ArticleHepatology (Baltimore, Md.)2018
Targeting senescent cholangiocytes and activated fibroblasts with B-cell lymphoma-extra large inhibitors ameliorates fibrosis in multidrug resistance 2 gene knockout (Mdr2
Article in Hepatology (Baltimore, Md.), 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 85 papers.
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Who cites it
85 citing papers in PubMed, 128 citations in OpenAlex.
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- Preclinical Evaluation of Combined Polo-like Kinase 1 Inhibition and Navitoclax in Experimental Models of Lung Cancer.International journal of molecular sciences · 2026Article
- Melatonin Alleviates Graft Biliary Fibrosis by Inhibiting VIMAdvanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Cellular senescence in liver diseases: From molecular drivers to therapeutic targeting.Journal of hepatology · 2026Review
- Cellular senescence in Crohn's disease: a double-edged sword in intestinal fibrosis.Frontiers in immunology · 2026Review
- Mesothelin/Mucin 16 Signaling in Activated Portal Fibroblasts Drives the Development of Cholestatic Fibrosis and Hepatocellular Carcinoma in Aged Female Multidrug Resistance Protein 2 Knockout Mice.Cellular and molecular gastroenterology and hepatology · 2026Article
- Senotherapeutics in Malignant Brain Cancer Therapy.Current oncology reports · 2025Review
- Targeting the BCL2 Family: Advances and Challenges in BH3 Mimetic-Based Therapies.International journal of molecular sciences · 2025Review
- 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
- Microenvironmental control of the ductular reaction: balancing repair and disease progression.Cell death & disease · 2025Review
- The BCL2 family: from apoptosis mechanisms to new advances in targeted therapy.Signal transduction and targeted therapy · 2025Review
- Review
- SenNet recommendations for detecting senescent cells in different tissues.Nature reviews. Molecular cell biology · 2024Review
- Regulation of intestinal senescence during cholestatic liver disease modulates barrier function and liver disease progression.JHEP reports : innovation in hepatology · 2024Article
- Biliary fibrosis is an important but neglected pathological feature in hepatobiliary disorders: from molecular mechanisms to clinical implications.Medical review (2021) · 2024Review
- Ageing microenvironment mediates lymphocyte carcinogenesis and lymphoma drug resistance: From mechanisms to clinical therapy (Review).International journal of oncology · 2024Review
- Unlocking the Therapeutic Potential of BCL-2 Associated Protein Family: Exploring BCL-2 Inhibitors in Cancer Therapy.Biomolecules & therapeutics · 2024Review
- Validation of NBD-coupled taurocholic acid for intravital analysis of bile acid transport in liver and kidney of mice.EXCLI journal · 2024Article
- The potential for senotherapy as a novel approach to extend life quality in veterinary medicine.Frontiers in veterinary science · 2024Review
25 more citing papers are in PubMed but not listed here.
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Authors and funding
17 authors at 4 institutions in 3 countries.
Funding
Abstract
Cholangiocyte senescence has been linked to primary sclerosing cholangitis (PSC). Persistent secretion of growth factors by senescent cholangiocytes leads to the activation of stromal fibroblasts (ASFs), which are drivers of fibrosis. The activated phenotype of ASFs is characterized by an increased sensitivity to apoptotic stimuli. Here, we examined the mechanisms of apoptotic priming in ASFs and explored a combined targeting strategy to deplete senescent cholangiocytes and ASFs from fibrotic tissue to ameliorate liver fibrosis. Using a coculture system, we determined that senescent cholangiocytes promoted quiescent mesenchymal cell activation in a platelet-derived growth factor (PDGF)-dependent manner. We also identified B-cell lymphoma-extra large (Bcl-xL) as a key survival factor in PDGF-activated human and mouse fibroblasts. Bcl-xL was also up-regulated in senescent cholangiocytes. In vitro, inhibition of Bcl-xL by the small molecule Bcl-2 homology domain 3 mimetic, A-1331852, or Bcl-xL-specific small interfering RNA induced apoptosis in PDGF-activated fibroblasts, but not in quiescent fibroblasts. Likewise, inhibition of Bcl-xL reduced the survival and increased apoptosis of senescent cholangiocytes, compared to nonsenescent cells. Treatment of multidrug resistance 2 gene knockout (Mdr2
conclusionBcl-xL is a key survival factor in ASFs as well as in senescent cholangiocytes. Treatment with the Bcl-xL-specific inhibitor, A-1331852, reduces liver fibrosis, possibly by a dual effect on activated fibroblasts and senescent cholangiocytes. This mechanism represents an attractive therapeutic strategy in biliary fibrosis. (Hepatology 2018;67:247-259).
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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.