Inhibition of LNC EBLN3P Enhances Radiation-Induced Mitochondrial Damage in Lung Cancer Cells by Targeting the Keap1/Nrf2/HO-1 Axis

SIMPLE SUMMARY: The intrinsic radioresistance of cancer cells is a major barrier to effective radiotherapy for NSCLC. The long non-coding RNA, endogenous bornavirus-like nucleoprotein 3 (LNC EBLN3P), was initially discovered to exhibit upregulation in NSCLC and promote the progression of NSCLC. The aim of this study was to elucidate the correlation between elevated expression levels of LNC EBLN3P and radioresistance in NSCLC cells, as well as to investigate the underlying molecular mechanism. We confirmed that the inhibition of LNC EBLN3P can enhance the production of reactive oxygen species (ROS) and trigger mitochondrial impairment in NSCLC cells, thereby mitigating the radioresistance of NSCLC cells. Therefore, the inhibition of LNC EBLN3P presents a promising approach for the development of novel radiosensitizers. ABSTRACT: Lung cancer remains the leading cause of cancer-related deaths in both women and men, claiming millions of lives worldwide. Radiotherapy is an effective modality for treating early-stage lung cancer; however, it cannot completely eradicate certain tumor cells due to their radioresistance. Radioresistance is commonly observed in conventionally fractionated radiotherapy, which can lead to treatment failure, metastasis, cancer recurrence, and poor prognosis for cancer patients. Identifying the underlying molecular mechanisms of radioresistance in lung cancer can promote the development of effective radiosensitizers, thereby improving patients’ life expectancy and curability. In this study, we identified LNC EBLN3P as a regulator of lung cancer cell proliferation and radiosensitivity. The repression of LNC EBLN3P could increase ROS production and mitochondrial injury in NSCLC cells. In addition, knocking down LNC EBLN3P increased the binding of Nrf2 to Keap1, resulting in enhanced Nrf2 degradation, decreased translocation of Nrf2 to the nucleus, reduced expression of antioxidant protein HO-1, weakened cellular antioxidant capacity, and increased radiosensitivity of NSCLC cells. These findings suggest that targeting LNC EBLN3P could be a promising strategy for developing novel radiosensitizers in the context of conventional radiotherapy for NSCLC.