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©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.
Cryptotanshinone induces apoptosis of activated hepatic stellate cells via modulating endoplasmic reticulum stress
Xiao-Xue Hou, Yu-Wen Li, Jia-Li Song, Wen Zhang, Rui Liu, Hui Yuan, Tian-Tong Feng, Zheng-Yi Jiang, Wen-Ting Li, Chuan-Long Zhu
Xiao-Xue Hou, Jia-Li Song, Wen Zhang, Hui Yuan, Tian-Tong Feng, Zheng-Yi Jiang, Chuan-Long Zhu, Department of Infectious Disease, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210009, Jiangsu Province, China
Yu-Wen Li, Department of Pediatrics, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210009, Jiangsu Province, China
Rui Liu, Wen-Ting Li, Department of Infectious and Tropical Diseases, The Second Affiliated Hospital of Hainan Medical University, Haikou 570000, Hainan Province, China
Author contributions: Zhu CL and Hou XX designed the research; Hou XX, Li YW and Song JL performed the research; Li WT analyzed data and wrote the article; Zhang W and Feng TT checked the statistical calculations; Yuan H, Liu R and Jiang ZY commented on and revised the paper; all authors have read and approved the final paper.
Supported by Science and Technology Plan of Hainan Province (Clinical Research Center), No. LCYX202103 and No. LCYX202204; Hainan Province Science and Technology Special Fund, No. ZDYF2022SHFZ067; and Hainan Province Clinical Medical Center.
Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Institutional Animal Care and Use Committee of The First Affiliated Hospital of Nanjing Medical University (IACUC protocol number: IACUC-2209028).
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Data sharing statement: All data generated or analyzed supporting conclusions are included in the current manuscript.
ARRIVE guidelines statement: The authors have read the ARRIVE Guidelines, and the manuscript was prepared and revised according to the ARRIVE Guidelines.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
https://creativecommons.org/Licenses/by-nc/4.0/ Corresponding author: Chuan-Long Zhu, Founder, Professor, Department of Infectious Disease, The First Affiliated Hospital of Nanjing Medical University, No. 300 Guangzhou Road, Nanjing 210009, Jiangsu Province, China. zhuchuanlong@jsph.org.cn
Received: November 4, 2022
Peer-review started: November 4, 2022
First decision: February 18, 2023
Revised: February 28, 2023
Accepted: April 10, 2023
Article in press: April 10, 2023
Published online: May 7, 2023
BACKGROUND
Cryptotanshinone (CPT) has wide biological functions, including anti-oxidative, antifibrosis, and anti-inflammatory properties. However, the effect of CPT on hepatic fibrosis is unknown.
AIM
To investigate the effects of CPT treatment on hepatic fibrosis and its underlying mechanism of action.
METHODS
Hepatic stellate cells (HSCs) and normal hepatocytes were treated with different concentrations of CPT and salubrinal. The CCK-8 assay was used to determine cell viability. Flow cytometry was used to measure apoptosis and cell cycle arrest. Reverse transcription polymerase chain reaction (RT-PCR) and Western blot analyses were used to measure mRNA levels and protein expression of endoplasmic reticulum stress (ERS) signaling pathway related molecules, respectively. Carbon tetrachloride (CCL4) was used to induce in vivo hepatic fibrosis in mice. Mice were treated with CPT and salubrinal, and blood and liver samples were collected for histopathological examination.
RESULTS
We found that CPT treatment significantly reduced fibrogenesis by modulating the synthesis and degradation of the extracellular matrix in vitro. CPT inhibited cell proliferation and induced cell cycle arrest at the G2/M phase in cultured HSCs. Furthermore, we found that CPT promoted apoptosis of activated HSCs by upregulating expression of ERS markers (CHOP and GRP78) and activating ERS pathway molecules (PERK, IRE1α, and ATF4), which were inhibited by salubrinal. Inhibition of ERS by salubrinal partially eliminated the therapeutic effect of CPT in our CCL4-induced hepatic fibrosis mouse model.
CONCLUSION
CPT can promote apoptosis of HSCs and alleviate hepatic fibrosis through modulating the ERS pathway, which represents a promising strategy for treating hepatic fibrosis.
Core Tip: Hepatic fibrosis is a necessary stage of liver cirrhosis, and there is currently no effective treatment. Cryptotanshinone (CPT), one of the extracts of Chinese herbal medicine Radix Salviae Miltiorrhizae, has a good anti-fibrosis effect. Through this study, we found that CPT can treat hepatic fibrosis by activating endoplasmic reticulum stress and leading to apoptosis of hepatic stellate cells, which provides a new method for the treatment of hepatic fibrosis.
