Cerebral cavernous malformations: epidemiology, molecular pathogenesis, diagnosis and therapy

Abstract Cerebral cavernous malformations (CCMs) are cerebrovascular diseases characterized by vascular lesions of the central nervous system (CNS) that can result in epileptic seizures, headaches, focal neurologic deficits (FNDs), and hemorrhagic stroke. Germline and somatic loss-of-function (LOF) mutations in one of the three established CCM-associated genes, namely CCM1 (or krev interaction trapped protein 1, KRIT1), CCM2, and CCM3 (or programmed cell death 10, PDCD10), which have been validated as core drivers of CCM pathogenesis and progression. Over the past few decades, a substantially improved understanding of the hallmarks and molecular basis of CCMs has been achieved. Key pathological hallmarks include but are not limited to excessive angiogenesis, vascular leakage, endothelial-mesenchymal transition (EndMT), defective autophagy, inflammation and immune response, oxidative stress, influenced gut microbiome and altered brain vascular microenvironment. These hallmarks are orchestrated by dysregulated signaling cascades, notably MEKK3-KLF2/4, PI3K-mTOR, and RhoA-ROCK, which integrate genetic, inflammatory, and hemodynamic cues. Concurrently, sophisticated neuroimaging (MRI with SWI/QSM) and genetic testing now enable precise diagnosis and risk stratification. Although surgical resection remains the mainstay for accessible symptomatic lesions, a wave of mechanism‑based pharmacological candidates has shown promising efficacy in preclinical models, and several have advanced to early‑phase clinical trials. This review summarizes the current understanding of CCM epidemiology, molecular pathogenesis, diagnosis and therapy, highlighting how the evolving multi‑hit concept and the dissection of downstream signaling are paving the way towards personalized management of this complicated vascular disease.