Decoding sepsis-associated encephalopathy: From blood-brain barrier injury to mechanism-based subphenotypes.

Sepsis-associated encephalopathy (SAE) is a frequent but underrecognized complication of systemic infection, characterized by acute brain dysfunction and long-term cognitive impairment in the absence of direct central nervous system infection. Despite its high morbidity and mortality, the mechanistic basis of SAE remains poorly defined, limiting early diagnosis and targeted intervention. This review synthesizes recent advances in the molecular and cellular pathophysiology of SAE, with emphasis on blood-brain barrier (BBB) disruption, neuroinflammation, glial cell activation, mitochondrial dysfunction, and neurotransmitter imbalance. We highlight the central role of BBB breakdown in facilitating peripheral-to-central immune signaling, which triggers a cascade of neuroinflammatory and metabolic events that collectively disrupt synaptic homeostasis and neuronal integrity. Emerging evidence also supports the existence of biologically distinct SAE subphenotypes, such as ischemic-hypoxic, inflammatory-dominant, and metabolic-degenerative types-each associated with specific molecular features and clinical outcomes. These insights underscore the need for biomarker-driven patient stratification and mechanism-targeted therapeutic strategies. Future research should prioritize the development of integrated diagnostic platforms, molecular phenotyping tools, and neuroprotective therapies that address the heterogeneous nature of SAE. A refined understanding of its pathogenesis holds promise for transforming the clinical management of SAE and improving long-term neurological recovery in sepsis survivors.