Copyright
©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.
Dihydroergotamine ameliorates liver fibrosis by targeting transforming growth factor β type II receptor
Ke-Xin Zheng, Shou-Li Yuan, Meng Dong, Han-Lin Zhang, Xiao-Xiao Jiang, Chun-Long Yan, Rong-Cai Ye, Hui-Qiao Zhou, Li Chen, Rui Jiang, Zi-Yu Cheng, Zhi Zhang, Qi Wang, Wan-Zhu Jin, Wen Xie
Ke-Xin Zheng, Qi Wang, Wen Xie, Center of Liver Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
Shou-Li Yuan, Meng Dong, Han-Lin Zhang, Xiao-Xiao Jiang, Chun-Long Yan, Rong-Cai Ye, Hui-Qiao Zhou, Li Chen, Rui Jiang, Zi-Yu Cheng, Zhi Zhang, Wan-Zhu Jin, Key Laboratory of Animal Ecology and Conservation Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
Shou-Li Yuan, Han-Lin Zhang, Xiao-Xiao Jiang, Rong-Cai Ye, Hui-Qiao Zhou, Li Chen, Rui Jiang, Zi-Yu Cheng, Zhi Zhang, Graduate School, University of the Chinese Academy of Sciences, Beijing 100049, China
Chun-Long Yan, Graduate School, Agriculture College of Yanbian University, Yanji 133002, Jilin Province, China
Author contributions: Xie W designed experiments and revised the manuscript; Jin WZ and Wang Q reversed the manuscript; Zheng KX and Yuan SL performed experiments, analyzed data, and wrote the manuscript; Dong M and Zhang HL performed experiments, analyzed data, and revised the manuscript; Other authors helped with the experiments; All authors read and approved the final version of the article.
Supported by the Special Research Project for Capital Health Development, No. 2022-2-2174; and the Beijing Municipal Science and Technology Commission, No. Z191100007619037.
Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Institutional Animal Care and Use Committee the Institute of Zoology, Chinese Academy of Sciences, IACUC protocol No. IOZ-IACUC-2020-114.
Conflict-of-interest statement: Dr. Xie reports in addition, Dr. Xie has a patent Application of dihydroergotamine in the treatment of liver fibrosis issued.
Data sharing statement: No additional data are available.
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: Wen Xie, MD, Doctor, Center of Liver Diseases, Beijing Ditan Hospital, Capital Medical University, No. 8 Jingshun East Street, Chaoyang District, Beijing 100015, China. xiewen6218@163.com
Received: February 6, 2023
Peer-review started: February 6, 2023
First decision: March 21, 2023
Revised: April 1, 2023
Accepted: April 24, 2023
Article in press: April 24, 2023
Published online: May 28, 2023
BACKGROUND
The transforming growth factor β (TGFβ) signaling pathway plays a crucial role in the development of liver fibrosis by activating TGFβ type II receptor (TGFβR2), followed by the recruitment of TGFβR1 finally triggering downstream signaling pathway.
AIM
To find drugs targeting TGFβR2 that inhibit TGFβR1/TGFβR2 complex formation, theoretically inhibit TGFβ signaling pathway, and thereby ameliorate liver fibrosis.
METHODS
Food and Drug Administration-approved drugs were screened for binding affinity with TGFβR2 by virtual molecular docking. We identified 6 candidates and further explored their potential by Cell Counting Kit-8 (CCK-8) cell cytotoxic experiment to validate toxicity and titrated the best cellular working concentrations. Next, we further demonstrated the detailed molecular working mechanisms using mutagenesis analysis. Finally, we used a mouse model to investigate its potential anti-liver fibrosis effect.
RESULTS
We identified 6 drug candidates. Among these 6 drugs, dihydroergotamine (DHE) shows great ability in reducing fibrotic gene expressions such as collagen, p-SMAD3, and α-SMA in TGFβ induced cellular model of liver fibrosis in LX-2 cells. Furthermore, we demonstrated that DHE binds to TGFβR2. Moreover, mutation of Leu27, Phe30, Thr51, Ser52, Ile53, and Glu55 of TGFβR2 disrupted the binding of TGFβR2 with DHE. In addition, DHE significantly improved liver fibrosis, as evidenced by Masson’s trichrome staining of liver sections. This is further supported by the width and the velocity of the portal vein, and serum markers of liver function. In line with those observations, DHE also decreased macrophages infiltration and extracellular matrix deposition in the liver.
CONCLUSION
DHE alleviates liver fibrosis by binding to TGFβR2 thereby suppressing TGFβ signaling pathway. We show here that as far as drug repurposing, DHE has great potential to treat liver fibrosis.
Core Tip: An effective and safe drug for treating liver fibrosis is urgently needed in current clinical practice. Here, we investigated and discovered that dihydroergotamine (DHE) could alleviate liver fibrosis by specific binding of transforming growth factor β type II receptor (TGFβR2) to disrupt the binding of TGFβR2 with TGFβ1, and ultimately suppressing its downstream TGFβ signaling pathway. DHE may be an effective anti-liver fibrosis drug, which could be employed in liver cirrhotic patients.
