Epigenetic Mechanisms in Perioperative Medicine: From Neuroinflammation and NETosis to Organ Dysfunction and Precision Therapeutics.

Perioperative stress induces profound molecular and cellular responses that contribute to postoperative complications, including perioperative neurocognitive disorders (PND), chronic postsurgical pain, organ dysfunction, immunothrombosis, fibrosis, and cancer progression. Increasing evidence demonstrates that epigenetic mechanisms act as central regulators linking surgical trauma, inflammation, metabolic stress, ischemia-reperfusion injury, and immune activation to long-term alterations in gene expression and tissue remodeling. DNA methylation, histone modifications, chromatin remodeling, non-coding RNAs, and RNA epitranscriptomic mechanisms such as N6-methyladenosine (m6A) collectively orchestrate perioperative responses across multiple organ systems. Recent translational studies have identified histone deacetylases (HDACs), histone methyltransferases, NETosis-associated chromatin signaling, HMGB1/NF-κB activation, and epigenetic regulation of neuroimmune pathways as major contributors to postoperative cognitive dysfunction, chronic pain, cardiac dysfunction, pulmonary injury, and fibrosis. In parallel, advances in liquid biopsy, circulating tumor DNA (ctDNA), and single-cell epigenomics have opened new opportunities for biomarker-guided perioperative precision medicine. This review summarizes current evidence regarding epigenetic regulation in perioperative medicine with special emphasis on neuroepigenetics, NETosis, fibrosis, cardiac epigenetics, immune remodeling, and perioperative oncological outcomes. Furthermore, we discuss emerging therapeutic strategies targeting HDACs, DNA methylation, m6A pathways, and chromatin-associated inflammatory signaling as potential future interventions for perioperative complications.