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

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.