RASA1 deficiency aggravates the lesion burden of cerebral cavernous malformations via the Ras/Raf/MAPK pathway.

Cerebral cavernous malformations (CCMs) are cerebrovascular lesions that can be influenced by genetic alterations affecting endothelial signaling. Here, we investigated how RASA1 deficiency modifies CCM progression using bioinformatic analyses, hCMEC/D3 endothelial knockdown and rescue models, Seahorse metabolic profiling, Ras-GTP pull-down assays, and a PDCD10-deficient mouse model with endothelial Rasa1 knockdown. RASA1 deficiency promoted endothelial proliferation, reduced ZO-1 expression, shifted energy metabolism from oxidative phosphorylation toward glycolysis, and activated Ras/Raf/MAPK signaling. RASA1 rescue or pharmacological Ras inhibition with RMC-7977 partially reversed these abnormalities in vitro, and RMC-7977 reduced lesion severity and Ras/Raf/MAPK activation in vivo. These findings provide mechanistic evidence that RASA1 deficiency aggravates CCM-like pathology through Ras/Raf/MAPK pathway activation and support further investigation of Ras-targeted strategies for genetically defined CCM subtypes.