Jeongha Kim¹, Hyunkoo Kang¹, Beomseok Son², Min-Jung Kim^3,11, JiHoon Kang⁴, Kang Hyun Park^5,6, Jaewan Jeon⁷, Sunmi Jo⁷, Hae Yu Kim8, HyeSook Youn⁹ and BuHyun Youn^1,10

¹Department of Integrated Biological Science, Pusan National University, Busan 46241, Republic of Korea. 
²siRNAgen Therapeutics, Daejeon 34302, Republic of Korea. 
³Nuclear Science Research Institute, Pusan National University, Busan 46241, Republic of Korea. 
⁴Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA. 
⁵Department of Chemistry, Pusan National University, Busan 46241, Republic of Korea. 
⁶SoulDot Co., Ltd, Pusan National University, Busan 46241, Republic of Korea. 
⁷Department of Radiation Oncology, Haeundae Paik Hospital, Inje University School of Medicine, Busan 48108, Republic of Korea. 
⁸Department of Neurosurgery, Haeundae Paik Hospital, Inje University College of Medicine, Busan 48108, Republic of Korea. 
⁹Department of Integrative Bioscience and Biotechnology, Sejong University, Seoul, Republic of Korea. 
¹⁰Department of Biological Sciences, Pusan National University, Busan, Republic of Korea. 
¹¹Present address: Department of Naval Architecture and Ocean Engineering, Pusan National University, Busan 46241, Republic of Korea. 

Corresponding authors : Correspondence to HyeSook Youn or BuHyun Youn.

Overcoming therapeutic resistance in glioblastoma (GBM) is an essential strategy for improving cancer therapy. However, cancer cells possess various evasion mechanisms, such as metabolic reprogramming, which promote cell survival and limit therapy. The diverse metabolic fuel sources that are produced by autophagy provide tumors with metabolic plasticity and are known to induce drug or radioresistance in GBM. This study determined that autophagy, a common representative cell homeostasis mechanism, was upregulated upon treatment of GBM cells with ionizing radiation (IR). Nuclear receptor binding factor 2 (NRBF2)-a positive regulator of the autophagy initiation step-was found to be upregulated in a GBM orthotopic xenograft mouse model. Furthermore, ATP production and the oxygen consumption rate (OCR) increased upon activation of NRBF2-mediated autophagy. It was also discovered that changes in metabolic state were induced by alterations in metabolite levels caused by autophagy, thereby causing radioresistance. In addition, we found that lidoflazine-a vasodilator agent discovered through drug repositioning-significantly suppressed IR-induced migration, invasion, and proliferation by inhibiting NRBF2, resulting in a reduction in autophagic flux in both in vitro models and in vivo orthotopic xenograft mouse models. In summary, we propose that the upregulation of NRBF2 levels reprograms the metabolic state of GBM cells by activating autophagy, thus establishing NRBF2 as a potential therapeutic target for regulating radioresistance of GBM during radiotherapy.