# Brd4 BD1 Domain Antagonism of MS436 Preserves Blood‐Brain Barrier Integrity via Rnf43/β‐Catenin Signaling Pathway

## TL;DR

The study shows that MS436, a Brd4 BD1 inhibitor, protects the blood-brain barrier by preventing tight junction protein degradation, offering a new treatment strategy for cerebrovascular diseases.

## Contribution

The paper identifies a novel Brd4 BD1/Rnf43/β-catenin pathway that regulates blood-brain barrier integrity and demonstrates the therapeutic potential of BD1 antagonism.

## Key findings

- MS436 reduces blood-brain barrier leakage and improves neurological outcomes after stroke.
- Brd4's BD1 domain, not BD2, is critical for destabilizing tight junctions via Rnf43 and β-catenin.
- Brd4 BD1 inhibition preserves BBB integrity by suppressing tight junction protein degradation.

## Abstract

Blood‐brain barrier (BBB) disruption is central to neurodegenerative and cerebrovascular diseases, but its causal role and therapeutic targeting remain challenging. Bromodomain and extraterminal domain (BET) proteins, particularly Brd4, regulate transcription via dual bromodomains (BD1, BD2). While BD1 antagonists are explored for tumors and BD2 antagonists for inflammation, their impact on cerebrovascular integrity is unclear. Crucially, opposing BBB effects of domain‐specific BET antagonism: the BD2 antagonist RVX208 disrupt the BBB, whereas the BD1 antagonist MS436 significantly reduces leakage and improves neurological outcomes, revealing therapeutic potential is demonstrated. Mechanistically, endothelial Brd4 critically suppresses BBB stability. Its ablation upregulates tight junction (TJ) proteins. Brd4, acting exclusively through its BD1 domain, destabilizes TJs via Rnf43 is identified, which promotes β‐catenin and TJ protein degradation. This defines a novel Brd4 BD1/Rnf43/β‐catenin axis essential for BBB integrity. The findings establish Brd4 BD1 inhibition as a novel BBB‐protective strategy and position MS436 for repurposing in cerebrovascular diseases, necessitating reevaluation of domain‐specific BET targeting for neurovascular pathologies.

MS436 competitively binds to the BD1 domain of Brd4, thereby suppressing Brd4 induced degradation of tight junction proteins via the Rnf43‐Fzd4‐β‐catenin signaling pathway. Consequently, this attenuation of degradation reduces blood‐brain barrier leakage, leading to an improved overall prognosis after stroke.