VCPIP1 ameliorates sepsis-associated encephalopathy by promoting microglia autophagy via the PI3K/AKT/mTOR pathway.

Sepsis-associated encephalopathy (SAE) is acute diffuse brain dysfunctional clinically caused by systemic infections originating outside the central nervous system (CNS), characterized by acute delirium, coma, and persistent cognitive dysfunction. Multiple studies have demonstrated a crucial role of microglia in the development of SAE. Bioinformatics analysis of the Human Protein Atlas and single-cell RNA sequencing datasets revealed that valosin-containing protein interaction protein 1 (VCPIP1) is expressed at the highest levels in hippocampal microglia, suggesting its potential involvement in neuroinflammatory regulation. In a murine cecal ligation and perforation (CLP) model of SAE, VCPIP1 was upregulated in hippocampal tissue. VCPIP1 deletion could exacerbate learning and memory impairment in CLP-induced conditions, along with suppressed microglial autophagy and increased proinflammatory cytokine production. Mechanistically, VCPIP1 deficiency activated the PI3K/AKT/mTOR signaling axis in microglia, thereby inhibiting autophagic flux. Inhibiting activation of PI3K by LY294002 reversed these effects, restoring autophagy, attenuating neuroinflammation, and mitigating neuronal injury. These results suggest that VCPIP1 improves autophagy by inhibiting the PI3K/AKT/mTOR pathway, highlighting its potential as a therapeutic target for SAE.