The neurovascular unit under siege: Molecular mechanisms and potential drug target for cerebral edema

Cerebral edema, a life-threatening accumulation of fluid in the brain parenchyma, is a common complication of neurological injuries that leads to elevated intracranial pressure and high mortality. Current mainstay treatments, primarily osmotic therapies offer only transient relief from symptoms without targeting the underlying pathophysiology and are hampered by significant side effects and a high rate of therapeutic refractoriness. Elucidating the precise molecular mechanisms that drive cerebral edema remains a significant challenge, which has critically limited the identification of viable drug targets and the subsequent development of effective interventions. This review reframes cerebral edema as a failure of multicellular communication within the neurovascular unit (NVU). It examines how disrupted NVU components drive the progression of cytotoxic, ionic, and vasogenic edema through interconnected pathways governing intercellular signaling, ion-water coupling, and glymphatic clearance. Finally, emerging therapeutic strategies are evaluated through the lens of NVU-centered pathophysiology, with emphasis on approaches that restore multicellular dialogue and phase-specific interventions informed by the dynamic evolution of cellular dysfunction after injury.