Multi-omics profiling reveals mitochondrial dysfunction and epigenetic dysregulation in postoperative cognitive dysfunction: identification of novel biomarkers in an aged mouse model.

Postoperative cognitive dysfunction (POCD) is a prevalent neurocognitive disorder in elderly patients following surgery and anesthesia. However, the underlying mechanisms remain poorly understood, and treatment options are limited. This study applied a multi-omics strategy, combining cognitive-behavioral assessments with proteomic and metabolomic profiling, to uncover the molecular basis of POCD in an aged mouse model. Behavioral assessments, including the Morris Water Maze (MWM), Open Field Test (OFT), and Novel Object Recognition (NOR), revealed significant cognitive deficits in POCD mice. Proteomic analysis identified 103 differentially expressed proteins (DEPs), with 34 upregulated and 69 downregulated, alongside significant correlations among 16 proteins. Enrichment analysis indicated disturbances in mitochondrial energy metabolism and epigenetic regulation, linked to neurodegenerative pathways. Metabolomic profiling detected 99 metabolites, with 66 upregulated and 33 downregulated, confirming their differential expression between groups. Correlation analysis between DEPs and metabolites led to the identification of nine key proteins (PSB9, COA7, PFD2, CUTA, LEG1, LEG9, BET1L, CHIL3, KV5AG) as potential biomarkers and therapeutic targets for POCD. These findings emphasize the complex relationship between cognitive dysfunction, molecular alterations, and metabolic disruptions in POCD, suggesting a multifactorial pathogenesis that warrants further investigation to develop targeted interventions.