Astrocyte autophagy-neuroinflammation axis in ischemic stroke: From molecular mechanisms to translational medicine

Astrocyte autophagy has emerged as a pivotal regulator of neuroinflammatory dynamics and ischemic brain injury, exhibiting context-dependent dual roles in stroke pathology. Cerebral ischemia triggers the activation of two functionally polarized astrocyte subtypes: the neurotoxic A1 phenotype and the neuroprotective A2 phenotype. While previous studies have primarily focused on astrocytic involvement in neuroinflammation, glial scar formation, and blood-brain barrier disruption, emerging research has shifted attention to their autophagic regulation as a critical mechanism in ischemia-reperfusion injury. Autophagy, an evolutionarily conserved quality-control mechanism, serves as a master regulator of cellular homeostasis, energy metabolism, and phenotypic determination. Recent studies reveal that astrocyte autophagy exerts essential control over neuroinflammatory cascades, acting as a decisive factor influencing neuronal survival and functional recovery post-ischemia. This review (1) outlines ischemia-induced phenotypic switching in astrocytes; (2) describes interventions targeting astrocytic autophagy to modulate pathological progression following cerebral ischemia, emphasizing the potential of astrocyte autophagy as a therapeutic node to disrupt neuroinflammatory cascades; and (3) elucidates the molecular mechanisms by which astrocyte autophagy regulates neuroinflammation, further highlighting its translational potential. Additionally, we discuss novel preclinical strategies utilizing pharmacological enhancers and inhibitors of autophagy to mitigate ischemic brain injury. This review provides a novel perspective by focusing on the crosstalk between astrocyte autophagy and neuroinflammation in the context of ischemic injury. By delineating how autophagic pathways modulate inflammatory signaling within astrocytes, we highlight autophagy as an important regulator with therapeutic potential.