ArticleScience advances2025
Hyperammonemia induces programmed liver cell death.
Article in Science advances, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers, 1 of them a synthesis that pooled it.
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Who cites it
15 citing papers in PubMed, 1 synthesis or guideline pooled it.
- Can ammonia scavenging treat MASLD? Evaluating the evidence for L-ornithine L-aspartate-A systematic review.European journal of clinical investigation · 2026Pooled it
- Amino Acid Metabolism in Health and Disease.MedComm · 2026Review
- Review
- Precise delivery of medical gases by engineered nanomedicine for enhanced liver fibrosis therapy.Materials today. Bio · 2026Review
- Article
- The cGAS-STING pathway in senescence and aging-related diseases: mechanisms and therapeutic opportunities.Cell communication and signaling : CCS · 2026Review
- Nitric Oxide Synthase Dysregulation in Hyperammonemia: Opportunities and Challenges Toward Therapeutic Targeting to Combat Neurological Complications.Neurochemical research · 2026Review
- Human hepatic cell line 5: In-vitro model for hepatic immunobiology.Molecular biology reports · 2026Article
- Hepatocyte HIF2α Downregulates the Urea Cycle Through Suppression of HNF4α.Gastro hep advances · 2026Article
- Targeting Kupffer Cell CD44-Mediated Ammonia Death via the ELAVL1-GLS Metabolic Circuit in Radiation-Induced Liver Disease.International journal of biological sciences · 2026Article
- RIPK1 inhibition reduces biliary injury and fibrosis in primary sclerosing cholangitis.Science advances · 2025Article
- Ammonia in cancer: dual roles and therapeutic strategies.Cancer cell international · 2025Review
- O-GlcNAc as ammonia-induced glycosylation during the development of hyperammonemia.Journal of molecular histology · 2025Article
- Nitrogen Scavengers: History, Clinical Considerations and Future Prospects.Journal of inherited metabolic disease · 2025Review
- Unveiling ammonia-induced cell death: a new frontier in clear cell renal cell carcinoma prognosis.Frontiers in immunology · 2025Article
Corrections and comments
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Authors and funding
24 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Hyperammonemia is common in liver cirrhosis and causally associated with hepatic encephalopathy development. Little is known about its hepatotoxic effects, which we aimed to characterize in this study. In a mouse model of chronic hyperammonemia without preexisting liver disease, we observed development of liver fibrogenesis and necroptotic cell death. Hyperammonemia also induced dysregulation of its main metabolic pathway, the urea cycle, as reflected by down-regulation of urea cycle enzyme protein expression and accumulation of its metabolites. Inhibition of receptor-interacting serine/threonine-protein kinase 1 (RIPK1) and its upstream inducer Toll-like receptor 4 (TLR4) protected against liver injury and further hyperammonemia. In clinically relevant rodent models of hyperammonemia (genetic ornithine transcarbamylase deficiency and bile duct ligation-induced cirrhosis), TLR4 inhibition reduced circulating ammonia. In conclusion, hyperammonemia induces liver fibrogenesis and RIPK1-mediated cell death, which is associated with urea cycle dysfunction. Inhibition of RIPK1 and TLR4 protects against hyperammonemia-induced liver injury and are potential therapeutic targets for hyperammonemia and chronic liver disease progression.
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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.