Astrocytic aquaporin-4 expression, localization, and polarization: mechanisms and therapeutic potential in...

Aquaporin-4 (AQP4) is a water channel that maintains cerebrospinal fluid homeostasis through polarized membrane localization and serves as a primary mediator for the clearance of neurotoxic metabolites within the central nervous system (CNS). The precise localization and functional stability of AQP4 rely on multiple regulatory processes, including transcriptional readthrough, interactions with cytoskeletal components, isoform assembly, and post-translational modifications. Disruption of these mechanisms leads to AQP4 depolarization, contributing to the pathogenesis of several neurological diseases including cerebrovascular diseases, neurodegenerative conditions, traumatic brain injury, and epilepsy. This review synthesizes current research advances on AQP4 localization and polarization, aiming to summarize its roles in normal physiology and disease pathogenesis. Preclinical findings in restoring AQP4 polarization, including pharmaceutical facilitator, matrix metalloproteinase inhibitor, repurposed drugs, hormone-based interventions, and stem cell/exosome therapies, underscore AQP4 polarization as a promising therapeutic target. To bridge the gap in clinical translation, we propose that future research should focus on investigating the deeper molecular mechanisms regulating AQP4 polarization and exploring clinically effective therapeutic approaches with high selectivity for CNS astrocytes.