Interaction between autophagy and senescence is required for dihydroartemisinin to alleviate liver fibrosis
Open accessAbstract
Autophagy and cellular senescence are stress responses essential for homeostasis. Therefore, they may represent new pharmacologic targets for drug development to treat diseases. In this study, we sought to evaluate the effect of dihydroartemisinin (DHA) on senescence of activated hepatic stellate cells (HSCs), and to further elucidate the underlying mechanisms. We found that DHA treatment induced the accumulation of senescent activated HSCs in rat fibrotic liver, and promoted the expression of senescence markers p53, p16, p21 and Hmga1 in cell model. Importantly, our study identified the transcription factor GATA6 as an upstream molecule in the facilitation of DHA-induced HSC senescence. GATA6 accumulation promoted DHA-induced p53 and p16 upregulation, and contributed to HSC senescence. By contrast, siRNA-mediated knockdown of GATA6 dramatically abolished DHA-induced upregulation of p53 and p16, and in turn inhibited HSC senescence. Interestingly, DHA also appeared to increase autophagosome generation and autophagic flux in activated HSCs, which was underlying mechanism for DHA-induced GATA6 accumulation. Autophagy depletion impaired GATA6 accumulation, while autophagy induction showed a synergistic effect with DHA. Attractively, p62 was found to act as a negative regulator of GATA6 accumulation. Treatment of cultured HSCs with various autophagy inhibitors, led to an inhibition of DHA-induced p62 degradation, and in turn, prevented DHA-induced GATA6 accumulation and HSC senescence. Overall, these results provide novel implications to reveal the molecular mechanism of DHA-induced senescence, by which points to the possibility of using DHA based proautophagic drugs for the treatment of liver fibrosis.
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Cellular senescence and autophagy are potential therapeutic targets for age-related diseases.
“Cellular senescence and autophagy are not only essential for homeostasis but are potential therapeutic targets for age-related diseases [27].”
From Fibrates as drugs with senolytic and autophagic activity for osteoarthritis therapy (2019) · cites this paper as [27]
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1 retracted
Zhang, Z., Zhao, S., Yao, Z., Wang, L., Shao, J., Chen, A., Zhang, F., & Zheng, S. (2016) · Redox Biology · doi:10.1016/j.redox.2016.12.021 · Cited by 108 · see citing works
Self-citationRetractedGuidelines for the use and interpretation of assays for monitoring autophagy (3rd edition).
Klionsky, D. J., Abdelmohsen, K., Abe, A., Abedin, M. J., Abeliovich, H., Acevedo Arozena, A., Adachi, H., Adams, C. M., Adams, P. D., Adeli, K., et al. (2016) · Autophagy · doi:10.1080/15548627.2015.1100356 · Cited by 5,894 · see citing works
Self-citationSenescence of activated stellate cells limits liver fibrosis
Krizhanovsky, V., Yon, M., Dickins, R. A., Hearn, S., Simon, J., Miething, C., Yee, H., Zender, L., & Lowe, S. W. (2008) · Cell · doi:10.1016/j.cell.2008.06.049 · Cited by 2,029 · see citing works
Senescence of Activated Stellate Cells Limits Liver Fibrosis
Krizhanovsky, V., Yon, M., Dickins, R. A., Hearn, S., Simon, J., Miething, C., Yee, H., Zender, L., & Lowe, S. W. (2008) · Cell · doi:10.1016/j.cell.2008.09.015 · Cited by 2,027
Autophagy maintains stemness by preventing senescence
García-Prat, L., Martínez-Vicente, M., Perdiguero, E., Ortet, L., Rodríguez-Ubreva, J., Rebollo, E., Ruiz-Bonilla, V., Gutarra, S., Ballestar, E., Serrano, A. L., et al. (2016) · Nature · doi:10.1038/nature16187 · Cited by 1,355 · see citing works
The DNA damage response induces inflammation and senescence by inhibiting autophagy of GATA4.
Kang, C., Xu, Q., Martin, T. D., Li, M. Z., Demaria, M., Aron, L., Lu, T., Yankner, B. A., Campisi, J., & Elledge, S. J. (2015) · Science · doi:10.1126/science.aaa5612 · Cited by 982 · see citing works
Pathobiology of liver fibrosis: a translational success story
Lee, Y. A., Wallace, M. C., & Friedman, S. L. (2015) · Gut · doi:10.1136/gutjnl-2014-306842 · Cited by 894 · see citing works
Senescence and aging: the critical roles of p53
Rufini, A., Tucci, P., Celardo, I., & Melino, G. (2013) · Oncogene · doi:10.1038/onc.2012.640 · Cited by 798 · see citing works
Romagosa, C., Simonetti, S., López-Vicente, L., Mazo, A., Lleonart, M. E., Castellvi, J., & Ramon y Cajal, S. (2011) · Oncogene · doi:10.1038/onc.2010.614 · Cited by 509 · see citing works
Interleukin-22 induces hepatic stellate cell senescence and restricts liver fibrosis in mice
Kong, X., Feng, D., Wang, H., Hong, F., Bertola, A., Wang, F.-S., & Gao, B. (2012) · Hepatology · doi:10.1002/hep.25744 · Cited by 448 · see citing works
The emerging role of GATA transcription factors in development and disease
Lentjes, M. H. F. M., Niessen, H. E. C., Akiyama, Y., A, A. P. D. B., Melotte, V., & van Engeland, M. (2016) · Expert Reviews in Molecular Medicine · doi:10.1017/erm.2016.2 · Cited by 249 · see citing works
How autophagy both activates and inhibits cellular senescence
Kang, C., & Elledge, S. J. (2016) · Autophagy · doi:10.1080/15548627.2015.1121361 · Cited by 228 · see citing works
Five dysfunctional telomeres predict onset of senescence in human cells
Kaul, Z., Cesare, A. J., Huschtscha, L. I., Neumann, A. A., & Reddel, R. R. (2012) · The EMBO Reports · doi:10.1038/embor.2011.227 · Cited by 225 · see citing works
Hepatic stellate cells: Partners in crime for liver metastases?
Kang, N., Gores, G. J., & Shah, V. H. (2011) · Hepatology · doi:10.1002/hep.24384 · Cited by 201 · see citing works
Carloni, V., Luong, T. V., & Rombouts, K. (2014) · Liver International · doi:10.1111/liv.12465 · Cited by 174 · see citing works
Targeting molecules to medicine with mTOR, autophagy and neurodegenerative disorders.
Maiese, K. (2016) · British Journal of Clinical Pharmacology · doi:10.1111/bcp.12804 · Cited by 173 · see citing works
Cellular senescence impact on immune cell fate and function
Vicente, R., Mausset-Bonnefont, A.-L., Jorgensen, C., Louis-Plence, P., & Brondello, J.-M. (2016) · Aging Cell · doi:10.1111/acel.12455 · Cited by 151 · see citing works
CDK-Dependent Hsp70 Phosphorylation Controls G1 Cyclin Abundance and Cell-Cycle Progression
Truman, A. W., Kristjánsdóttir, K., Wolfgeher, D. J., Hasin, N., Polier, S., Zhang, H., Perrett, S., Prodromou, C., Jones, G. W., & Kron, S. J. (2012) · Cell · doi:10.1016/j.cell.2012.10.051 · Cited by 143 · see citing works
Jin, H., Lian, N., Zhang, F., Chen, L., Chen, Q., Lu, C., Bian, M., Shao, J., Wu, L., & Zheng, S. (2016) · Cell Death and Disease · doi:10.1038/cddis.2016.92 · Cited by 143 · see citing works
Self-citationHepatic Stellate Cells and microRNAs in Pathogenesis of Liver Fibrosis
Kitano, M., & Bloomston, M. (2016) · Journal of Clinical Medicine · doi:10.3390/jcm5030038 · Cited by 121 · see citing works
Hepatic stellate cells: central modulators of hepatic carcinogenesis
Thompson, A., Conroy, K. P., & Henderson, N. C. (2015) · BMC Gastroenterology · doi:10.1186/s12876-015-0291-5 · Cited by 102 · see citing works
Zhang, Z., Guo, M. L., Zhao, S., Shao, J., & Zheng, S. (2016) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2016.10.498 · Cited by 102 · see citing works
Self-citationAutophagy and Immune Senescence
Zhang, H., Puleston, D. J., & Simon, A. K. (2016) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2016.06.001 · Cited by 93 · see citing works
Hasasna, H. E., Athamneh, K., Alsamri, H., Karuvantevida, N. S., Dhaheri, Y. A., Hisaindee, S., Ramadan, G. A., Tamimi, N. A., AbuQamar, S. F., Eid, A. H., et al. (2015) · Scientific Reports · doi:10.1038/srep13013 · Cited by 81 · see citing works
Autophagy suppresses melanoma tumorigenesis by inducing senescence
Liu, H., He, Z., & Simon, H. (2013) · Autophagy · doi:10.4161/auto.27163 · Cited by 79 · see citing works
Kagawa, S., Natsuizaka, M., Whelan, K. A., Facompre, N. D., Naganuma, S., Ohashi, S., Kinugasa, H., Egloff, A. M., Basu, D., Gimotty, P. A., et al. (2014) · Oncogene · doi:10.1038/onc.2014.169 · Cited by 71 · see citing works
Shao, A.-W., Sun, H., Geng, Y., Peng, Q., Wang, P., Chen, J., Xiong, T., Cao, R., & Tang, J. (2016) · Cell Death and Differentiation · doi:10.1038/cdd.2015.150 · Cited by 71 · see citing works
Lee, S. K. (1998) · International Journal of Molecular Medicine · doi:10.3892/ijmm_00000068 · Cited by 60 · see citing works
Zhang, Z., Guo, Y., Zhang, S., Zhang, Y., Wang, Y., Ni, W., Kong, D., Chen, W., & Zheng, S. (2013) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2013.09.042 · Cited by 57 · see citing works
Self-citationKim, K.-H., Park, B., Rhee, D., & Pyo, S. (2014) · Chemical Research in Toxicology · doi:10.1021/tx500341z · Cited by 56 · see citing works
Zhang, F., Zhang, Z., Kong, D., Zhang, X., Chen, L., Zhu, X., Lu, Y., & Zheng, S. (2013) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2013.09.020 · Cited by 50 · see citing works
Self-citationZhang, X., Li, G., Zhao, S.-S., et al. (2014) · Parasitology Research · doi:10.1007/s00436-014-3822-z · Cited by 49 · see citing works
Self-citationChen, Q., Chen, L., Kong, D., Shao, J., Wu, L., & Zheng, S. (2016) · International Immunopharmacology · doi:10.1016/j.intimp.2016.03.011 · Cited by 48 · see citing works
Self-citationChen, Q., Chen, L., Wu, X., Zhang, F., Jin, H., Lu, C., Shao, J., Kong, D., Wu, L., & Zheng, S. (2016) · IUBMB Life · doi:10.1002/iub.1478 · Cited by 46 · see citing works
Self-citationPI3K is involved in PDGF-β receptor upregulation post-PDGF-BB treatment in mouse HSC
Lechuga, C. G., Nazará, Z., Hernández, E., Bustamante, M., Desierto, G., Cotty, A., Dharker, N., Choe, M., & Rojkind, M. (2006) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00058.2005 · Cited by 43 · see citing works
The role of miRNAs in stress-responsive hepatic stellate cells during liver fibrosis
Lambrecht, J., Mannaerts, I., & van Grunsven, L. A. (2015) · Frontiers in Physiology · doi:10.3389/fphys.2015.00209 · Cited by 41 · see citing works
Fan, T. T., Huang, Z. L., Chen, L., Wang, W., Zhang, B., Xu, Y. Q., Pan, S., Mao, Z., Hu, H., & Geng, Q. (2016) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2016.08.026 · Cited by 41 · see citing works
Tai, X., Cai, X.-B., Zhang, Z., & Wei, R. (2016) · Oncology Letters · doi:10.3892/ol.2016.5187 · Cited by 41 · see citing works
Self-citationGATA transcription factors as tissue-specific master regulators for induced responses
Block, D. H. S., & Shapira, M. (2015) · Worm · doi:10.1080/21624054.2015.1118607 · Cited by 39 · see citing works
Xu, W., Lu, C., Yao, L., et al. (2016) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2016.12.001 · Cited by 36 · see citing works
Wu, C., Liu, J., Pan, X., Xian, W., Li, B., Peng, W., Wang, J., Yang, D., & Zhou, H. (2013) · Molecules · doi:10.3390/molecules18066866 · Cited by 34 · see citing works
Isolation and Time Lapse Microscopy of Highly Pure Hepatic Stellate Cells
Bartneck, M., Warzecha, K. T., Tag, C. G., Sauer-Lehnen, S., Heymann, F., Trautwein, C., Weiskirchen, R., & Tacke, F. (2015) · Analytical Cellular Pathology · doi:10.1155/2015/417023 · Cited by 32 · see citing works
Dihydroartemisinin restricts hepatic stellate cell contraction via an FXR‐S1PR2 ‐dependent mechanism
Xu, W., Lu, C., Zhang, F., Shao, J., & Zheng, S. (2016) · IUBMB Life · doi:10.1002/iub.1492 · Cited by 31 · see citing works
Self-citationLevchenko, M., Lorenzi, I., & Dudek, J. (2016) · PLoS ONE · doi:10.1371/journal.pone.0168518 · Cited by 26 · see citing works
Enhanced Efficacy of Doxorubicin by microRNA-499-Mediated Improvement of Tumor Blood Flow
Okamoto, A., Asai, T., Ryu, S., et al. (2016) · Journal of Clinical Medicine · doi:10.3390/jcm5010010 · Cited by 22 · see citing works
Cassidy, L. D., & Narita, M. (2015) · Science · doi:10.1126/science.aad2501 · Cited by 14 · see citing works
Kim, K. M., Kim, J. M., Yoo, Y. H., Kim, J. I., & Park, Y. C. (2012) · International Journal of Molecular Medicine · doi:10.3892/ijmm.2012.892 · Cited by 13 · see citing works
mTOR, autophagy, and reprogramming
Tang, B. L. (2014) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2013.00004 · Cited by 5 · see citing works
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Huda, N., Liu, G., Hong, H., Yan, S., Khambu, B., & Yin, X.-M. (2019) · World Journal of Gastroenterology · doi:10.3748/wjg.v25.i34.5069 · Cited by 100 · see citing works
- Authors
- Zhang, Z., Yao, Z., Zhao, S., Shao, J., Chen, A., Zhang, F., & Zheng, S.
- Affiliations
- Nanjing University of Chinese Medicine (CN)
- Saint Louis University (US)
- Corresponding author
- Zheng, Shizhong
- Venue
- Cell Death & Disease
- Published
- 2017-06-15
- Volume
- 8
- Issue
- 6
- Pages
- e2886-e2886
- ISSN
- 2041-4889 (ISSN-L)
- PMC
- PMC5520911
- OpenAlex
- W2624796717
- Cited by
- 97
- References
- 48
- Citations by year
- 2026: 5 · 2025: 6 · 2024: 3 · 2023: 9 · 2022: 12 · 2021: 18 · 2020: 14 · 2019: 14 · 2018: 12 · 2017: 3
- FWCI
- 7.25
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Cell Death and Disease (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China ([2015]02, 31401210, 31600653, 81270514, 81600483, 31571455)
- Government of Jiangsu Province (BK20140955)
- Natural Science Foundation of Jiangsu Province (BK20140955)
- Priority Academic Program Development of Jiangsu Higher Education Institutions (31401210)
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica (JKLPSE201502, 201502)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Keywords
- dihydroartemisinin, liver fibrosis, autophagy, cellular senescence, hepatic stellate cells, GATA6, p53, p16, p21, HMGA1, p62, autophagic flux
- MeSH terms
- Animals, Autophagy, Cells, Cultured, Fibrosis, Liver, Liver Cirrhosis, Male, Mice, Inbred ICR, Signal Transduction, Cellular Senescence, Rats, Sprague-Dawley, RNA, Small Interfering, Artemisinins, Cell Line, Tumor, Cell Proliferation, GATA6 Transcription Factor, Mice, Rats, Hepatic Stellate Cells
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