Integrated multi-omics reveals synaptic vulnerability, mitochondrial impairment, and systemic lipid remodeling as...

Postoperative cognitive dysfunction (POCD) is a common complication after surgery, but its systemic molecular mechanisms remain unclear. Using a murine model combining 2% isoflurane anesthesia and laparotomy, we integrated spatial proteomics (frontal cortex, hippocampus, and hypothalamus), serum proteomics, and serum lipidomics to elucidate the pathophysiology of POCD. POCD mice showed significant behavioral deficits (reduced open field exploration and impaired Morris water maze performance). Proteomics revealed synaptic dysregulation in the frontal cortex (e.g., Sptan1 upregulation) and mitochondrial dysfunction in the hippocampus (e.g., Ogdh downregulation), along with activated MAPK signaling. Serum lipidomics revealed elevated triglyceride and lysophosphatidylcholine (LPC) (22:6) levels and decreased sphingomyelin and ether lipid levels. Integrated pathway analysis revealed neuroinflammation, oxidative stress, and proteostasis disruption. These findings demonstrate that POCD arises from synergistic dysregulation of synaptic integrity, systemic lipid metabolism, and mitochondrial function. Key molecules such as Sptan1 and Ogdh and those with altered TG/LPC (22:6) ratios have emerged as candidate molecules associated with POCD, suggesting potential directions for therapeutic intervention.