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Targeted Degradation of Bromodomain-Containing Protein 4 Enabled by Reactive Oxygen Species-Activatable NanoPROTACs
Tao Bi1,2, Pan Liang1,2, Qixin Zhao1,2
1National Traditional Chinese Medicine Clinical Research Base and Drug Research Center of Integrated Traditional Chinese and Western Medicine, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, Sichuan 646000, China.
Abstract:
Liver fibrosis is an inadequate response to tissue stress, with reactive oxygen species (ROS) overproduction in activated hepatic stellate cells (aHSCs). Bromodomain-containing protein 4 (BRD4) was found to be upregulated in aHSCs and has been identified as an effective target for the treatment of liver fibrosis. However, inhibition of BRD4 with traditional kinase inhibitors achieved only limited success because of its low therapeutic efficiency. Furthermore, the exact mechanism by which BRD4 regulates liver fibrosis remains unclear and needs to be elucidated. In this work, we proposed an efficiency strategy, i.e., targeted degradation of BRD4 by ROS-activatable NanoPROTACs, for the treatment of liver fibrosis, both in vitro and in vivo. More importantly, we clarified the mechanism by which BRD4 regulates liver fibrosis. Thus, this strategy may represent an alternative to previously reported strategies and may be extensively applied to the design of ROS-activatable proteolysis-targeting chimeras for the treatment of other organ fibrosis.
Insights
Targeted degradation of Bromodomain-containing protein 4 (BRD4) using ROS-activatable NanoPROTACs offers a novel strategy for liver fibrosis treatment. This approach enhances therapeutic efficiency and clarifies BRD4
Area of Science:
- Biochemistry
- Molecular Biology
- Drug Discovery
Background:
- Liver fibrosis results from tissue stress and reactive oxygen species (ROS) overproduction in activated hepatic stellate cells (aHSCs).
- Bromodomain-containing protein 4 (BRD4) is upregulated in aHSCs and is a potential therapeutic target for liver fibrosis.
- Conventional BRD4 inhibition shows limited therapeutic efficiency and unclear mechanisms in liver fibrosis.
Purpose of the Study:
- To develop an efficient strategy for treating liver fibrosis by targeting BRD4.
- To elucidate the mechanism by which BRD4 regulates liver fibrosis.
- To investigate the efficacy of ROS-activatable NanoPROTACs for BRD4 degradation.
Main Methods:
- Development and application of ROS-activatable NanoPROTACs for targeted BRD4 degradation.
- In vitro and in vivo studies to evaluate the therapeutic strategy.
- Mechanistic studies to clarify BRD4's role in liver fibrosis.
Main Results:
- Targeted degradation of BRD4 was achieved using ROS-activatable NanoPROTACs.
- The proposed strategy demonstrated therapeutic efficiency in both in vitro and in vivo models of liver fibrosis.
- The mechanism of BRD4 in regulating liver fibrosis was successfully elucidated.
Conclusions:
- ROS-activatable NanoPROTACs represent a promising and efficient strategy for liver fibrosis treatment.
- This approach offers an alternative to traditional methods with improved therapeutic outcomes.
- The strategy has potential for broad application in designing ROS-activatable proteolysis-targeting chimeras for other fibrotic diseases.
