Epigenetic mechanisms in traumatic brain injury: a focus on astrocyte and therapeutic implications

Abstract Traumatic brain injury (TBI) triggers complex molecular and cellular responses that persist well beyond the initial injury. Neuroinflammation is a prominent feature of the post-injury response and a significant contributor to progressive neuronal dysfunction and increased risk of chronic neurodegeneration. Epigenetic mechanisms have emerged as important regulators of the injury response. Astrocytes are increasingly recognized as key mediators of this epigenetic regulation. Injury-induced epigenetic reprogramming in astrocytes may perpetuate maladaptive inflammatory and metabolic states, thereby increasing vulnerability to delayed neurodegeneration. Preclinical studies suggest that pharmacologic or genetic modulation of epigenetic regulators can improve outcomes after experimental TBI. However, clinical translation remains constrained by limited cell-type specificity and potential off-target effects. This review evaluates current evidence on epigenetic regulation after TBI, with an emphasis on astrocyte-centered mechanisms linking acute injury to chronic pathology. We further discuss key translational challenges and highlight emerging precision strategies aimed at cell-type-specific, temporally controlled epigenetic modulation to mitigate long-term neurological consequences.