TET3 accelerates facial nerve regeneration by promoting Schwann cell functions through DNA demethylation of ATF3

Facial nerve injury (FNI) causes facial paralysis and severely impairs patients’ quality of life. Schwann cells (SCs) are crucial for peripheral nerve regeneration, but the epigenetic mechanisms regulating SC function after FNI remain unclear. This study investigated the role of Tet methylcytosine dioxygenase 3 (TET3) in facial nerve repair. A rat facial nerve crush model was used to assess TET3 expression after injury. Gain- and loss-of-function experiments were performed in SCs to evaluate proliferation, migration, and paracrine activity. In vivo TET3 overexpression was used to examine facial nerve functional recovery and myelin regeneration. RNA sequencing, chromatin immunoprecipitation, targeted bisulfite sequencing, and luciferase assays were conducted to explore the mechanism. TET3 expression was significantly upregulated after FNI. TET3 overexpression promoted SC proliferation, migration, and neurotrophic factor secretion, whereas TET3 knockdown had opposite effects. In vivo , TET3 overexpression promoted functional recovery and enhanced myelin regeneration. Mechanistically, TET3 directly bound to the Activating Transcription Factor 3 (ATF3) promoter, reduced its methylation, and increased its transcriptional activity. ATF3 overexpression rescued the inhibitory effects of TET3 depletion. TET3 promotes facial nerve regeneration by enhancing SC repair-related functions through ATF3 promoter demethylation and highlights the TET3-ATF3 axis as a potential therapeutic target for FNI.