Cited by 97Liver physiology and pathologyAutophagy in Disease and TherapyTelomeres, Telomerase, and Senescence

Interaction between autophagy and senescence is required for dihydroartemisinin to alleviate liver fibrosis

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Zhang, Zili, Yao, Zhen, Zhao, Shifeng, Shao, Jiangjuan, Chen, Anping, Zhang, Feng, Zheng, Shizhong·2017·Cell Death & Disease

Abstract

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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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)
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
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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