Metabolic reprogramming in sepsis-associated encephalopathy: emerging mechanisms, candidate biomarkers, and future therapeutic directions

Sepsis-associated encephalopathy (SAE) affects up to 70% of septic patients, causing significant mortality and long-term cognitive impairment. Traditional mechanisms-neuroinflammation, blood-brain barrier disruption, and oxidative stress-fail to explain SAE heterogeneity and post-septic cognitive sequelae. Metabolic reprogramming, the systematic remodeling of cellular metabolic pathways, has emerged as an integrative paradigm for understanding SAE pathogenesis. This review examines how metabolic reprogramming drives SAE through four core pathways: glycolysis/Warburg effect, tricarboxylic acid cycle dysfunction, lipid dysregulation, and amino acid disturbance. We discuss cell-type-specific adaptations in microglia, neurons, and astrocytes, and the modulatory role of gut-brain axis crosstalk. We further evaluate metabolomics-driven biomarkers for early diagnosis and emerging metabolic-targeted therapies, including metformin and dichloroacetate. Finally, we highlight single-cell metabolomics and multi-omics integration as critical frontiers toward precision medicine for SAE.