The RSPO‐LGR4/5‐ZNRF3/RNF43 module in liver homeostasis, regeneration, and disease
Abstract
WNT/β-catenin signaling plays pivotal roles during liver development, homeostasis, and regeneration. Likewise, its deregulation disturbs metabolic liver zonation and is responsible for the development of a large number of hepatic tumors. Liver fibrosis, which has become a major health burden for society and a hallmark of NASH, can also be promoted by WNT/β-catenin signaling. Upstream regulatory mechanisms controlling hepatic WNT/β-catenin activity may constitute targets for the development of novel therapies addressing these life-threatening conditions. The R-spondin (RSPO)-leucine-rich repeat-containing G protein-coupled receptor (LGR) 4/5-zinc and ring finger (ZNRF) 3/ring finger 43 (RNF43) module is fine-tuning WNT/β-catenin signaling in several tissues and is essential for hepatic WNT/β-catenin activity. In this review article, we recapitulate the role of the RSPO-LGR4/5-ZNRF3/RNF43 module during liver development, homeostasis, metabolic zonation, regeneration, and disease. We further discuss the controversy around LGR5 as a liver stem cell marker.
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In zone 3, there is a well-known histologic pattern of liver damage in diseases that culminate in HCC, and zone 3 is frequently associated with oxidative stress.
“In zone 3, there is a well-known histologic pattern of liver damage in diseases that culminate in HCC (61, 62), and zone 3 is frequently associated with oxidative stress (63, 64).”
From The origin of hepatocellular carcinoma depends on metabolic zonation (2026) · cites this paper as [62]
The RSPO-LGR4/5-ZNRF3/RNF43 module controlling WNT/β-catenin signalling is a growth and size rheostat in the liver.
“The RSPO-LGR4/5-ZNRF3/RNF43 module controlling WNT/β-catenin signalling is a growth and size rheostat in the liver.”
From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [90]
RSPO injections reversibly increased liver size by inducing hepatocyte proliferation, whereas WNT/β-catenin signalling blockade resulted in smaller livers.
“RSPO injections reversibly increased liver size by inducing hepatocyte proliferation, whereas WNT/β-catenin signalling blockade resulted in smaller livers.44,90,91”
From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [90]
Activating mutations in the WNT/β-catenin pathway are frequently found in liver tumours, and hepatocytes with high WNT/β-catenin activity are highly susceptible to malignant transformation in experimental tumour models.
“Activating mutations in the WNT/β-catenin pathway are frequently found in liver tumours and hepatocytes with high WNT/β-catenin activity are highly susceptible to malignant transformation in experimental tumour models.50,90,91,85”
From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [90]
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RSPO2 gene rearrangement: a powerful driver of β-catenin activation in liver tumours
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RSPOs facilitated HSC activation and promoted hepatic fibrogenesis
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LGR4 protects hepatocytes from injury in mouse
Li, Z., Liu, S., Lou, J., Mulholland, M. T., & Zhang, W. (2018) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00056.2018 · Cited by 27 · see citing works
LGR4 acts as a link between the peripheral circadian clock and lipid metabolism in liver
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R‐spondin 2 Drives Liver Tumor Development in a Yes‐Associated Protein‐Dependent Manner
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Rspo1/Rspo3‐LGR4 signaling inhibits hepatic cholesterol synthesis through the AMPKα‐SREBP2 pathway
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No Zones Left Behind: Democratic Hepatocytes Contribute to Liver Homeostasis and Repair
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R-Spondin2 Activates Hepatic Stellate Cells and Promotes Liver Fibrosis
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R-spondin1 arguments hepatic fibrogenesis in vivo and in vitro
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Prometheus revisited: liver homeostasis and repair
Sun, T., Annunziato, S., & Tchorz, J. S. (2020) · Aging · doi:10.18632/aging.102957 · Cited by 6 · see citing works
Self-citationTchorz, J. S. (2020) · Gene Expression · doi:10.3727/105221620x16007982788168 · Cited by 6 · see citing works
Self-citationAbsent expansion of pericentral hepatocytes and altered physiology in Axin2CreERT2 micePreprint
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Flagged first, then by citations
3 of the 98 references couldn’t be matched to a known paper.
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Bipotent transitional liver progenitor cells contribute to liver regeneration
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Self-citationSpatiotemporal Metabolic Liver Zonation and Consequences on Pathophysiology
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Distinct hepatocyte identities in liver homeostasis and regeneration
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Self-citationDetermination of key events in mouse hepatocyte maturation at the single-cell level
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The origin of hepatocellular carcinoma depends on metabolic zonation
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Self-citationNuclear Acly protects the liver from ischemia-reperfusion injury
Gao, W., Zhang, L., Li, Z., Wu, T., Lang, C., Mulholland, M. W., & Zhang, W. (2023) · Hepatology · doi:10.1097/hep.0000000000000692 · Cited by 19 · see citing works
Cell competition in primary and metastatic colorectal cancer
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TRIB1 regulates liver regeneration by antagonizing the NRF2-mediated antioxidant response
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Primary Liver Cancers: Connecting the Dots of Cellular Studies and Epidemiology with Metabolomics
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New insights into fibrotic signaling in hepatocellular carcinoma
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Wnt Signaling Pathway: Biological Function, Diseases, and Therapeutic Interventions
Jin, X., Wang, J., Cao, R., & Jiang, D. (2026) · MedComm · doi:10.1002/mco2.70580 · Cited by 14 · see citing works
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Guan, Y., Fang, Z., Hu, A., Roberts, S., Wang, M., Ren, W., Johansson, P. K., Heilshorn, S. C., Enejder, A., & Peltz, G. (2025) · JCI Insight · doi:10.1172/jci.insight.187099 · Cited by 6 · see citing works
A Spatial Atlas of Wnt Receptors in Adult Mouse Liver
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The role of roof plate-specific spondins in liver homeostasis and disease
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Cellular senescence is associated with age-related loss of liver zonation and hepatocyte functionPreprint
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- Authors
- Annunziato, S., Sun, T., & Tchorz, J. S.
- Affiliations
- Novartis (Switzerland) (CH)
- Corresponding author
- Tchorz, Jan S.
- Venue
- Hepatology
- Published
- 2022-02-20
- Volume
- 76
- Issue
- 3
- Pages
- 888-899
- ISSN
- 0270-9139 (ISSN-L)
- 1527-3350
- OpenAlex
- W4205791102
- Cited by
- 45
- References
- 98
- Citations by year
- 2026: 7 · 2025: 13 · 2024: 9 · 2023: 14 · 2022: 2
- FWCI
- 0.99
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Hepatology (publishedVersion)
- PubMed (publishedVersion)
- The Novartis Repository (Novartis) (acceptedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Keywords
- R-spondin, ZNRF3, RNF43, Wnt/β-catenin signaling, liver homeostasis, liver regeneration, liver development, metabolic zonation, liver fibrosis, NASH, liver tumors, liver stem cells, Lgr5
- MeSH terms
- Homeostasis, Liver, Thrombospondins, Receptors, G-Protein-Coupled, Ubiquitin-Protein Ligases, beta Catenin, Wnt Signaling Pathway
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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.
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