting Mitochondrial Dysfunction and Senescence in the Aging Liver.Aging cell · 2026Article
- Necroptosis induced by MLKL overexpression in liver triggers cellular senescence and leads to chronic inflammation and fibrosis.GeroScience · 2026Article
- Regulated necrosis at the crossroads of liver inflammation and cancer development.Nature reviews. Gastroenterology & hepatology · 2026Review
- RIPK3 Orchestrates Scar-Associated Macrophage Dysfunction to Drive Pulmonary Fibrosis.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- MLKL in liver parenchymal cells promotes liver cancer in murine metabolic dysfunction-associated steatotic liver disease.Cell death & disease · 2026Article
- Focus on necroptosis: its role in the pathogenesis and therapeutic potential of osteoarthritis.Frontiers in immunology · 2026Review
- The effect of enhanced glycolysis on cardiac aging.GeroScience · 2025Article
- Impact of Mlkl or Ripk3 deletion on age-associated liver inflammation, metabolic health, and lifespan.GeroScience · 2025Article
- Necroptosis in obesity: a complex cell death event.Apoptosis : an international journal on programmed cell death · 2025Review
- MLKL deficiency elevates testosterone production in male mice independently of necroptotic functions.Cell death & disease · 2024Article
- Review
- MLKL overexpression leads to CaCell calcium · 2024Article
- Necroptosis contributes to non-alcoholic fatty liver disease pathoetiology with promising diagnostic and therapeutic functions.World journal of gastroenterology · 2024Review
- Cell Death in Liver Disease and Liver Surgery.Biomedicines · 2024Review
- Non-Necroptotic Roles of MLKL in Diet-Induced Obesity, Liver Pathology, and Insulin Sensitivity: Insights from a High-Fat, High-Fructose, High-Cholesterol Diet Mouse Model.International journal of molecular sciences · 2024Article
- Mediators of necroptosis: from cell death to metabolic regulation.EMBO molecular medicine · 2024Review
- Characterization of novel mouse models to study the role of necroptosis in aging and age-related diseases.GeroScience · 2023Article
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Authors and funding
16 authors at 5 institutions in 1 country.
Funding
Abstract
Nonalcoholic fatty liver disease (NAFLD) is one of the etiologies that contribute to hepatocellular carcinoma (HCC), and chronic inflammation is one of the proposed mediators of HCC. Because necroptosis is a cell death pathway that induces inflammation, we tested whether necroptosis-induced inflammation contributes to the progression of NAFLD to HCC in a mouse model of diet-induced HCC. Male and female wild-type (WT) mice and mouse models where necroptosis is blocked (Ripk3-/- or Mlkl-/- mice) were fed either a control diet, choline-deficient low-fat diet or choline-deficient high-fat diet. Blocking necroptosis reduced markers of inflammation [proinflammatory cytokines (TNFα, IL6, and IL1β), F4/80+ve macrophages, CCR2+ve infiltrating monocytes], inflammation-associated oncogenic pathways (JNK, PD-L1/PD-1, β-catenin), and HCC in male mice. We demonstrate that hepatic necroptosis promotes recruitment and activation of liver macrophages leading to chronic inflammation, which in turn trigger oncogenic pathways leading to the progression of NAFLD to HCC in male mice. Whereas in female mice, blocking necroptosis reduced HCC independent of inflammation. Our data show a sex-specific difference in the development of inflammation, fibrosis, and HCC in WT mice. However, blocking necroptosis reduced HCC in both males and females without altering liver fibrosis. Thus, our study suggests that necroptosis is a valid therapeutic target for NAFLD-mediated HCC. IMPLICATIONS: Necroptosis is a major contributor to hepatic inflammation that drives the progression of NAFLD to HCC and therefore represents a valid target for NAFLD-mediated HCC.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.