Sepsis-associated encephalopathy: Unraveling molecular mechanisms, emerging therapeutics, and translational frontiers

Sepsis-associated encephalopathy is a debilitating complication of systemic infection, marked by acute cognitive impairment and long-term neurological deficits in the absence of direct central nervous system (CNS) infection. Its pathogenesis involves a multifactorial interplay of neuroinflammation (e.g., cytokine storms), immune dysregulation, blood-brain barrier (BBB) disruption, metabolic derangements, and impaired neuronal repair. These mechanisms synergistically contribute to neuronal injury and persistent cognitive dysfunction. Emerging therapeutic strategies-such as targeted immunomodulators, BBB-stabilizing agents, and novel CNS-targeted drug delivery-aim to interrupt this cascade and improve outcomes. Concurrently, precision medicine approaches leverage molecular profiling to tailor interventions. However, current clinical management remains supportive, hindered by incomplete mechanistic understanding and a paucity of disease-modifying therapies. This review synthesizes recent advances in the pathophysiology of sepsis-associated encephalopathy, critically evaluates these mechanism-based therapeutic approaches, and highlights translational roadblocks in biomarker development and preclinical-to-clinical bridging. We also propose future directions to accelerate the development of targeted pharmacotherapies and personalized treatment paradigms for sepsis-associated encephalopathy.