Neurofascin stabilization by contactin-associated protein-like 2 and CTCF alleviates mitochondrial dysfunction in Schwann cells during facial nerve injury.

During the growth or treatment of oral and maxillofacial tumors, the facial nerve is susceptible to injury, resulting facial dysfunction. Iodine-125 (I-125) seed brachytherapy is widely used in the treatment of various tumors due to its precise and sustained radiation characteristics, yet it may also cause nerve damage. However, the underlying mechanism of I-125 seed implantation-induced facial nerve injury (FNI) remains unclear. Here, a rabbit FNI model was established, and the neural injury mechanism was further investigated through I-125 seed implantation combined with transcriptome sequencing. Results found that neurofascin (NFASC) expression was reduced in injured rabbit facial nerves, and the implantation of I-125 particles further decreased NFASC expression. Overexpression of NFASC repressed oxidative stress and mito-chondrial dysfunction in I-125-treated Schwann cells (SCs), promoted cell proliferation, migration, and expression of myelin genes. Mechanistic studies revealed a protein-protein interaction between contactin-associated protein-like 2 (CNTNAP2) and NFASC, with CNTNAP2 positively regulating NFASC levels. CCCTC-binding factor (CTCF), as a transcription factor, positively regulated CNTNAP2 transcription. Compared to the groups overexpressing either CTCF or CNTNAP2 alone, simultaneous overexpression of CTCF and CNTNAP2 demonstrated an enhanced inhibitory effect on the oxidative stress in I-125-treated SCs, promoted cell proliferation, migration, and expression of myelin genes. CTCF overexpression improved demyelination of the facial nerve in rabbits with I-125 seed implantation and transverse injury by promoting CNTNAP2 and NFASC. In conclusion, CTCF/CNTNAP2/NFASC represents a critical pathway through which SCs mediate facial nerve damage caused by I-125 seed implantation. This finding provides potential therapeutic targets for the repair of FNI.