Targeted Degradation of Bromodomain-Containing Protein 4 Enabled by Reactive Oxygen Species–Activatable NanoPROTACs as an Efficient Strategy to Reverse Liver Fibrosis in Chronic Liver Injury

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.