Inhibition of MEKK3 Prevents Cerebral Cavernous Malformation Progression Via Restoring Endothelial Integrity and Restricting Microglial Activation.

Authors

Weiwei Zheng, Suyun Yu, Liwenyu Chen, Jing Ma, Peiliang Shen, Chang Yu, Xiaoqing Xin, Qiuhong Shen, Jing Chen, Song Ke, Hao Liu, Xiaobing Jiang, Ruogu Qi, Juming Yan, Jia Li, Jaesung P Choi, Yin Lu, Yang Zhao

Published in

Advanced science (Weinheim, Baden-Wurttemberg, Germany). Pages e78132. Oct 06, 2026. Epub Oct 06, 2026.

Abstract

Cerebral cavernous malformations (CCMs) are characterized by aberrant MEKK3 activation, yet how MEKK3 governs lesion maturation and whether it represents a viable therapeutic target remain unclear. We demonstrate that endothelial MEKK3 initiates lesion formation, whereas microglial MEKK3 exacerbates late-stage progression. Mechanistically, MEKK3 activation in endothelial cells disrupts junctional integrity and promotes fibrinogen leakage; fibrinogen-recruited microglia subsequently amplify vascular injury via MEKK3-NF-κB-dependent uptake of damaged endothelial debris. Through AI-assisted drug design and structural optimization, we identified (R)-1,6-dimethyl-11-phenyl-1,10-dihydro-2H-furo[2',3':1,2]phenanthrol[3,4-d]imidazole (DPDH) as a potent MEKK3 inhibitor. DPDH suppresses MEKK3-KLF2/4 signaling in endothelial cells to restore barrier integrity and inhibits MEKK3-NF-κB in microglia to restrain their activation and uptake of damaged endothelial cells. Collectively, our findings establish that MEKK3 signaling in both endothelial cells and microglia drives CCM progression, and position DPDH as a promising therapeutic candidate for CCM treatment.

PMID:
42839637
Bibliographic data and abstract were imported from PubMed on 07 Oct 2026.

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