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The purinergic P2Y14 receptor links hepatocyte death to hepatic stellate cell activation and fibrogenesis in the liver
Open accessAbstract
Fibrosis contributes to ~45% of deaths in western countries. In chronic liver disease, fibrosis is a major factor determining outcomes, but efficient antifibrotic therapies are lacking. Although platelet-derived growth factor and transforming growth factor–β constitute key fibrogenic mediators, they do not account for the well-established link between cell death and fibrosis in the liver. Here, we hypothesized that damage-associated molecular patterns (DAMPs) may link epithelial cell death to fibrogenesis in the injured liver. DAMP receptor screening identified purinergic receptor P2Y14 among several candidates as highly enriched in hepatic stellate cells (HSCs), the main fibrogenic cell type of the liver. Conversely, P2Y14 ligands uridine 5′-diphosphate (UDP)–glucose and UDP-galactose were enriched in hepatocytes and were released upon different modes of cell death. Accordingly, ligand-receptor interaction analysis that combined proteomic and single-cell RNA sequencing data revealed P2Y14 ligands and P2Y14 receptor as a link between dying cells and HSCs, respectively. Treatment with P2Y14 ligands or coculture with dying hepatocytes promoted HSC activation in a P2Y14-dependent manner. P2Y14 ligands activated extracellular signal–regulated kinase (ERK) and Yes-associated protein (YAP) signaling in HSCs, resulting in ERK-dependent HSC activation. Global and HSC-selective P2Y14 deficiency attenuated liver fibrosis in multiple mouse models of liver injury. Functional expression of P2Y14 was confirmed in healthy and diseased human liver and human HSCs. In conclusion, P2Y14 ligands and their receptor constitute a profibrogenic DAMP pathway that directly links cell death to fibrogenesis.
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“Mederacke et al. uncovered the purinergic receptor P2Y14 as highly enriched on HSCs and showed that the P2Y14 ligands UDP-glucose, UDP-galactose and UDP-glucuronic acid act as danger signals that are released upon liver injury and promote HSC activation and liver fibrosis.48”
From Understanding the cellular interactome of non-alcoholic fatty liver disease (2022) · cites this paper as [48]
In the citing paper
“Dying or damaged hepatocytes secrete damage-associated molecular patterns including high mobility group box 1 protein (HMGB1), osteopontin (SPP1), purinoceptor 14 (P2Y14) ligands, apoptotic bodies, microRNA (miRNA), and DNA that can be packaged into microvesicles and directly taken up by HSCs, leading to their activation into collagen-producing myofibroblasts (see “Cellular plasticity”, below) (23”
From Found in translation—Fibrosis in metabolic dysfunction–associated steatohepatitis (MASH) (2023) · cites this paper as [31]
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Research works printed but not linked: 1
- National Research Council Division on Earth and Life Studies Institute for Laboratory Animal Research Committee for the Update of the Guide for the Care and Use of Laboratory Animals Guide for the Care and Use of Laboratory Animals (The National Academies Press Washington DC ed. 8 2011).
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Hepatic inflammatory responses in liver fibrosis
Hammerich, L., & Tacke, F. (2023) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-023-00807-x · Cited by 803
Akkız, H., Gieseler, R. K., & Canbay, A. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25147873 · Cited by 191
“In mice, an experimental P2Y 14 deficiency led to reduced fibrosis [65].”
BackgroundFound in translation—Fibrosis in metabolic dysfunction–associated steatohepatitis (MASH)
Wang, S., & Friedman, S. L. (2023) · Science Translational Medicine · doi:10.1126/scitranslmed.adi0759 · Cited by 158
“…(SPP1), purino-ceptor 14 (P2Y14) ligands, apoptotic bodies, microRNA (miRNA), and DNA that can be packaged into microvesicles and directly taken up by HSCs, leading to their activation into collagen-producing my-ofibroblasts (see the “ Cellular plasticity and heterogeneity ” section) ( 23 – 31 ).”
BackgroundUnderstanding the cellular interactome of non-alcoholic fatty liver disease
Wallace, S. J., Tacke, F., Schwabe, R. F., & Henderson, N. C. (2022) · JHEP Reports · doi:10.1016/j.jhepr.2022.100524 · Cited by 116
“uncovered the purinergic receptor P2Y14 as highly enriched on HSCs and showed that the P2Y14 ligands UDP-glucose, UDP-galactose and UDP-glucuronic acid act as danger signals that are released upon liver injury and promote HSC activation and liver fibrosis.(48)”
BackgroundSelf-citationSchwabe, R. F., & Brenner, D. A. (2025) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-025-01068-6 · Cited by 112
“A wide range of additional mediators, including angiotensin, leptin, IGF1 and P2Y14 ligands, have been described to contribute to HSC activation, proliferation and migration 7,167–172 .”
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Metadata
- Authors
- Mederacke, I., Filliol, A., Affo, S., Nair, A., Hernandez, C., Sun, Q., Hamberger, F., Brundu, F., Chen, Y., Ravichandra, A., Huebener, P., Anke, H., Shi, H., Martínez García de la Torre, R. A., Smith, J. R., Henderson, N. C., Vondran, F. W. R., Rothlin, C. V., Baehre, H., Tabas, I., Sancho-Bru, P., & Schwabe, R. F.
- Affiliations
- Medizinische Hochschule Hannover (DE)
- Columbia University (US)
- Department of Medicine, Columbia University, New York, NY 10032, USA.
- Columbia University Irving Medical Center (US)
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
- Centre for Inflammation Research (GB)
- Yale University (US)
- Stiftung Charité (DE)
- Corresponding author
- Mederacke, Ingmar
- Filliol, Aveline
- Schwabe, Robert F.
- ORCID
- Mederacke, Ingmar
- Filliol, Aveline
- Affo, Silvia
- Nair, Ajay
- Hernandez, Celine
- Brundu, Francesco
- Ravichandra, Aashreya
- Huebener, Peter
- Shi, Hongxue
- Martínez García de la Torre, Raquel A.
- Smith, James R.
- Henderson, Neil C.
- Vondran, Florian W. R.
- Rothlin, Carla V.
- Baehre, Heike
- Tabas, Ira
- Sancho-Bru, Pau
- Schwabe, Robert F.
- Venue
- Science Translational Medicine
- Published
- 2022-04-06
- Volume
- 14
- Issue
- 639
- Pages
- eabe5795-eabe5795
- ISSN
- 1946-6234 (ISSN-L)
- 1946-6242
- PMC
- PMC9436006
- OpenAlex
- W4223585521
- Cited by
- 103
- References
- 71
- Citations by year
- 2026: 23 · 2025: 34 · 2024: 21 · 2023: 19 · 2022: 6
- FWCI
- 12.76
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science Translational Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- mediaTUM (Technical University of Munich) (submittedVersion)
- Funders
- Wellcome Trust (219542/Z/19/Z, 104366/Z/14/Z)
- National Institutes of Health (UL1TR001873)
- National Cancer Institute (R01CA200597, P30CA013696)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK124104, R01DK116620, P30DK132710)
- National Center for Advancing Translational Sciences
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Adenosine and Purinergic Signaling
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
- Keywords
- P2Y14 receptor, purinergic signaling, liver fibrosis, hepatic stellate cell activation, hepatocyte death, damage-associated molecular patterns, UDP-glucose, UDP-galactose, ERK signaling, YAP signaling, chronic liver disease, antifibrotic therapy
- MeSH terms
- YAP-Signaling Proteins, Animals, Humans, Ligands, Liver, Liver Cirrhosis, Uridine Diphosphate, Receptors, Purinergic P2, Hepatocytes, Proteomics, Extracellular Signal-Regulated MAP Kinases, Mice, Hepatic Stellate Cells, Receptors, Purinergic P2Y, Single-Cell Analysis
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