Abstract

Background Microglial pyroptosis-mediated neuroinflammation is a key pathogenic mechanism in Sepsis-Associated Encephalopathy (SAE). However, the role of prodynorphin (PDYN) in SAE and the relationship between PDYN and microglial pyroptosis remain unknown. Methods Mice were subjected to cecal ligation and puncture (CLP) or sham surgery. Microglial cells were treated with lipopolysaccharide (LPS) in vitro . Cognitive function was assessed using the Morris water maze, novel object recognition, and open field tests. Transferase-mediated deoxyuridine triphosphate-biotin nick end labeling (TUNEL) staining was used to observe glial apoptosis; Nissl staining was used to observe microglial infiltration; H&E staining was used to detect histopathological changes. Pyroptosis and the expression levels of relevant signaling molecules were assessed by Western blot analysis. Results PDYN protected against neuronal damage and cognitive impairment in septic mice. PDYN inhibits microglial pyroptosis and secretion of inflammatory cytokines in vivo and in vitro . Further examination revealed that PDYN inhibits microglial pyroptosis by inhibiting the PI3K/AKT/mTORC pathway. Moreover, the PI3K activator 740Y-P promoted microglial pyroptosis by activating the PI3K/AKT/mTORC pathway. Conclusion This study reveals, for the first time, that PDYN exerts neuroprotective effects in SAE by suppressing microglial pyroptosis through inhibition of the PI3K/AKT/mTOR signaling pathway. These findings identify PDYN and the PI3K/AKT/mTOR-pyroptosis axis as novel therapeutic targets for SAE, providing a mechanistic foundation for developing adjunctive neuroprotective strategies alongside standard sepsis care.