Targeting epigenetic remodeling of the blood-brain barrier: current knowledge for drug therapy

The blood - brain barrier (BBB) is a dynamic regulator of brain homeostasis, and its dysfunction is a hallmark of many neurological and psychiatric disorders. Yet, in most conditions, the causal relationship between BBB injury and disease progression remains unclear, as shared systemic risk factors, such as inflammation, infection, oxidative stress, and genetic predisposition, produce highly variable patterns of barrier disruption. Epigenetic mechanisms, including DNA and RNA methylation, histone modifications, chromatin remodeling, and noncoding RNAs, have emerged as key regulators of BBB integrity. Their dysregulation contributes to pathological BBB remodeling in disorders such as cerebrovascular and neurodegenerative diseases, promoting a decline in barrier function (structural and biochemical) and accelerating disease progression. Owing to their reversible nature, epigenetic modifications represent promising therapeutic targets, and their disease-stage-specific patterns offer potential as biomarkers for BBB injury and recovery. This review summarizes current knowledge on how epigenetic processes drive BBB dysfunction and highlights emerging epigenetic signatures with diagnostic and therapeutic relevance across neurological and psychiatric diseases.