The blood-brain barrier(BBB)plays a critical role in maintaining brain homeostasis. However,dysfunction of the BBB is closely associated with various neurodegenerative diseases and acute brain injuries,which not only impair the brain's defense mechanisms but may also exacerbate the progression of pathological conditions.Nitric oxide (NO),as an important biological signaling molecule,exerts a wide range of effects on the central nervous system,influencing both physiological and pathological states.This review summarizes the production and metabolism of NO and their effects on blood-brain barrier permeability, followed by an introduction to the role of NO in pathological conditions such as cerebral ischemia-reperfusion injury, neurodegenerative diseases, and brain tumors.Furthermore,NO regulates the integrity of the BBB through regulation of tight junction proteins and the vascular endothelial growth factor receptor2(VEGFR2).The review further delves into the potential of NO as a therapeutic target in drug delivery and gene therapy.Additionally,it explores NO's potential to enhance drug penetration across the BBB.These explorations provide novel perspectives for future therapeutic strategies.