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We demonstrate that endothelial MEKK3 initiates lesion formation, whereas microglial MEKK3 exacerbates late\u2010stage progression. Mechanistically, MEKK3 activation in endothelial cells disrupts junctional integrity and promotes fibrinogen leakage; fibrinogen\u2010recruited microglia subsequently amplify vascular injury via MEKK3\u2013NF\u2010\u03baB\u2013dependent uptake of damaged endothelial debris. Through AI\u2010assisted drug design and structural optimization, we identified (R)\u20101,6\u2010dimethyl\u201011\u2010phenyl\u20101,10\u2010dihydro\u20102H\u2010furo[2\u2032,3\u2032:1,2]phenanthrol[3,4\u2010d]imidazole (DPDH) as a potent MEKK3 inhibitor. DPDH suppresses MEKK3\u2010KLF2\/4 signaling in endothelial cells to restore barrier integrity and inhibits MEKK3\u2013NF\u2010\u03baB in microglia to restrain their activation and uptake of damaged endothelial cells. 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