<![CDATA[Objectives: To assess whether DNA methylation (DNAm) analysis can serve as a predictive biomarker for postoperative delirium (POD) in patients undergoing head surgery, and to synthesize current evidence linking perioperative epigenetic alterations with POD incidence.Study design: Systematic review of prospective observational studies conducted in accordance with PRISMA guidelines. Eligible studies included cohort designs evaluating DNAm profiles in relation to POD. Risk of bias was assessed using the ROBINS-E tool. Due to methodological heterogeneity and limited sample size, meta-analysis was not performed.Data sources: A comprehensive search of PubMed, Google Scholar, and ScienceDirect was conducted for studies published between January 2020 and December 2025. Reference lists of included articles were also screened to identify additional relevant studies.Data synthesis: Four prospective cohort studies met the inclusion criteria. Across studies, POD was associated with differential DNAm in immune- and inflammation-related pathways, including cytokine signaling and immune system regulation. Epigenetic alterations were identified in both central nervous system tissue and peripheral samples. Dysregulation of glial cell–related pathways and surgery-induced methylation changes in proinflammatory genes were consistently reported. Although no individual CpG site achieved genome-wide significance, pathway-level analyses and composite methylation indices demonstrated moderate discriminatory potential for POD.Conclusions: DNAm alterations are associated with POD following head surgery, particularly through immune and neuroinflammatory mechanisms. Current evidence remains exploratory and limited by small sample sizes and heterogeneity. Larger, well-designed longitudinal studies are required to validate the clinical utility of epigenetic biomarkers for POD prediction.Registration: This review was not prospectively registered.]]>
