Inhibition of neutrophil extracellular trap formation ameliorates astrocyte pyroptosis via CUL7-dependent NLRP3 ubiquitination in mice with sepsis-associated encephalopathy

Biochem Pharmacol. 2026 Oct 29:118579. doi: 10.1016/j.bcp.2026.118579. Online ahead of print.

ABSTRACT

Sepsis-associated encephalopathy (SAE) encompasses acute brain dysfunction during sepsis and may be followed by persistent cognitive impairment among survivors. Although neutrophil extracellular traps (NETs) have been implicated in sepsis-related organ injury, their role in astrocyte fate determination and neuroinflammation during SAE remains poorly defined. Here, using a cecal ligation and puncture (CLP) model, we demonstrate that NETs accumulate in both the circulation and hippocampus following sepsis. Pharmacological inhibition or degradation of NETs markedly alleviated blood-brain barrier disruption, neuroinflammation, neuronal death, and acute neurobehavioral abnormalities. Mechanistically, NET accumulation was associated with enhanced astrocyte pyroptosis via activation of the NOD-like receptor family pyrin domain-containing 3 (NLRP3)-caspase-1-gasdermin D (GSDMD) pathway. Activation of NLRP3 abolished the neuroprotective effects conferred by NET inhibition. Transcriptomic analysis of human hippocampal tissues identified cullin 7 (CUL7) as a sepsis-associated candidate, and subsequent experiments showed that its expression was restored following NET inhibition. CUL7 physically interacted with NLRP3, enhanced its ubiquitination, and reduced its protein stability, thereby restraining astrocyte pyroptosis. Notably, CUL7 overexpression improved acute neurobehavioral outcomes, preserved blood-brain barrier integrity, and attenuated neuroinflammation in septic mice. Collectively, our findings identify a previously unrecognized NETs-CUL7-NLRP3 axis that governs astrocyte pyroptosis and contributes to the pathogenesis of SAE, highlighting CUL7 as a potential therapeutic target.

PMID:42957055 | DOI:10.1016/j.bcp.2026.118579