Exploring therapeutic targets for neuroinflammation in sepsis-associated encephalopathy: a combined network...

Sepsis-associated encephalopathy (SAE) is a frequent but underrecognized complication of sepsis, yet no effective pharmacological interventions are currently available. Traditional Chinese medicine (TCM) offers a promising multi-component and multi-target strategy.

We used an integrative strategy combining network pharmacology, bioinformatics, and molecular modeling was employed to investigate a seven-herb TCM formula. Active compounds were retrieved from the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database, and disease-related genes were obtained from GSE135838. Overlapping targets were subjected to Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and protein-protein interaction (PPI) analyses, and network topology analysis was performed to identify key hub genes and core compounds. Compound-target interactions were evaluated using molecular docking, molecular dynamics (MD) simulation, and molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) analysis.

A total of 121 active compounds and 255 targets were identified, with 29 overlapping genes related to SAE. Five hub genes-amyloid precursor protein (APP), B-cell lymphoma 2 (BCL2), caspase-3 (CASP3), intercellular adhesion molecule 1 (ICAM1), and interleukin-6 (IL-6)-and five core compounds (quercetin, luteolin, kaempferol, β-sitosterol, and 7-O-methylisomucronulatol) were identified. Molecular docking revealed favorable compound-target interactions (binding energies: -5.7 to -9.1 kcal/mol). MD simulations confirmed stable APP-ligand complexes throughout the 100 ns simulation period. MM-PBSA analysis showed that β-sitosterol exhibited the strongest binding affinity toward APP (ΔGbind = -23.67 kcal/mol).

This study highlights the multi-target and multi-pathway therapeutic potential of a seven-herb TCM formula against SAE and identifies potential bioactive compounds and therapeutic targets for further investigation.