Astrocytic N-myc downstream-regulated gene 2 is involved in neural injury induced by sepsis-associated encephalopathy

SAE is a systemic inflammatory response syndrome resulting from severe infection, which can progress to multiorgan dysfunction and mortality. Astrocytic-specific NDRG2, a stress response gene, has been implicated in regulating astrocyte reactivity and glutamate homeostasis in various neurological disorders. In this study, we initially investigated the expression and functional role of NDRG2 in SAE. Our results demonstrated that the upregulation of NDRG2 primarily inhibited Na⁺/K⁺-ATPase β1 and EAAT2, subsequently leading to glutamate toxicity and then induced astrocyte activation, neuronal dysfunction, and cellular apoptosis, ultimately leading to cognitive impairment. The deficiency of NDRG2 significantly mitigated these detrimental changes, including astrocytic activation, impaired glutamate clearance, and cognitive deficits in SAE, partly through the modulation of Na⁺/K⁺-ATPase β1. Our findings may provide new strategies for the intervention and treatment of patients with SAE in the future.