Disrupting BRD4-BD1–p62 Engagement Restores Protective Autophagy
Description
Protective autophagy is profoundly impaired in idiopathic pulmonary fibrosis (IPF), yet no therapies directly restore this fundamental cellular defense mechanism. Here, we identify the BRD4-BD1-p62 interface as a druggable regulator of protective autophagy and develop SKLB-39b, a BRD4-BD1-selective inhibitor that disrupts this interaction. By engaging Leu92 and Ile146, SKLB-39b restores ULK1-dependent autophagy, suppresses fibroblast activation and epithelial-mesenchymal transition, and attenuates pulmonary fibrosis with improved tolerability relative to pan-BET inhibition in the mouse studies performed here. These findings establish a mechanistic framework for domain-selective BET inhibition and demonstrate how disrupting a disease-associated protein-protein interaction within an epigenetic reader can restore protective autophagy. More broadly, this work identifies the BRD4-BD1-p62 interface as a therapeutic opportunity for autophagy-deficient fibrotic diseases.
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Institutions
- Sichuan UniversitySichuan, Chengdu