Targeting YAP-mediated HSC death susceptibility and senescence for treatment of liver fibrosis
Open accessAbstract
Background and Aims: Liver fibrosis results from the accumulation of myofibroblasts (MFs) derived from quiescent HSCs, and yes-associated protein (YAP) controls this state transition. Although fibrosis is also influenced by HSC death and senescence, whether YAP regulates these processes and whether this could be leveraged to treat liver fibrosis are unknown. Approach and Results: YAP activity was manipulated in MF-HSCs to determine how YAP impacts susceptibility to pro-apoptotic senolytic agents or ferroptosis. Effects of senescence on YAP activity and susceptibility to apoptosis versus ferroptosis were also examined. CCl 4 -treated mice were treated with a ferroptosis inducer or pro-apoptotic senolytic to determine the effects on liver fibrosis. YAP was conditionally disrupted in MFs to determine how YAP activity in MF-HSC affects liver fibrosis in mouse models. Silencing YAP in cultured MF-HSCs induced HSC senescence and vulnerability to senolytics, and promoted ferroptosis resistance. Conversely, inducing HSC senescence suppressed YAP activity, increased sensitivity to senolytics, and decreased sensitivity to ferroptosis. Single-cell analysis of HSCs from fibrotic livers revealed heterogeneous sensitivity to ferroptosis, apoptosis, and senescence. In mice with chronic liver injury, neither the ferroptosis inducer nor senolytic improved fibrosis. However, selectively depleting YAP in MF-HSCs induced senescence and decreased liver injury and fibrosis. Conclusion: YAP determines whether MF-HSCs remain activated or become senescent. By regulating this state transition, Yap controls both HSC fibrogenic activity and susceptibility to distinct mechanisms for cell death. MF-HSC-specific YAP depletion induces senescence and protects injured livers from fibrosis. Clarifying determinants of HSC YAP activity may facilitate the development of novel anti-fibrotic therapies.
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- Authors
- Du, K., Maeso-Díaz, R., Oh, S. H., Wang, E., Chen, T., Pan, C., Xiang, K., Dutta, R. K., Wang, X.-F., Chi, J.-T., & Diehl, A. M.
- Affiliations
- Duke University (US)
- Department of Medicine, Duke University, Durham, North Carolina, USA
- Corresponding author
- Du, Kuo
- Diehl, Anna Mae
- ORCID
- Venue
- Hepatology
- Published
- 2023-02-24
- Volume
- 77
- Issue
- 6
- Pages
- 1998-2015
- ISSN
- 0270-9139 (ISSN-L)
- PMC
- PMC10416614
- OpenAlex
- W4321597920
- Cited by
- 102
- References
- 31
- Citations by year
- 2026: 28 · 2025: 39 · 2024: 25 · 2023: 10
- FWCI
- 17.24
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Hepatology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- American Association for the Study of Liver Diseases
- National Institutes of Health (5r37aa010154-20)
- National Institute on Alcohol Abuse and Alcoholism (R37 AA-010154)
- National Cancer Institute (R01CA244564)
- National Institute of General Medical Sciences (R01GM124062)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK077794, R56DK106633)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hippo pathway signaling and YAP/TAZ
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Keywords
- liver fibrosis, YAP, hepatic stellate cells, myofibroblasts, cellular senescence, ferroptosis, apoptosis, senolytics, antifibrotic therapy, carbon tetrachloride-induced liver injury
- MeSH terms
- Senotherapeutics, Animals, Liver, Liver Cirrhosis, Cell Death, Adaptor Proteins, Signal Transducing, Mice, Hepatic Stellate Cells
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