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.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Mederacke et al. uncovered the purinergic receptor P2Y14 as highly enriched on HSCs and showed that P2Y14 ligands UDP-glucose, UDP-galactose and UDP-glucuronic acid act as danger signals released upon liver injury and promote HSC activation and liver fibrosis.
“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]
Dying or damaged hepatocytes release damage-associated molecular patterns, including HMGB1, SPP1, P2Y14 ligands, apoptotic bodies, miRNA, and DNA, which can be taken up by HSCs and activate them into collagen-producing myofibroblasts.
“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]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2
Love, M. I., Huber, W., & Anders, S. (2014) · Genome Biology · doi:10.1186/s13059-014-0550-8 · Cited by 95,106 · see citing works
Fast unfolding of communities in large networks
Blondel, V. D., Guillaume, J.-L., Lambiotte, R., & Lefebvre, E. (2008) · Journal of Statistical Mechanics: Theory and Experiment · doi:10.1088/1742-5468/2008/10/p10008 · Cited by 21,424 · see citing works
Silhouettes: A graphical aid to the interpretation and validation of cluster analysis
Rousseeuw, P. J. (1987) · Journal of Computational and Applied Mathematics · doi:10.1016/0377-0427(87)90125-7 · Cited by 21,392 · see citing works
Complex heatmaps reveal patterns and correlations in multidimensional genomic data
Gu, Z., Eils, R., & Schlesner, M. (2016) · Bioinformatics · doi:10.1093/bioinformatics/btw313 · Cited by 10,122 · see citing works
UMAP: Uniform Manifold Approximation and Projection
McInnes, L., Healy, J., Saul, N., & Großberger, L. (2018) · Journal of Open Source Software · doi:10.21105/joss.00861 · Cited by 9,826 · see citing works
SCANPY: large-scale single-cell gene expression data analysis
Wolf, F. A., Angerer, P., & Theis, F. J. (2018) · Genome Biology · doi:10.1186/s13059-017-1382-0 · Cited by 8,881 · see citing works
UMAP: Uniform Manifold Approximation and Projection for Dimension Reduction
McInnes, L., Healy, J., & Melville, J. (2018) · arXiv · doi:10.48550/arxiv.1802.03426 · Cited by 7,101 · see citing works
Burden of liver diseases in the world
Asrani, S. K., Devarbhavi, H., Eaton, J., & Kamath, P. S. (2019) · Journal of Hepatology · doi:10.1016/j.jhep.2018.09.014 · Cited by 3,783 · see citing works
Mechanisms of fibrosis: therapeutic translation for fibrotic disease
Wynn, T. A., & Ramalingam, T. R. (2012) · Nature Medicine · doi:10.1038/nm.2807 · Cited by 3,541 · see citing works
Efremova, M., Vento-Tormo, M., Teichmann, S. A., & Vento-Tormo, R. (2020) · Nature Protocols · doi:10.1038/s41596-020-0292-x · Cited by 3,449 · see citing works
Angulo, P., Kleiner, D. E., Dam-Larsen, S., Adams, L. A., Bjornsson, E. S., Charatcharoenwitthaya, P., Mills, P. R., Keach, J. C., Lafferty, H. D., Stahler, A., et al. (2015) · Gastroenterology · doi:10.1053/j.gastro.2015.04.043 · Cited by 2,987 · see citing works
Mechanisms of hepatic stellate cell activation
Tsuchida, T., & Friedman, S. L. (2017) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/nrgastro.2017.38 · Cited by 2,909 · see citing works
Ekstedt, M., Hagström, H., Nasr, P., Fredrikson, M., Stål, P., Kechagias, S., & Hultcrantz, R. (2015) · Hepatology · doi:10.1002/hep.27368 · Cited by 2,287 · see citing works
Dulai, P. S., Singh, S., Patel, J., Soni, M., Prokop, L. J., Younossi, Z., Sebastiani, G., Ekstedt, M., Hagstrom, H., Nasr, P., et al. (2017) · Hepatology · doi:10.1002/hep.29085 · Cited by 1,965 · see citing works
TLR4 enhances TGF-β signaling and hepatic fibrosis
Seki, E., De Minicis, S., Österreicher, C. H., Kluwe, J., Osawa, Y., Brenner, D. A., & Schwabe, R. F. (2007) · Nature Medicine · doi:10.1038/nm1663 · Cited by 1,942 · see citing works
Self-citationFibrosis: from mechanisms to medicines
Henderson, N. C., Rieder, F., & Wynn, T. A. (2020) · Nature · doi:10.1038/s41586-020-2938-9 · Cited by 1,868 · see citing works
Self-citationMapping the Mouse Cell Atlas by Microwell-Seq
Han, X., Wang, R., Zhou, Y., Fei, L., Sun, H., Lai, S., Saadatpour, A., Zhou, Z., Chen, H., Ye, F., et al. (2018) · Cell · doi:10.1016/j.cell.2018.02.001 · Cited by 1,597 · see citing works
Self-citationSingle cell RNA sequencing of human liver reveals distinct intrahepatic macrophage populations
MacParland, S. A., Liu, J. C., Ma, X.-Z., Innes, B. T., Bartczak, A. M., Gage, B. K., Manuel, J., Khuu, N., Echeverri, J., Linares, I., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-06318-7 · Cited by 1,552 · see citing works
Mederacke, I., Hsu, C. C., Troeger, J. S., Huebener, P., Mu, X., Dapito, D. H., Pradere, J.-P., & Schwabe, R. F. (2013) · Nature Communications · doi:10.1038/ncomms3823 · Cited by 1,443 · see citing works
Self-citationNecroptosis: The Release of Damage-Associated Molecular Patterns and Its Physiological Relevance
Kaczmarek, A., Vandenabeele, P., & Krysko, D. V. (2013) · Immunity · doi:10.1016/j.immuni.2013.02.003 · Cited by 1,411 · see citing works
Prospective Study of Outcomes in Adults with Nonalcoholic Fatty Liver Disease
Sanyal, A. J., Van Natta, M. L., Clark, J., Neuschwander-Tetri, B. A., Diehl, A., Dasarathy, S., Loomba, R., Chalasani, N., Kowdley, K., Hameed, B., et al. (2021) · New England Journal of Medicine · doi:10.1056/nejmoa2029349 · Cited by 1,146 · see citing works
Pooling across cells to normalize single-cell RNA sequencing data with many zero counts
L. Lun, A. T., Bach, K., & Marioni, J. C. (2016) · Genome Biology · doi:10.1186/s13059-016-0947-7 · Cited by 1,108 · see citing works
Efferocytosis in health and disease
Doran, A. C., Yurdagul, A., & Tabas, I. (2020) · Nature Reviews Immunology · doi:10.1038/s41577-019-0240-6 · Cited by 1,066 · see citing works
Self-citationHippo pathway effector Yap promotes cardiac regeneration
Xin, M., Kim, Y., Sutherland, L. B., Murakami, M., Qi, X., McAnally, J., Porrello, E. R., Mahmoud, A. I., Tan, W., Shelton, J. M., et al. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1313192110 · Cited by 895 · see citing works
Henderson, N. C., Arnold, T. D., Katamura, Y., Giacomini, M. M., Rodriguez, J. D., McCarty, J. H., Pellicoro, A., Raschperger, E., Betsholtz, C., Ruminski, P. G., et al. (2013) · Nature Medicine · doi:10.1038/nm.3282 · Cited by 866 · see citing works
Self-citationVilar-Gomez, E., Calzadilla-Bertot, L., Wai-Sun Wong, V., Castellanos, M., Aller-de la Fuente, R., Metwally, M., Eslam, M., Gonzalez-Fabian, L., Alvarez-Quiñones Sanz, M., Conde-Martin, A. F., et al. (2018) · Gastroenterology · doi:10.1053/j.gastro.2018.04.034 · Cited by 806 · see citing works
Cell Death and Cell Death Responses in Liver Disease: Mechanisms and Clinical Relevance
Luedde, T., Kaplowitz, N., & Schwabe, R. F. (2014) · Gastroenterology · doi:10.1053/j.gastro.2014.07.018 · Cited by 760 · see citing works
Self-citationClassification of low quality cells from single-cell RNA-seq data
Ilicic, T., Kim, J. K., Kolodziejczyk, A. A., Bagger, F. O., McCarthy, D. J., Marioni, J. C., & Teichmann, S. A. (2016) · Genome Biology · doi:10.1186/s13059-016-0888-1 · Cited by 693 · see citing works
Mechanisms of Fibrosis Development in Nonalcoholic Steatohepatitis
Schwabe, R. F., Tabas, I., & Pajvani, U. B. (2020) · Gastroenterology · doi:10.1053/j.gastro.2019.11.311 · Cited by 671 · see citing works
Self-citationYounossi, Z. M., Stepanova, M., Rafiq, N., Makhlouf, H. R., Younoszai, Z., Agrawal, R., & Goodman, Z. D. (2011) · Hepatology · doi:10.1002/hep.24268 · Cited by 636 · see citing works
Apoptosis and necroptosis in the liver: a matter of life and death
Schwabe, R. F., & Luedde, T. (2018) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-018-0065-y · Cited by 582 · see citing works
Self-citationHigh-yield and high-purity isolation of hepatic stellate cells from normal and fibrotic mouse livers
Mederacke, I., Dapito, D. H., Affò, S., Uchinami, H., & Schwabe, R. F. (2015) · Nature Protocols · doi:10.1038/nprot.2015.017 · Cited by 541 · see citing works
Self-citationMetabolites released from apoptotic cells act as tissue messengers
Medina, C. B., Mehrotra, P., Arandjelovic, S., Perry, J. S. A., Guo, Y., Morioka, S., Barron, B. J., Walk, S. F., Ghesquière, B., Krupnick, A. S., et al. (2020) · Nature · doi:10.1038/s41586-020-2121-3 · Cited by 513 · see citing works
Apoptotic Body Engulfment by a Human Stellate Cell Line Is Profibrogenic
Canbay, A., Taimr, P., Torok, N., Higuchi, H., Friedman, S., & Gores, G. J. (2003) · Laboratory Investigation · doi:10.1097/01.lab.0000069036.63405.5c · Cited by 417 · cited 3× · see citing works
“We could not find a role for TAM receptors AXL or MerTK on HSCs in fibrogenesis, consistent with our finding that macrophageexpressed MerTK regulates liver fibrosis (48), but we cannot exclude that the described phagocytosis of apoptotic bodies by HSC (24, 25) occurs through other mechanisms.”
BackgroundThe Hippo pathway effector YAP controls mouse hepatic stellate cell activation
Mannaerts, I., Leite, S. B., Verhulst, S., Claerhout, S., Eysackers, N., Thoen, L. F. R., Hoorens, A., Reynaert, H., Halder, G., & van Grunsven, L. A. (2015) · Journal of Hepatology · doi:10.1016/j.jhep.2015.04.011 · Cited by 410 · see citing works
Mapping the Mouse Cell Atlas by Microwell-Seq
Han, X., Wang, R., Zhou, Y., Fei, L., Sun, H., Lai, S., Saadatpour, A., Zhou, Z., Chen, H., Ye, F., et al. (2018) · Cell · doi:10.1016/j.cell.2018.05.012 · Cited by 384 · see citing works
Self-citationThe HMGB1/RAGE axis triggers neutrophil-mediated injury amplification following necrosis
Huebener, P., Pradère, J., Hernandez, C., Gwak, G., Caviglia, J. M., Mu, X., Loike, J. D., Jenkins, R. E., Antoine, D. J., & Schwabe, R. F. (2014) · Journal of Clinical Investigation · doi:10.1172/jci76887 · Cited by 353 · see citing works
Self-citationAn, P., Wei, L.-L., Zhao, S., Sverdlov, D. Y., Vaid, K. A., Miyamoto, M., Kuramitsu, K., Lai, M., & Popov, Y. V. (2020) · Nature Communications · doi:10.1038/s41467-020-16092-0 · Cited by 319 · cited 1× · see citing works
“2 of 11 DNA, and high-mobility group box 1 HMGB1 (11, 19–21)] and may trigger HSC activation in vitro (21).”
BackgroundThe HMGB1/RAGE axis triggers neutrophil-mediated injury amplification following necrosis
Huebener, P., Pradère, J., Hernandez, C., Gwak, G., Caviglia, J. M., Mu, X., Loike, J. D., Jenkins, R. E., Antoine, D. J., & Schwabe, R. F. (2019) · Journal of Clinical Investigation · doi:10.1172/jci126975 · Cited by 301 · see citing works
Self-citationZhan, S.-S., Jiang, J. X., Wu, J., Halsted, C., Friedman, S. L., Zern, M. A., & Torok, N. J. (2006) · Hepatology · doi:10.1002/hep.21093 · Cited by 284 · see citing works
Macrophage MerTK Promotes Liver Fibrosis in Nonalcoholic Steatohepatitis
Cai, B., Dongiovanni, P., Corey, K. E., Wang, X., Shmarakov, I. O., Zheng, Z., Kasikara, C., Davra, V., Meroni, M., Chung, R. T., et al. (2020) · Cell Metabolism · doi:10.1016/j.cmet.2019.11.013 · Cited by 266 · see citing works
Self-citationGlycogen metabolism regulates macrophage-mediated acute inflammatory responses
Ma, J., Wei, K., Liu, J., Tang, K., Zhang, H., Zhu, L., Chen, J., Li, F., Xu, P., Chen, J., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-15636-8 · Cited by 248 · see citing works
Magness, S. T., Bataller, R. A., Yang, L., & Brenner, D. A. (2004) · Hepatology · doi:10.1002/hep.20427 · Cited by 246 · see citing works
Adenosine A 2A receptors play a role in the pathogenesis of hepatic cirrhosis
Chan, E. S. L., Montesinos, M. C., Fernández, P., Desai, A., Delano, D. L., Yee, H. T., Reiss, A. B., Pillinger, M. H., Chen, J., Schwarzschild, M. A., et al. (2006) · British Journal of Pharmacology · doi:10.1038/sj.bjp.0706812 · Cited by 229 · see citing works
Martin, K., Pritchett, J. P., Llewellyn, J., Mullan, A. F., Athwal, V. S., Dobie, R., Harvey, E., Zeef, L. A. H., Farrow, S. N., Streuli, C. H., et al. (2016) · Nature Communications · doi:10.1038/ncomms12502 · Cited by 220 · see citing works
Self-citationMDR3 (ABCB4) Defects: A Paradigm for the Genetics of Adult Cholestatic Syndromes
Trauner, M. A., Fickert, P., & Wagner, M. (2007) · Seminars in Liver Disease · doi:10.1055/s-2006-960172 · Cited by 212 · see citing works
Scraping fibrosis: Expressway to the core of fibrosis
Mehal, W. Z., Iredale, J. P., & Friedman, S. L. (2011) · Nature Medicine · doi:10.1038/nm0511-552 · Cited by 204 · see citing works
Harris, R., Harman, D. J., Card, T. R., Aithal, G. P., & Guha, I. N. (2017) · The Lancet. Gastroenterology & hepatology · doi:10.1016/s2468-1253(16)30205-9 · Cited by 197 · see citing works
Marra, F., Arrighi, M. C., Fazi, M., Caligiuri, A., Pinzani, M., Romanelli, R. G., Efsen, E., Laffi, G., & Geñtilini, P. (1999) · Hepatology · doi:10.1002/hep.510300406 · Cited by 160 · see citing works
Release of Cellular UDP-Glucose as a Potential Extracellular Signaling Molecule
Lazarowski, E. R., Shea, D. A., Boucher, R. C., & Harden, T. K. (2003) · Molecular Pharmacology · doi:10.1124/mol.63.5.1190 · Cited by 147 · see citing works
Ge, X., Arriazu, E., Magdaleno, F., Antoine, D. J., Cruz, R. D., Theise, N. D., & Nieto, N. (2018) · Hepatology · doi:10.1002/hep.30093 · Cited by 142 · see citing works
HMGB1 links chronic liver injury to progenitor responses and hepatocarcinogenesis
Hernandez, C., Huebener, P., Pradere, J.-P., Antoine, D. J., Friedman, R. A., & Schwabe, R. F. (2018) · Journal of Clinical Investigation · doi:10.1172/jci91786 · Cited by 110 · see citing works
Self-citationFoglia, B., Cannito, S., Bocca, C., Parola, M., & Novo, E. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20112700 · Cited by 110 · see citing works
Che, J., Chan, E. S. L., & Cronstein, B. N. (2007) · Molecular Pharmacology · doi:10.1124/mol.107.038760 · Cited by 107 · see citing works
HMGB1 promotes ductular reaction and tumorigenesis in autophagy-deficient livers
Khambu, B., Huda, N., Chen, X., Antoine, D. J., Li, Y., Dai, G., Köhler, U. A., Zong, W., Waguri, S., Werner, S., et al. (2018) · Journal of Clinical Investigation · doi:10.1172/jci91814 · Cited by 105 · see citing works
Skelton, L., Cooper, M., Murphy, M., & Platt, A. (2003) · The Journal of Immunology · doi:10.4049/jimmunol.171.4.1941 · Cited by 105 · see citing works
Integrative miRNA and Gene Expression Profiling Analysis of Human Quiescent Hepatic Stellate Cells
Coll, M., Taghdouini, A. E., Perea, L., Mannaerts, I., Vila-Casadesús, M., Blaya, D., Rodrigo‐Torres, D., Affò, S., Morales‐Ibanez, O., Graupera, I., et al. (2015) · Scientific Reports · doi:10.1038/srep11549 · Cited by 91 · see citing works
Self-citationHuebener, P., Gwak, G.-Y., Pradere, J.-P., Quinzii, C. M., Friedman, R., Lin, C.-S., Trent, C. M., Mederacke, I., Zhao, E., Dapito, D. H., et al. (2014) · Cell Metabolism · doi:10.1016/j.cmet.2014.01.014 · Cited by 86 · see citing works
Functional expression of the P2Y14 receptor in human neutrophils
Scrivens, M., & Dickenson, J. M. (2006) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2006.05.037 · Cited by 78 · see citing works
Freeman, K. B., Tsui, P., Moore, D. J., Emson, P. C., Vawter, L., Naheed, S., Lane, P., Bawagan, H., Herrity, N. C., Murphy, K., et al. (2001) · Genomics · doi:10.1006/geno.2001.6662 · Cited by 77 · see citing works
Lackner, C., Stauber, R. E., Davies, S. E., Denk, H., Dienes, H. P., Gnemmi, V., Guido, M., Miquel, R., Paradis, V., Schirmacher, P., et al. (2021) · Journal of Hepatology · doi:10.1016/j.jhep.2021.05.029 · Cited by 75 · see citing works
Xu, F., Moorman, A. C., Tong, X., Gordon, S. C., Rupp, L. B., Lü, M., Teshale, E. H., Spradling, P. R., Boscarino, J. A., Trinacty, C. M., et al. (2015) · Clinical Infectious Diseases · doi:10.1093/cid/civ860 · Cited by 71 · see citing works
Sesma, J. I., Kreda, S. M., Steinckwich, N., Dang, H., García‐Mata, R., Harden, T. K., & Lazarowski, E. R. (2012) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00138.2012 · Cited by 71 · see citing works
Determining the effector response to cell death
Rothlin, C. V., Hille, T. D., & Ghosh, S. (2020) · Nature reviews. Immunology · doi:10.1038/s41577-020-00456-0 · Cited by 68 · see citing works
Self-citationGi-Dependent Cell Signaling Responses of the Human P2Y14 Receptor in Model Cell Systems
Fricks, I., Carter, R. L., Lazarowski, E. R., & Harden, T. K. (2009) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.109.150730 · Cited by 67 · see citing works
The G Protein-coupled Receptor P2Y14 Influences Insulin Release and Smooth Muscle Function in Mice
Meister, J., Duc, D. L., Ricken, A. M., Burkhardt, R., Thiery, J., Pfannkuche, H., Polte, T., Grosse, J., Schöneberg, T., & Schulz, A. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.580803 · Cited by 62 · see citing works
Isolation and Identification of Paracetamol Metabolites
Andrews, R. S., Bond, C. C., Burnett, J. E. C., Saunders, A., & Watson, K. V. (1976) · Journal of International Medical Research · doi:10.1177/14732300760040s408 · Cited by 56 · see citing works
P2Y receptor signaling regulates phenotype and IFN-α secretion of human plasmacytoid dendritic cells
Shin, A., Toy, T., Rothenfußer, S., Robson, N. C., Vorac, J., Dauer, M., Stuplich, M., Endres, S., Cebon, J. S., Maraskovsky, E., et al. (2007) · Blood · doi:10.1182/blood-2007-02-071910 · Cited by 55 · see citing works
A Random Matrix Theory Approach to Denoise Single-Cell Data
Aparicio, L., Bordyuh, M., Blumberg, A. J., & Rabadán, R. (2020) · Patterns · doi:10.1016/j.patter.2020.100035 · Cited by 47 · see citing works
UDP-glucose modulates gastric function through P2Y14 receptor-dependent and -independent mechanisms
Bassil, A. K., Bourdu, S., Townson, K. A., Wheeldon, A., Jarvie, E. M., Zebda, N., Abuin, A., Grau, E., Livi, G. P., Punter, L., et al. (2009) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.90363.2008 · Cited by 46 · see citing works
Hepatic UDP-glucuronic acid regulation during acetaminophen biotransformation in rats.
Hjelle, J. J. (1986) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(25)25022-4 · Cited by 27 · see citing works
Generation and Use of Chimeric RIP Kinase Molecules to Study Necroptosis
Rodríguez, D. A., & Green, D. R. (2018) · Methods in molecular biology · doi:10.1007/978-1-4939-8754-2_7 · Cited by 4 · see citing works
Flagged first, then by citations
Research works printed but not linked: 1
- [51]N. R. C. U. C. f. t. U. o. t. G. f. t. C. a. U. o. L. Animals., Guide for the Care and Use of Laboratory Animals, 8th edition. (The National Academies Press, Washington (DC):, 2011).
Cited by
Sorted by citations
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 · see citing works
Akkız, H., Gieseler, R. K., & Canbay, A. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25147873 · Cited by 191 · see citing works
“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 · see citing works
“…(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 · see citing works
“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 · see citing works
“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 .”
Self-citationHepatic Stellate Cells: Dictating Outcome in Nonalcoholic Fatty Liver Disease
Wiering, L., Subramanian, P., & Hammerich, L. (2023) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2023.02.010 · Cited by 80 · see citing works
Yan, M., Cui, Y., & Xiang, Q. (2025) · Theranostics · doi:10.7150/thno.106597 · Cited by 76 · see citing works
A spatiotemporal atlas of cholestatic injury and repair in mice
Wu, B., Shentu, X., Nan, H., Guo, P., Hao, S., Xu, J., Shangguan, S., Cui, L., Cen, J., Deng, Q., et al. (2024) · Nature Genetics · doi:10.1038/s41588-024-01687-w · Cited by 65 · see citing works
Spatial genomics: mapping human steatotic liver disease
Matchett, K. P., Paris, J., Teichmann, S. A., & Henderson, N. C. (2024) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-024-00915-2 · Cited by 52 · see citing works
“Then, using a combination of proteomics and ligand–receptor analysis of scRNAseq data, uridine 5′-diphosphate (UDP)-glucose, UDP-galactose and their receptor P2Y14 were uncovered as the ligand–receptor pair most strongly linking dying hepatocytes with HSC activation 48 .”
Self-citationInflammation and cancer: molecular mechanisms and clinical consequences
Akkız, H., Şimşek, H., Balcı, D., Ülger, Y., Onan, E., Ozturk, N. A., & Delik, A. (2025) · Frontiers in Oncology · doi:10.3389/fonc.2025.1564572 · Cited by 51 · see citing works
Liu, C., Wang, H., Han, L., Zhu, Y., Ni, S., Zhi, J., Yang, X., Zhi, J., Tian, S., Li, H., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-46365-x · Cited by 47 · see citing works
Antifibrotic therapies for metabolic dysfunction-associated steatotic liver disease
Schwabe, R. F., Tacke, F., Sugimoto, A., & Friedman, S. L. (2025) · JHEP Reports · doi:10.1016/j.jhepr.2025.101421 · Cited by 50 · see citing works
Self-citationZheng, Y., Xie, L., Yang, D., Luo, K., & Li, X. (2023) · Phytomedicine · doi:10.1016/j.phymed.2023.154721 · Cited by 32 · see citing works
Hepatic stellate cell heterogeneity: Functional aspects and therapeutic implications
Geng, Y., & Schwabe, R. F. (2025) · Hepatology · doi:10.1097/hep.0000000000001386 · Cited by 32 · see citing works
Self-citationEfferocytosis in liver disease
Shi, H., Moore, M. P., Wang, X., & Tabas, I. (2024) · JHEP Reports · doi:10.1016/j.jhepr.2023.100960 · Cited by 30 · see citing works
Self-citationCheng, Z., Chu, H., Seki, E., Lin, R., & Yang, L. (2024) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2024.1431921 · Cited by 30 · see citing works
UDP-glucose sensing P2Y14R: A novel target for inflammation
Zhang, J.-Z., Shi, N.-R., Wu, J., Wang, X., Illés, P., & Tang, Y. (2023) · Neuropharmacology · doi:10.1016/j.neuropharm.2023.109655 · Cited by 29 · see citing works
Shi, H., Wang, X., Sloas, C., Gerlach, B., Yurdagul, A., Moore, M. P., Jung, E. J., Mirshahi, F., Ronzoni, L., Sanyal, A. J., et al. (2025) · Science Translational Medicine · doi:10.1126/scitranslmed.adv2106 · Cited by 30 · see citing works
Self-citationWu, Z., Zeng, W., Yang, W., Yi, J., Liu, D., Xu, Y., Liu, C. X., Bian, K., Wang, H., & Zhang, B. (2025) · Science Advances · doi:10.1126/sciadv.adt6082 · Cited by 25 · see citing works
Li, Z., Peng, W., Zhou, J., Shui, S., Liu, Y., Li, T., Zhan, X., Chen, Y., Lan, F., Ying, B., et al. (2024) · Advanced Materials · doi:10.1002/adma.202312799 · Cited by 23 · see citing works
Self-citationWang, S., Gao, J., Yang, M., Zhang, G., Yin, L., & Tong, X. (2024) · Advanced Science · doi:10.1002/advs.202405678 · Cited by 26 · see citing works
Immunological dynamics in MASH: from landscape analysis to therapeutic intervention
Rabiu, L., Zhang, P., Afolabi, L. O., Saliu, M., Dabai, S. M., Suleiman, R. B., Gidado, K. I., Ige, M. A., Ibrahim, A., Zhang, G.-Z., et al. (2024) · Journal of gastroenterology · doi:10.1007/s00535-024-02157-0 · Cited by 23 · see citing works
“Myofibroblasts derived from HSCs are characterized by their expression of alpha-smooth muscle actin (αSMA) and their ability to secrete extracellular matrix (ECM) proteins such as collagen, contributing to the fibrotic scarring observed in MASH [72–75].”
Cellular heterogeneity and plasticity during NAFLD progression
Park, H., Choi, J., Kim, H.-M., Yang, D.-Y., An, T. H., Lee, E., Han, B., Lee, S. C., Kim, W. K., Bae, K., et al. (2023) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2023.1221669 · Cited by 22 · see citing works
“HSCs can be activated by P2Y14 ligands or secretory factors from dying hepatocytes in a P2Y14dependent manner (Mederacke et al., 2022).”
BackgroundDissecting the mechanisms of MASLD fibrosis in the era of single-cell and spatial omics
Colella, F., Henderson, N. C., & Ramachandran, P. (2025) · Journal of Clinical Investigation · doi:10.1172/jci186421 · Cited by 22 · see citing works
“…promote a profibrogenic phenotype, e.g., via release of mitochondria-derived damage-associated molecular patterns (DAMPs) (73), secretion of high-mobility group box-1 (HMGB1) (74), or activation of the purinergic receptor P2Y14 on HSCs through the production of UDP-glucose and UDP-galactose (75).”
Self-citationZhang, T., Wang, C., Song, A., Xiao, L., Li, G., Sun, H. M., Wang, X., Geng, Z., Shu, G., & Deng, X. (2023) · Journal of Ethnopharmacology · doi:10.1016/j.jep.2023.117495 · Cited by 21 · see citing works
Liu, Y., Zhang, M., Huang, Y., Zhang, Y., Chen, Z., Guan, J., Xia, S., & Liao, J. (2025) · Journal of Molecular Medicine · doi:10.1007/s00109-025-02599-w · Cited by 21 · see citing works
“Hepatic stellate cells (HSCs) can identify DAMPs and be activated, thereby promoting liver fibrogenesis [86].”
Caron, P., Long, F. N. V., Rouleau, M., Bujold, E., Fortin, P. R., Mohammadi, S., Lévesque, É., Breton, S., & Guillemette, C. (2022) · Journal of Chromatography A · doi:10.1016/j.chroma.2022.463296 · Cited by 17 · see citing works
Cell atlas of CCl4-induced progressive liver fibrosis reveals stage-specific responses
Guo, P.-C., 吉林大学动物医学学院人兽共患病研究所人兽共患病研究教育部重点实验室, 人., Zuo, J., Huang, K.-K., Lai, G., Zhang, X., An, J., Li, J., Li, L., Wu, L. L., et al. (2023) · 动物学研究 · doi:10.24272/j.issn.2095-8137.2023.031 · Cited by 17 · see citing works
“To complement and/or validate aspects of our work, we also reanalyzed data from previously published studies (Filliol et al., 2022; Mederacke et al., 2022; Yang et al., 2021).”
ResultGuo, Y., Mao, T., Fang, Y., Wang, H., Yu, J., Zhu, Y., Shen, S., Zhou, M., Li, H., & Hu, Q. (2024) · Journal of Advanced Research · doi:10.1016/j.jare.2024.03.027 · Cited by 16 · see citing works
Rueschpler, L., & Schloer, S. (2025) · Pharmacological Research · doi:10.1016/j.phrs.2025.107884 · Cited by 15 · see citing works
Garcia, N., Mellergaard, M., González-King, H., Salomon, C., & Handberg, A. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241713326 · Cited by 14 · see citing works
Ma, J., Xie, N., Wang, Z., Liang, X., Han, Y., Zhao, Q., Wang, M., Lu, H., Kou, W., Alazawi, W., et al. (2026) · Advanced Science · doi:10.1002/advs.202519109 · Cited by 14 · see citing works
Self-citationLiu, W., Mao, S., Wang, Y., Wang, M., Li, M., Sun, M., Yao, Y., Song, C., & Duan, Y. (2024) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.4c00555 · Cited by 13 · see citing works
Wang, L., Huang, Y., Chen, J., Gao, J., Chen, S., Zhao, M., Lin, J., Zhou, S., Shen, Y., & Cheng, Y. (2025) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2025.1635763 · Cited by 14 · see citing works
Zhou, M., Liu, C., Guo, Y., Qian, J., Wang, Y., Zhang, Z., Hao, K., Jiang, C., & Hu, Q. (2022) · International Immunopharmacology · doi:10.1016/j.intimp.2022.109507 · Cited by 12 · see citing works
The UDP-glucose/P2Y14 receptor axis promotes eosinophil-dependent large intestinal inflammation
Liu, L., Ito, T., Li, B., Tani, H., Okuzaki, D., Motooka, D., Miyazaki, H., Ogino, T., Nakamura, S., Takeda, K., et al. (2023) · International Immunology · doi:10.1093/intimm/dxad050 · Cited by 12 · see citing works
The Role of Yes‐Associated Protein in Inflammatory Diseases and Cancer
Zhong, B., Du, J., Liu, F., & Sun, S. (2025) · MedComm · doi:10.1002/mco2.70128 · Cited by 10 · see citing works
Du, L., Ji, Y., Bing, X., Zhang, J., Lu, L., Glass, C. K., & Feng, G. (2023) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2023.02.011 · Cited by 11 · see citing works
Multilayer omics reveals the molecular mechanism of early infection of Clonorchis sinensis juvenile
Wu, Y., Deng, X., Wu, Z., Liu, D., Fu, X., Tang, L., He, S., Lv, J., Wang, J., Li, Q., et al. (2023) · Parasites & Vectors · doi:10.1186/s13071-023-05891-1 · Cited by 10 · see citing works
“It has been documented that P2Y14 not only plays an important role in the immune and inflammatory responses but also promotes toxicity and hepatobiliary fibrosis [60, 61].”
BackgroundWen, Z., Pramanik, A., Lewicki, S. A., Jung, K., Gao, Z.-G., Randle, J. C. R., Breton, S., Chen, Z., Whitehead, G. S., Salvemini, D., et al. (2024) · ACS Pharmacology & Translational Science · doi:10.1021/acsptsci.4c00489 · Cited by 10 · see citing works
Wang, C., Dong, D., Zhao, N., Zhao, S., Hua, J., Bai, C., Cui, R., Zhao, T., Ji, N., Li, H., et al. (2025) · Hepatology · doi:10.1097/hep.0000000000001393 · Cited by 10 · see citing works
Zhang, J., Xie, Z., Zhu, X., Xu, C., Lin, J., Zhao, M., & Cheng, Y. (2025) · International Immunopharmacology · doi:10.1016/j.intimp.2025.114864 · Cited by 11 · see citing works
A comprehensive molecular atlas of the mesenchymal cell types in the mouse liver
Pietilä, R. S., Genové, G., Mocci, G., Miao, Y., Liu, J., Leptidis, S., Gaudio, F. D., Uhrbom, M., Vázquez-Liébanas, E., Gustafsson, S., et al. (2025) · EMBO Reports · doi:10.1038/s44319-025-00580-9 · Cited by 14 · see citing works
“To this end, scRNA-seq data from two independent studies of mouse disease models (Dobie et al, 2019b; Mederacke et al, 2022b) were reprocessed and analyzed.”
The Glycosyltransferase Pathway: An Integrated Analysis of the Cell Metabolome
Audet-Delage, Y., Rouleau, M., Villeneuve, L., & Guillemette, C. (2022) · Metabolites · doi:10.3390/metabo12101006 · Cited by 10 · see citing works
“Our findings further suggest that UGT enzymes may influence other cellular pathways in which UDP-sugars also participate, including the synthesis of the extracellular matrix component hyaluronan, protein glycosylation, and as ligands of the purinergic receptor P2Y14, which is involved in inflammation, asthma, fibrosis…”
BackgroundNing, M., Lu, D., Liang, D., & Ren, P. (2025) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2025.1513993 · Cited by 9 · see citing works
A mesothelial differentiation gateway drives fibrosis
Kadri, S., Fischer, A., Mück-Häusl, M., Han, W., Kadri, A., Lin, Y., Yang, L., Hu, S., Ye, H., Ramesh, P., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-63990-2 · Cited by 10 · see citing works
Hepatocyte GPCR signaling regulates IRF3 to control hepatic stellate cell transdifferentiation
Yu, J.-H., Choi, M. G., Lee, N. Y., Kwon, A., Lee, E., & Koo, J. H. (2024) · Cell Communication and Signaling · doi:10.1186/s12964-023-01416-6 · Cited by 8 · see citing works
“However, how hepatocyte IRF3 regulates liver fibrosis or trandifferentiation of HSCs, the cells primarily responsible for fibrogenesis in the liver [14, 15], is poorly understood.”
BackgroundXue, Y., Zhu, W., Qiao, F., Yang, Y., Qiu, J., Zou, C., Gao, Y., Zhang, X., Li, M., Shang, Z., et al. (2024) · Journal of Ethnopharmacology · doi:10.1016/j.jep.2024.118169 · Cited by 8 · see citing works
Inhibiting Liver Autophagy and Promoting Hepatocyte Apoptosis by Schistosoma japonicum Infection
Yu, Z., Jiang, T., Xu, F., Zhang, J., Hu, Y., & Cao, J. (2024) · Tropical Medicine and Infectious Disease · doi:10.3390/tropicalmed9020042 · Cited by 8 · see citing works
Insights of affinity-based probes for target identification in drug discovery
Wang, H., Liu, L., Zhang, Z., Li, C., Wang, K., Gao, J., Hu, Q., Wang, W., & Li, H. (2025) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2025.117711 · Cited by 7 · see citing works
Purinergic Signaling in Non-Parenchymal Liver Cells
Martínez, E. M., Ramírez‐Ledesma, M. G., Vázquez‐Victorio, G., Hernández-Muñoz, R. E., Díaz‐Muñoz, M., & Vázquez‐Cuevas, F. G. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25179447 · Cited by 7 · see citing works
“These fi ndings show that, in receptor, activated HSCs express an ATP-sensitive receptor that is not a Moreover, the systemic or HSC-specific P2Y14 receptor abrogation diminished fibrosis induction in different models of liver damage [113]. receptor.”
BackgroundStructural insights into ligand recognition and activation of human purinergic receptor P2Y14
Gu, Q., Lv, Z., Wang, T., Tang, W., Guo, X., Huang, X., Li, F., & Wang, J. (2025) · Cell Discovery · doi:10.1038/s41421-025-00799-9 · Cited by 7 · see citing works
Shi, S., Zhang, M., Zhu, C., Zhu, S., Yu, J., Sui, Q., Xu, J., Ren, J., Zhang, J., Chen, P., et al. (2025) · Chemico-Biological Interactions · doi:10.1016/j.cbi.2025.111586 · Cited by 7 · see citing works
Neutrophil-T cell cross talk in noninfectious liver diseases
Gromová, B., Kupčová, V., Longhi, M. S., & Gardlík, R. (2025) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00192.2025 · Cited by 6 · see citing works
“SLD is rising, with MASLD affecting 25% of adults worldwide and at least 10% of them will develop cirrhosis, the end-stage of liver damage without the possibility of self-regeneration (95).”
InfluentialCheng, X., Cheng, B., Jin, R., Zheng, H., Zhou, J., & Shan, S. (2024) · Archives of Dermatological Research · doi:10.1007/s00403-024-03116-8 · Cited by 5 · see citing works
Xu, X., Lü, F., Wang, Y., & Liu, S. (2024) · Gene · doi:10.1016/j.gene.2024.148826 · Cited by 5 · see citing works
Kim, H., & Kim, S. (2024) · Immunological Investigations · doi:10.1080/08820139.2024.2411388 · Cited by 5 · see citing works
“Additionally, a recent study showed that P2Y 14 can bind ligands other than UDPG, highlighting its diverse roles in the immune response (Mederacke et al., 2022).”
Hu, Z., Tian, D., Yang, Z., Zhang, J., Zhang, L., Xu, Y., & Lu, X. (2026) · Frontiers in Pharmacology · doi:10.3389/fphar.2026.1754721 · Cited by 5 · see citing works
“HSC activation increases α - smooth muscle actin ( α SMA), transforming HSCs into myofibroblasts and contributing to liver fibrosis (Peiseler et al., 2022).”
InfluentialPrimary cilium‐mediated signaling cascade suppresses age‐related biliary fibrosis
Hong, R., Tian, X., Ma, H., Ni, H., Yang, J. N., Bu, W., Li, T., Yang, S., Li, D., Liu, M., et al. (2023) · Journal of Cellular Physiology · doi:10.1002/jcp.31113 · Cited by 4 · see citing works
“In the context of liver fibrosis, it has been demonstrated that ERK stimulates hepatic stellate cells, resulting in their activation and subsequent production and deposition of ECM proteins, leading to the development of liver fibrosis (Mederacke et al., 2022; Popescu et al., 2019).”
BackgroundStromal KITL/SCF Maintains Pancreas Tissue Homeostasis and Restrains Tumor Progression
Oñate, M. K., Oon, C. H., Bhattacharyya, S., Low, V., Chen, C., Zhao, X., Arnold, F., Yan, Z., Pramod, S., Hang, Y., et al. (2025) · Cancer Discovery · doi:10.1158/2159-8290.cd-24-1079 · Cited by 4 · see citing works
UDPG/P2Y14-STAT1 axis mediates LPS-induced reactive astrogliosis
Wang, M., Deng, Y.-H., Ran, X.-F., Yang, P., Ren, W.-J., Lin, S.-S., Rubini, P., Illés, P., & Tang, Y. (2025) · Neuropharmacology · doi:10.1016/j.neuropharm.2025.110723 · Cited by 3 · see citing works
Tao, Y., Niu, Q., Yao, Y., Wang, K., Dong, H., Zhao, X., Zeng, Z., & Li, H. (2025) · Frontiers in Pharmacology · doi:10.3389/fphar.2024.1528100 · Cited by 3 · see citing works
Zheng, Y., Yang, Z., Luo, K., & Li, X. (2022) · doi:10.22541/au.166542685.54449876/v1 · Cited by 2 · see citing works
Li, C., Wang, H., Liu, L., Liu, C., Wang, Y.-Y., Yin, L., Yang, Y.-L., Tian, S., Qian, J., Zhou, M., et al. (2025) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.5c02078 · Cited by 2 · see citing works
P2Y14 receptor activation and neutrophil signaling: linking inflammation to systemic pathophysiology
Ebone, R. S., Doleski, P. H., Jantsch, M. H., da Silveira, R. P., & Leal, D. B. R. (2026) · Purinergic Signalling · doi:10.1007/s11302-025-10113-7 · Cited by 2 · see citing works
“Mederacke et al. (2022) identified P2Y14’s involvement in hepatic fibrosis through the activation of hepatic stellate cells in response to hepatocyte injury and death.”
Palomurto, S., Flam, E. L., Kamińska, D., Virtanen, K. A., Kärjä, V. J., Käkelä, P., Pajukanta, P., Eberlé, D., Haas, J. T., Raverdy, V., et al. (2026) · Liver International · doi:10.1111/liv.70552 · Cited by 2 · see citing works
Danger! P2Y14 receptor links cell death to liver fibrosis
Ray, K. (2022) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-022-00621-x · Cited by 2 · see citing works
Zhou, M., Li, Y., Qian, J., Dong, X., Guo, Y., Yin, L., Liu, C., Hao, K., & Hu, Q. (2025) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2025.01.004 · Cited by 2 · see citing works
Akkız, H., Şinşek, H., Balcı, D., Ülger, Y., Onan, E., Ozturk, N. A., & Delik, A. (2024) · Preprints.org · doi:10.20944/preprints202410.1660.v1 · Cited by 1 · see citing works
Harnessing the UDP-G/P2Y14R axis to promote liver regeneration in acute liver failure
Fang, J., & Bi, H. (2025) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2025.01.008 · Cited by 2 · see citing works
Shan, M., Apolinario, M. E. C., Tokumaru, T., Shikano, K., Phurpa, P., Kato, A., Teranishi, H., Shinichiro, K., Shimizu, N., Kurokawa, T., et al. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27020614 · Cited by 1 · see citing works
“…patterns (DAMPs), released from metabolically stressed or dying hepatocytes, including extracellular ATP (eATP) and its metabolite, extracellular adenosine (eAdo), activate purinergic receptors and amplify inflammatory and metabolic stress responses in both autocrine and paracrine manners [4–6].”
Metabolomics-based investigation of PFOS-induced molecular perturbations across multiple rat organs
Yen, T.-H., Lee, S.-H., Liang, H., Huang, Z.-X., Chen, C.-T., Li, C., & Lin, C.-Y. (2026) · Environmental Toxicology and Pharmacology · doi:10.1016/j.etap.2026.104957 · Cited by 1 · see citing works
FXR–YAP signalling maintains biliary epithelial cell identity and preserves liver homeostasis
Sánchez-Sánchez, P., Wang, Z., Zagorac, S., Domínguez, M., Boskovic, J., Nair, A., Macías‐Camero, A., Villaseñor, A., Schwabe, R. F., & Djouder, N. (2026) · Nature Metabolism · doi:10.1038/s42255-026-01521-z · Cited by 1 · see citing works
“1 were obtained from the GEO (GSE212039 and GSE172492) 27,48 .”
Self-citationYang, J., Li, S.-Y., Jiang, P., Wu, G.-L., Luo, Z., Guo, X., Liu, X.-K., Sun, H., & Jiang, Y.-C. (2026) · Journal of Ethnopharmacology · doi:10.1016/j.jep.2026.121759 · Cited by 1 · see citing works
Yang, X., Steffani, M., Nadella, S., Sheppard, D., Rieder, F., Rinkevich, Y., Kramann, R., Tuveson, D. A., & Schwabe, R. F. (2026) · JCI Insight · doi:10.1172/jci.insight.202529 · Cited by 1 · see citing works
“Besides HSC activation by TGF-β , angiotensin, leptin, CTGF, and DAMPs from dying hepatocytes (153), HSC proliferation, mediated largely by PDGF, is also a key contributor to liver fibrosis, as demonstrated in mice with HSC-selective deletion of cyclin E1 (154).”
Self-citationInvestigating the Role of Gene Body Methylation and CpG Methylation in Cancer Subtyping
Jilani, M., & Haspel, N. (2023) · International Conference on Bioinformatics Research and Applications (ICBRA) · doi:10.1145/3632047.3632056 · Cited by 1 · see citing works
“P2RY14 (Purinergic Receptor P2Y14) is also linked to metastasis in colon cancer [14].”
BackgroundPreoperative donor urinary UDP-Glc as an independent risk factor for delayed graft function
Ma, M., Han, F., Leng, Q., Chen, X., Tang, Z., Zhang, J., Luo, Y., Zhang, Y., Huang, Z., & Na, N. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1545280 · Cited by 1 · see citing works
Hepatic Stellate Cell Depletion and Genetic Manipulation
Sun, Q., & Schwabe, R. F. (2023) · Methods in molecular biology · doi:10.1007/978-1-0716-3207-9_12 · Cited by 1 · see citing works
Self-citationShi, H., Wang, X., Gerlach, B. D., Yurdagul, A., Moore, M. P., Mirshahi, F., Ronzoni, L., Sanyal, A. J., Valenti, L. V. C., Lin, C., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.01.30.578023 · Cited by 1 · see citing works
“In theory, the accumulation of apoptotic hepatocytes could directly contribute to fibrosis, e.g. , via their release of fibrogenic factors 7,8 .”
BackgroundSelf-citationMultifaceted Functions of RNA m6A Modification in Modulating Regulated Cell Death
Zhan, G., Liu, J., Lin, J., Chen, J., Sun, S., Maimaitiyiming, Y., & Hsu, C.-H. (2023) · RNA technologies · doi:10.1007/978-3-031-36390-0_24
Metabolic reaction fluxes as amplifiers and buffers of risk alleles for coronary artery disease
Foguet, C., Jiang, X., Ritchie, S. C., Persyn, E., Xu, Y., Ben-Eghan, C., Taylor, H. J., Angelantonio, E. D., Danesh, J., Butterworth, A. S., et al. (2025) · Molecular Systems Biology · doi:10.1038/s44320-025-00097-2
“Indeed, there is ample evidence of crosstalk between TGF-β signalling and purinergic receptors (Chen et al, 2022; Mederacke et al, 2022; Borges da Silva et al, 2020) suggesting a second potential mechanism of interaction (Fig.”
A comprehensive molecular atlas of the cell types in the mouse liverPreprint
Pietilä, R. S., Genové, G., Mocci, G., Miao, Y., Liu, J., Leptidis, S., Gaudio, F. D., Uhrbom, M., Vázquez-Liébanas, E., Gustafsson, S., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.01.24.634721
Wang, J., Tao, J., Xia, C., Tang, M., Stoica, A.-F., Yuan, S., Li, Y., Guo, L., Kong, X., & Wang, J. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.11.25.690307
Martínez, E. M., Juárez‐Mercado, A. P., González‐Gallardo, A., Núñez-Ríos, J. D., Díaz‐Muñoz, M., Hernández-Muñoz, R. E., & Vázquez‐Cuevas, F. G. (2025) · Cells · doi:10.3390/cells14231845
“Furthermore, total or HSC-directed knockout of P2Y14 receptor reduced fibrosis induction in different hepatotoxic models [11].”
Біомаркери оцінки якості донорської нирки
Korol, L., Shifris, І., Shuba, А., & Kolesnyk, М. (2025) · Ukrainian Journal of Nephrology and Dialysis · doi:10.31450/ukrjnd.4(88).2025.09
Wu, Y., Deng, X., Wu, Z., Liu, D., Fu, X., Tang, L., He, S., Lv, J., Wang, J., Li, Q., et al. (2023) · Figshare · doi:10.6084/m9.figshare.23972837
Wu, Y., Deng, X., Wu, Z., Liu, D., Fu, X., Tang, L., He, S., Lv, J., Wang, J., Li, Q., et al. (2023) · Figshare · doi:10.6084/m9.figshare.23972840
CDK5RAP3 sustains hepatocyte homeostasis by maintaining glucose metabolism through HSP90AA1
Sheng, L., Gj, Z., Yan, H., CHEN, F., Yang, F., Wu, L., Huang, H., Li, H. W., Teng, Y., & Cai, Y. (2026) · Genes & Diseases · doi:10.1016/j.gendis.2026.102061
P2Y14 receptor in the nervous system: Pharmacology, mechanisms, and therapeutic potential
Lin, J., Su, X., Feng, X., Mao, Y., Xia, Z., Gan, F., Chen, Q., Ciruela, F., Wang, Z., & Fang, X. (2026) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2026.109001
Wang, H., Xiao, P., Chen, L., Zhou, M., Zhang, J., Xiao, J., Zhao, R., Zhao, J., Pan, T., 盛珏, et al. (2026) · Nature Communications · doi:10.1038/s41467-026-73280-0
Ren, S., Wang, K., Wang, J., Xie, J., Zhou, J., Hou, W., Tong, R., Qinghua, H. U., & Li, H. (2026) · Medicinal Research Reviews · doi:10.1002/med.70066
“Animal studies further confirmed that P2Y 14 R knockout significantly reduced fibrosis severity across multiple hepatic fibrosis models [55].”
GDF15 in Liver Fibrosis: Molecular Mechanisms, Immunoregulatory Functions, and Therapeutic Potential
Gan, X., Zhang, L., Yu, T., Jin, S., Wu, Y., Xu, R., Zhang, Y., Zhang, J., Xu, L., & Wang, X. (2026) · Biomolecules · doi:10.3390/biom16071060
“These factors activate pathogen recognition receptors, including membrane bound Toll-like receptors and intra-cellular nucleotide binding oligomerization domain-like receptors, which are expressed on various immune cells as well as parenchymal cells in the liver [81,82].”
Chen, Y., Sun, Y., Chen, X., Liu, Y., & Wang, H. (2026) · Targetome · doi:10.48130/targetome-0026-0031
Self-citationWang, J., Zhang, Y., Sun, S., Hu, L., & Yang, D. (2026) · Frontiers in Pharmacology · doi:10.3389/fphar.2026.1877634
Wu, J., Hu, X., Liu, J., Peng, H., Chen, B., Li, Y., Jia, B., Cao, Z., Yuan, Q., Liu, W., et al. (2026) · Journal of Ethnopharmacology · doi:10.1016/j.jep.2026.122313
Matrix stiffness shapes early transcriptional trajectories during hepatic stellate cell activation
Inada, K., Miyoshi, M., Kakinuma, S., Watakabe, K., Mochida, T., Shimizu, T., Tsuchiya, J., Nobusawa, T., Kaneko, S., Kawai‐Kitahata, F., et al. (2026) · Hepatology International · doi:10.1007/s12072-026-11141-0
Pramanik, A., Kurma, S. H., Wen, Z., Cai, H., Violet, P.-C., Walter, P. J., Demby, T. C., Gavrilova, O., Pittala, S., Sajiir, H., et al. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.09.01.748648
“P2Y 14 R expression in liver and hepatic stellate cells (HSCs) was upregulated in a CCl 4 -induced liver fibrosis mouse model, which was associated with UDP-G release from dying hepatocytes causing activation of HSCs. P2Y 14 R deletion from HSCs selectively attenuates liver fibrosis in mouse [16].”
Xia, S., Shen, X., Chen, G., Liu, R., & Yang, X. P. (2026) · Viruses · doi:10.3390/v18101075
“Mederacke et al. demonstrated that P2Y purinoceptor 14 (P2Y14) is a molecular link connecting hepatocyte death to HSC activation and fibrogenesis [8].”
Chen, R., Yang, Y., Chen, G., Cai, X., Lu, L., & Ge, Q. (2026) · Journal of Translational Gastroenterology · doi:10.14218/jtg.2026.00026
- 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
