Targeting neuroglial aromatase for CNS injuries: molecular insights and therapeutic prospects

Aromatase (AROM) is the key enzyme that catalyzes estrogens (mainly 17β-estradiol, E2) biosynthesis. While high levels of AROM have been detected in specific neurons in the central nervous system (CNS), emerging evidence reveals differential levels of AROM in nonneuronal cells such as astrocytes, microglia, and ependymal cells. This review integrates current knowledge on the dynamic regulation and neuroprotective roles of neuroglial AROM, particularly following CNS injuries such as traumatic brain injury and ischemic stroke. Neuroglia cells, especially astrocytes, significantly fluctuate in AROM expression in response to injury and disease, which is mediated by E2 feedback and cytokine signaling. Astrocyte-derived E2 exerts multiple neuroprotective effects through genomic (ERα/ERβ activation) and nongenomic pathways (GPR30-mediated signaling), modulating neuroinflammation by regulating microglial activation and reducing reactive astrogliosis. Notably, sexual dimorphism in AROM regulation, with females exhibiting higher basal and injury-induced AROM activity, may explain their greater resilience to brain injuries. Although challenges remain in optimizing blood‒brain barrier penetration and sex-specific dosing regimens, targeting neuroglial AROM and its downstream effectors exhibits promise for enhancing postinjury recovery. Future studies should employ multiple omics methods to characterize AROM-positive glial subpopulations and develop conditional knockout models to dissect cell type-specific mechanisms, ultimately paving the way for precision therapies for the treatment of brain injuries, AROM-associated neural disease and other CNS disorders.