识别用于预测放疗疗效的生物标志物对于优化个性化治疗至关重要。我们之前报道过，miR-4274种子区的rs1553867776可以预测接受术后放化疗的直肠癌患者的生存率。因此，为了探讨遗传变异的分子机制及其对结直肠癌（CRC）放射敏感性的影响，本研究通过生物信息学分析与功能实验相结合，证实过氧化物酶体生物合成因子5（PEX5）作为miR的直接靶点。 -4274。 miR-4274 rs1553867776 变体影响 miR-4274 和 PEX5 mRNA 的结合，从而调节 PEX5 蛋白的表达。通过免疫共沉淀和免疫荧光验证了 PEX5 和 Ku70 之间的相互作用。建立异种移植肿瘤模型以验证 miR-4274 和 PEX5 对 CRC 进展和体内放射敏感性的影响。 PEX5 的过表达通过阻止 Ku70 进入细胞核并减少细胞核中 Ku70/Ku80 复合物对电离辐射 (IR) 诱导的 DNA 损伤的修复来增强放射敏感性。此外，PEX5 表达的增强与 IR 诱导的铁死亡增加有关。因此，针对这一机制可能会有效提高 CRC 的放射敏感性。这些发现为癌症放射抵抗机制提供了新的见解，并对临床放射治疗具有重要意义。© 2024。高等教育出版社。

Identifying biomarkers for predicting radiotherapy efficacy is crucial for optimizing personalized treatments. We previously reported that rs1553867776 in the miR-4274 seed region can predict survival in patients with rectal cancer receiving postoperative chemoradiation therapy. Hence, to investigate the molecular mechanism of the genetic variation and its impact on the radiosensitivity of colorectal cancer (CRC), in this study, bioinformatics analysis is combined with functional experiments to confirm peroxisomal biogenesis factor 5 (PEX5) as a direct target of miR-4274. The miR-4274 rs1553867776 variant influences the binding of miR-4274 and PEX5 mRNA, which subsequently regulates PEX5 protein expression. The interaction between PEX5 and Ku70 was verified by co-immunoprecipitation and immunofluorescence. A xenograft tumor model was established to validate the effects of miR-4274 and PEX5 on CRC progression and radiosensitivity in vivo. The overexpression of PEX5 enhances radiosensitivity by preventing Ku70 from entering the nucleus and reducing the repair of ionizing radiation (IR)-induced DNA damage by the Ku70/Ku80 complex in the nucleus. In addition, the enhanced expression of PEX5 is associated with increased IR-induced ferroptosis. Thus, targeting this mechanism might effectively increase the radiosensitivity of CRC. These findings offer novel insights into the mechanism of cancer radioresistance and have important implications for clinical radiotherapy.© 2024. Higher Education Press.