<scp>A11</scp> Peptide Enhances Radiosensitivity by Degrading <scp>EphA2</scp> in Nasopharyngeal Carcinoma

Nasopharyngeal carcinoma (NPC) is a malignant tumor characterized by significant radioresistance and poor clinical outcomes. EphA2, a protein frequently overexpressed in various malignancies, has been implicated in promoting tumor growth and metastasis. This study explored the role and mechanism of EphA2 in driving radioresistance in NPC and evaluated the therapeutic potential of the A11 peptide in overcoming this resistance. Clinical analysis of 104 NPC tissues (26 radioresistant and 78 radiosensitive) revealed that high EphA2 expression was significantly associated with radioresistance and independently predicted reduced overall survival. Functional studies using EphA2-knockdown NPC cell lines (5-8F and CNE2) demonstrated that silencing EphA2 enhanced radiosensitivity, as evidenced by in vitro assays including clonogenic formation, apoptosis analysis, and γ-H2AX detection, as well as in vivo xenograft experiments. Mechanistically, EphA2 drives radioresistance through a radiation-induced RSK-EphA2-AKT signaling cascade. Specifically, radiation triggered RSK-mediated phosphorylation of EphA2 at Ser897, which subsequently facilitated AKT phosphorylation at Ser473. The A11 peptide broke this signaling cascade by degrading EphA2 and blocking its S897 phosphorylation, thereby markedly enhancing radiosensitivity. These findings indicate that EphA2 overexpression and its S897 phosphorylation play a critical role in NPC radioresistance. The A11 peptide emerges as a promising therapeutic agent by degrading EphA2 and blocking its phosphorylation, offering a potential strategy to enhance radiotherapy efficacy and improve outcomes in NPC patients.