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. The blood-brain barrier (BBB) is a dynamic interface that maintains the brain’s stable internal environment by precisely controlling the exchange of molecules between the bloodstream and the central nervous system. Its dysfunction is a hallmark of many neurological and psychiatric disorders, often driven by factors like inflammation and oxidative stress that disrupt this delicate balance. Emerging research indicates that these disruptions are governed by epigenetic mechanisms, such as DNA methylation and chromatin remodeling, that regulate gene activity without changing the underlying DNA code. While these epigenetic processes normally maintain the barrier’s structural and biochemical integrity, their dysregulation can weaken the interface and accelerate disease progression. Critically, because epigenetic modifications are reversible, they represent a promising frontier for therapy; unlike fixed genetic mutations, these molecular signals can potentially be “reset” to restore barrier function. By identifying these unique epigenetic signatures, scientists can develop new biomarkers to diagnose brain injury earlier and monitor recovery more accurately, paving the way for targeted, stage-specific treatments for a wide range of complex brain diseases.