Therapeutic potential and pathophysiological role of vitamin D in cerebral cavernous malformations: Systematic review of preclinical and clinical evidence

Abstract

Background and purpose: Cerebral cavernous malformations (CCMs) are vascular lesions characterized by blood-brain barrier instability and a propensity for recurrent hemorrhage. While RhoA-ROCK signaling dysregulation is the canonical driver of pathogenesis, vitamin D has emerged as a potential molecular modifier. This systematic review synthesizes clinical, genetic, and preclinical evidence to evaluate the biological role of vitamin D and its receptor signaling pathways in CCM pathogenesis. Methods: Following PRISMA guidelines, a comprehensive search was conducted across MEDLINE, EMBASE, Web of Science, and Scopus through February 2026. Eligible studies included clinical cohorts, genetic association analyses, and preclinical models investigating vitamin D signaling in CCM. Quality assessment was performed using NIH, JBI, and SYRCLE tools. Results: Nine studies representing 971 patients and several preclinical models were included. Observational clinical data indicate that lower serum 25-hydroxyvitamin D (25(OH)D) levels are associated with chronically aggressive disease phenotypes and hemorrhagic presentation, though these findings are limited to small, associative cohorts. Genetically, polymorphisms in the vitamin D receptor (VDR) and metabolic enzymes (CYP27A1, CYP27B1) correlate with clinical heterogeneity and lesion burden. Mechanistically, preclinical cell and animal models demonstrate that vitamin D can non-canonically inhibit the RhoA-ROCK axis, reduce local oxidative stress, and induce autophagy via mTORC1 inhibition. In specific murine models, cholecalciferol supplementation reduced lesion burden by approximately 50%. Conclusions: Circulating vitamin D status and related genetic variants serve as hypothesis-generating biological correlates of CCM disease activity, but causality has not been established and current evidence is insufficient to recommend supplementation to alter clinical outcomes. While the VDR pathway constitutes a plausible molecular axis associated with endothelial structural homeostasis, routine clinical supplementation with a disease-modifying intent must await prospective, randomized controlled trials to formally establish safety and therapeutic efficacy.