journal article·2026-02Open access

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

Chenxiao Li, Xiaochen Zhang, Jiangwei Xia, Shuang Liu, Yushan Du, Sihan Li, Shukui Zhang, Yong Zhang, Fen Ji, Jianwei Jiao, Jingjing Zhang

Advanced Science· Volume 13· Issue 7

Abstract

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.
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Research context

OpenAlex topics: Protein Degradation and Inhibitors · Barrier Structure and Function Studies · Chromatin Remodeling and Cancer

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Zhanjiang Key Laboratory of Zebrafish Model for Development and Disease Affiliated Hospital of Guangdong Medical University Zhanjiang 524001 China

Key Laboratory of Organ Regeneration and Reconstruction Chinese Academy of Science Beijing 100101 China

University of Chinese Academy of Sciences Beijing 100049 China

Academy of Medical Engineering and Translational Medicine Tianjin University Tianjin 300072 China

Department of Neurology Xuanwu Hospital Capital Medical University, National Center for Neurological Disorders Beijing 100053 China

Jiaozuo Hospital of Traditional Chinese Medicine Jiaozuo 454150 China

College of Basic Medicine Qingdao University Qingdao 266071 China

Neuroscience Research Institute and Department of Neurobiology, School of Basic Medical Sciences Peking University, Key Laboratory for Neuroscience, Ministry of Education of China and National Health Commission of the People's Republic of China Beijing 100083 China

School of Medical Technology Guangdong Medical University Dongguan 523808 China

Funding

National Natural Science Foundation of China · National Key Research and Development Program of China

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