Astrocytes in Sepsis-Associated Encephalopathy: Pivotal Roles in Dual Pathogenesis and Therapeutic Perspectives

Sepsis-associated encephalopathy (SAE) is a diffuse brain dysfunction secondary to the systemic inflammatory response in sepsis. Clinically characterized by impaired cognition and altered consciousness, SAE contributes to poor patient prognosis. Astrocytes, one of the predominant glial cells in the central nervous system, are essential for maintaining central nervous system homeostasis. Mounting evidence highlights their critical involvement in SAE pathogenesis, driving increasing research interest. This review explores the mechanistic roles of astrocytes in SAE and identifies related therapeutic targets. We categorize astrocytic involvement in SAE into (1) mediation of neuroinflammation initiation and progression; (2) impairment of antioxidant defenses; (3) dual roles in blood-brain barrier integrity (protection and disruption); (4) modulation of energy metabolism; (5) modulation of neurotransmitter metabolism; (6) regulation of water and ion homeostasis; and (7) modulation of synaptic plasticity. Furthermore, we systematically review current astrocyte-targeted therapeutic strategies for SAE and elucidate their underlying mechanisms, offering insights for developing future targeted interventions.