Cell chemical biologyOct 8, 2026

Blocking BRD4-BD1-p62 interaction may restore protective cell cleaning process

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗

Updated Oct 9, 2026

Abstract

SKLB-39b exhibits over 100-fold selectivity for BRD4-BD1 relative to BRD4-BD2.

Impaired protective autophagy is linked to idiopathic pulmonary fibrosis (IPF).
SKLB-39b restores protective autophagy and reduces pulmonary fibrosis.
A specific interaction between BRD4-BD1 and p62 is identified as important for autophagy regulation.
SKLB-39b disrupts the BRD4-BD1-p62 interaction, leading to restored autophagy via ULK1.
In mouse studies, SKLB-39b demonstrated superior effectiveness over JQ-1 in dampening fibrosis-related processes without overt toxicity.

Simplified

Impaired protective autophagy contributes to idiopathic pulmonary fibrosis (IPF), yet therapeutic strategies that restore this process remain limited. Here, we identify SKLB-39b, a BRD4-BD1-selective inhibitor that restores protective autophagy and attenuates pulmonary fibrosis. SKLB-39b exhibits over 100-fold selectivity for BRD4-BD1 relative to BRD4-BD2 and nearly 10-fold greater affinity for BRD4-BD1 than for BRD2/3-BD1. Mechanistically, we identify a BRD4-BD1-p62 interaction that links BET bromodomain function to autophagy regulation. By engaging Leu92 and Ile146 through a hydrophobic binding mode, SKLB-39b disrupts this interaction, restores ULK1-dependent autophagy, and provides a structural framework for BD1-selective inhibitor design. SKLB-39b outperformed JQ-1 in suppressing fibroblast activation, epithelial-mesenchymal transition, and collagen deposition in experimental fibrosis while showing favorable pharmacokinetic exposure and no overt toxicity in the mouse studies performed. These findings establish the BRD4-BD1-p62 interface as a druggable target for restoring protective autophagy in IPF.

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Blocking BRD4-BD1-p62 interaction may restore protective cell cleaning process

Abstract

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