Efficient analysis of toxicity and mechanisms of isoflurane on postoperative delirium by network toxicology and molecular docking.

Postoperative delirium (POD), a prevalent neurological complication in older surgical patients, adversely affects recovery. Isoflurane, a common inhalational anesthetic, exhibits neurotoxic potential, but its role in POD pathogenesis remains unclear. Network toxicology and molecular docking strategies identified 38 shared targets between isoflurane (PubChem/ChEMBL) and POD (GeneCards). Protein-protein interaction networks (STRING/Cytoscape) screened eight core genes: catechol-O-methyltransferase (COMT), angiotensin l-converting enzyme (ACE), solute carrier family 6, member 3 (SLC6A3), cathepsin B (CTSB), apoptosis-related cysteine peptidase (CASP3), B-lymphoblastoma-2 gene (BCL-2), coagulation factor VII (F7), and nuclear receptor subfamily 3 (NR3C1). Functional enrichment (Gene Ontology [GO]/Kyoto Encyclopedia of Genes and Genomes [KEGG]) analyzed biological pathways. Key pathways implicated include calcium signaling, dopamine/catecholamine synaptic uptake, cholinergic synapses, endocrine resistance, and estrogen signaling. Molecular docking confirmed strong binding affinity between isoflurane and core targets (e.g., CASP3: affinity-5.54 kcal/mol), highlighting dopaminergic disruption and apoptotic activation. This study elucidates isoflurane's multi-target neurotoxicity in POD, providing a mechanistic foundation for mitigating postoperative neurological complications.