Design of RGD-functionalized GSH-responsive pegylated polymeric protacs for selective BRD4 degradation and EndMT-driven cardiac fibrosis inhibition.

ABSTRACT: Endothelial cells (ECs) of endothelial-to-mesenchymal transition (EndMT) are drivers of cardiac fibrosis. BRD4 has recently been identified as an epigenetic regulator of EndMT. Proteolysis-targeting chimera (PROTAC) technology has revolutionized targeted protein degradation, offering unprecedented opportunities for BRD4 modulation in diverse pathological contexts. Nevertheless, the non-selective cellular targeting profile of PROTACs poses significant limitations for their therapeutic application in cardiac fibrosis management. To address these limitations, we developed a GSH-responsive nanoscale PROTAC (RGD-PEG-MZ1) that targets activated platelets, leveraging their chemotactic properties to precisely degrade BRD4 in ECs. RGD-PEG-MZ1 exhibits selectivity for ECs and inhibition of EndMT, wh

SUBMITTER: Bi T 

PROVIDER: S-EPMC12933928 | biostudies-literature | 2026 Jan

REPOSITORIES: biostudies-literature