YAP Fuels Cerebral Cavernous Malformations by Regulating KLF4 Transcriptional Activity and Protein Stability

Cerebral cavernous malformations (CCMs), which frequently predispose patients to strokes or seizures, primarily arise from endothelial specific loss‐of‐function mutations in the CCM genes, and occasionally accompanied by gain‐of‐function mutations in PIK3CA and MAP3K3. While the Hippo pathway is a well‐established regulator of tissue homeostasis, its emerging relevance in vascular pathology particularly its precise role in CCM pathogenesis remains poorly understood. In this study, we demonstrate that CCM gene deficiency suppresses endothelial Hippo signaling, as evidenced by diminished LATS activity, alongside concomitant elevation of YAP expression and nuclear translocation in both human and mouse CCM lesions. Notably, endothelial‐specific deletion of Yap mitigates CCM lesion formation, reinforces endothelial junctions, enhances inflammatory resistance, and decreases KLF4 protein levels in a CCM mouse model. Conversely, intracranial Adeno‐associated virus (AAV)‐mediated inhibition of LATS or activation of YAP promoted CCMs formation under Ccm2 deficiency. Mechanistically, under the dual coordination of negative regulation by LATS and positive regulation by MAP3K3, YAP orchestrates KLF4 transcriptional activity and protein stability. This is achieved through a direct interaction with KLF4 that shields it from β‐TrCP‐mediated proteasomal degradation, thereby driving CCM progression. Collectively, our findings unveil a novel dimension to Hippo pathway regulation and underscore YAP as a pivotal driver of CCM pathogenesis.