ArticleHepatology (Baltimore, Md.)2014
Cholangiocyte senescence by way of N-ras activation is a characteristic of primary sclerosing cholangitis.
Article in Hepatology (Baltimore, Md.), 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 127 papers.
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Who cites it
127 citing papers in PubMed, 244 citations in OpenAlex.
- Prospective Clinical Trial of Rifaximin Therapy for Patients With Primary Sclerosing Cholangitis.American journal of therapeuticsTrial
- Cholangiocyte biology in primary sclerosing cholangitis and other cholangiopathies: pathogenesis, clinical insights, and experimental tools.Physiological reviews · 2026Review
- Plasma Biomarkers of Senescence in Cholestatic Liver Disease: A Signature of Risk Stratification and Progression.Journal of gastroenterology and hepatology · 2026Article
- Cholestatic and autoimmune liver diseases, bile duct injury, oxidative stress, and therapeutic strategies.Frontiers in physiology · 2026Review
- Cellular senescence in liver diseases: From molecular drivers to therapeutic targeting.Journal of hepatology · 2026Review
- Conserved Ductular Reaction Mechanisms in Biliary Atresia and Primary Sclerosing Cholangitis Derived From Single-Cell and Spatial Transcriptomics.Cellular and molecular gastroenterology and hepatology · 2026Review
- Taurocholic acid induces intrahepatic cholangiocyte cell proliferation via activating NRAS and YAP1.PloS one · 2026Article
- RIPK1 inhibition reduces biliary injury and fibrosis in primary sclerosing cholangitis.Science advances · 2025Article
- Central role for cholangiocyte pathobiology in cholestatic liver diseases.Hepatology (Baltimore, Md.) · 2025Review
- Development and Validation of a Scaffold-Free Human Multilineage Spheroid Model for Early Stage Cholangiopathies Driven by Cholangiocyte Senescence.Liver international : official journal of the International Association for the Study of the Liver · 2025Article
- Review
- Gut Microbiome and Bile Acid Interactions: Mechanistic Implications for Cholangiocarcinoma Development, Immune Resistance, and Therapy.The American journal of pathology · 2025Review
- Single-Nuclei RNA Sequencing Shows the Engagement of PPAR-Delta Target Genes Primarily in Hepatocytes and Cholangiocytes by the Selective PPAR-Delta Agonist Seladelpar.PPAR research · 2025Article
- Review
- Bile Acid Signaling in Metabolic and Inflammatory Diseases and Drug Development.Pharmacological reviews · 2024Review
- Bile Acids-Based Therapies for Primary Sclerosing Cholangitis: Current Landscape and Future Developments.Cells · 2024Review
- Single-Cell Transcriptomic Profiling of Cholangiocyte Organoids Derived from Bile Ducts of Primary Sclerosing Cholangitis Patients.Digestive diseases and sciences · 2024Article
- Regulation of intestinal senescence during cholestatic liver disease modulates barrier function and liver disease progression.JHEP reports : innovation in hepatology · 2024Article
- Surrogate markers of bile duct disease progression in primary sclerosing cholangitis - A prospective study with repeated ERCP examinations.JHEP reports : innovation in hepatology · 2024Article
- Cell competition in primary and metastatic colorectal cancer.Oncogenesis · 2024Review
67 more citing papers are in PubMed but not listed here.
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
unlabelledPrimary sclerosing cholangitis (PSC) is an incurable cholangiopathy of unknown etiopathogenesis. Here we tested the hypothesis that cholangiocyte senescence is a pathophysiologically important phenotype in PSC. We assessed markers of cellular senescence and senescence-associated secretory phenotype (SASP) in livers of patients with PSC, primary biliary cirrhosis, hepatitis C, and in normals by fluorescent in situ hybridization (FISH) and immunofluorescence microscopy (IFM). We tested whether endogenous and exogenous biliary constituents affect senescence and SASP in cultured human cholangiocytes. We determined in coculture whether senescent cholangiocytes induce senescence in bystander cholangiocytes. Finally, we explored signaling mechanisms involved in cholangiocyte senescence and SASP. In vivo, PSC cholangiocytes expressed significantly more senescence-associated p16(INK4a) and γH2A.x compared to the other three conditions; expression of profibroinflammatory SASP components (i.e., IL-6, IL-8, CCL2, PAI-1) was also highest in PSC cholangiocytes. In vitro, several biologically relevant endogenous (e.g., cholestane 3,5,6 oxysterol) and exogenous (e.g., lipopolysaccharide) molecules normally present in bile induced cholangiocyte senescence and SASP. Furthermore, experimentally induced senescent human cholangiocytes caused senescence in bystander cholangiocytes. N-Ras, a known inducer of senescence, was increased in PSC cholangiocytes and in experimentally induced senescent cultured cholangiocytes; inhibition of Ras abrogated experimentally induced senescence and SASP.
conclusionCholangiocyte senescence induced by biliary constituents by way of N-Ras activation is an important pathogenic mechanism in PSC. Pharmacologic inhibition of N-Ras with a resultant reduction in cholangiocyte senescence and SASP is a new therapeutic approach for PSC.
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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.