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Inhibition of endogenous hydrogen sulfide production reduces activation of hepatic stellate cells via the induction of cellular senescence
Open accessAbstract
In chronic liver injury, quiescent hepatic stellate cells (HSCs) transdifferentiate into activated myofibroblast-like cells and produce large amounts of extracellular matrix components, e.g. collagen type 1. Cellular senescence is characterized by irreversible cell-cycle arrest, arrested cell proliferation and the acquisition of the senescence-associated secretory phenotype (SASP) and reversal of HSCs activation. Previous studies reported that H2S prevents induction of senescence via its antioxidant activity. We hypothesized that inhibition of endogenous H2S production induces cellular senescence and reduces activation of HSCs. Rat HSCs were isolated and culture-activated for 7 days. After activation, HSCs treated with H2S slow-releasing donor GYY4137 and/or DL-propargylglycine (DL-PAG), an inhibitor of the H2S-producing enzyme cystathionine γ-lyase (CTH), as well as the PI3K inhibitor LY294002. In our result, CTH expression was significantly increased in fully activated HSCs compared to quiescent HSCs and was also observed in activated stellate cells in a in vivo model of cirrhosis. Inhibition of CTH reduced proliferation and expression of fibrotic markers Col1a1 and Acta2 in HSCs. Concomitantly, DL-PAG increased the cell-cycle arrest markers Cdkn1a (p21), p53 and the SASP marker Il6. Additionally, the number of β-galactosidase positive senescent HSCs was increased. GYY4137 partially restored the proliferation of senescent HSCs and attenuated the DL-PAG-induced senescent phenotype. Inhibition of PI3K partially reversed the senescence phenotype of HSCs induced by DL-PAG. Inhibition of endogenous H2S production reduces HSCs activation via induction of cellular senescence in a PI3K-Akt dependent manner. Our results show that cell-specific inhibition of H2S could be a novel target for anti-fibrotic therapy via induced cell senescence.
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Targeting the CTH/H2S axis induces p21/p53-dependent senescence in HSCs.
“Furthermore, studies suggest that targeting the CTH/H2S axis induces p21/p53-dependent senescence in HSCs, representing a novel approach to treating liver fibrosis [365].”
From Mechanisms, efficacy, and future perspectives of cellular-based therapies for liver fibrosis/cirrhosis: focusing on mesenchymal stromal cells (2025) · cites this paper as [365]
The Results section, “CTH inhibition induces cellular senescence in hepatic stellate cells” (page not specified), reports that CTH inhibition increased senescent HSCs and raised p21 and p53 markers. The paper does not establish that senescence depends on both p21 and p53; its mechanistic Results instead identify PI3K–Akt signaling as a mediator. The Discussion describes HSC senescence as a promising approach to liver fibrosis, not a demonstrated treatment. (LLM, conf=0.86)
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Metadata
- Authors
- Damba, T., Zhang, M., Serna Salas, S. A., Wu, Z., van Goor, H., Arenas, A. F., Muñoz-Ortega, M. H., Ventura-Juárez, J., Buist-Homan, M., & Moshage, H.
- Affiliations
- University Medical Center Groningen (NL)
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
- Morphology Department, Basic Sciences Center, Autonomous University of Aguascalientes, Aguascalientes, Mexico
- Chemistry Department, Basic Sciences Center, Autonomous University of Aguascalientes, Aguascalientes, Mexico
- Corresponding author
- Damba, Turtushikh
- Venue
- Cell Cycle
- Publisher
- Informa UK Limited
- Published
- 2024-03-18
- Volume
- 23
- Issue
- 6
- Pages
- 629-644
- ISSN
- 1538-4101 (ISSN-L)
- 1551-4005
- PMC
- PMC11229775
- OpenAlex
- W4399361133
- Cited by
- 5
- References
- 43
- Citations by year
- 2026: 2 · 2025: 3
- FWCI
- 1.31
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Cell Cycle (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, cc-by-nc-nd)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, other-oa)
- Funders
- Mongolian State Training Foundation Scholarship
- Ministry of Education and Science (623)
- Chinese Scholarship Council
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Sulfur Compounds in Biology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
- Keywords
- hydrogen sulfide, hepatic stellate cells, cellular senescence, cystathionine gamma-lyase, DL-propargylglycine, PI3K/Akt signaling, liver fibrosis, chronic liver injury, senescence-associated secretory phenotype, extracellular matrix synthesis, antifibrotic therapy, GYY4137
- MeSH terms
- Senescence-Associated Secretory Phenotype, Alkynes, Animals, Cells, Cultured, Chromones, Cystathionine gamma-Lyase, Glycine, Hydrogen Sulfide, Liver Cirrhosis, Male, Morpholines, Organothiophosphorus Compounds, Signal Transduction, Tumor Suppressor Protein p53, Cellular Senescence, Rats, Sprague-Dawley, Phosphatidylinositol 3-Kinases, Collagen Type I, Cell Proliferation, Cyclin-Dependent Kinase Inhibitor p21, Proto-Oncogene Proteins c-akt, Rats, Hepatic Stellate Cells
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