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<p>Primary solid tumors often exhibit accelerated glucose metabolism yet generate limited ATP due to reduced flux through the tricarboxylic acid (TCA) cycle. However, how these distinct metabolic alterations contribute to therapeutic resistance—and whether they represent targetable metabolic vulnerabilities—remains unclear. Here, we identify adenylate kinase 4 (AK4), a mitochondrial regulator of adenylate homeostasis, as a key mediator of radioresistance in glioblastoma (GBM) cells. We found that AK4 is upregulated in radioresistant GBM cells, where it suppresses mitochondrial oxidative phosphorylation to maintain redox homeostasis and promote cell survival following ionizing radiation (IR). Moreover, AK4 maintains elevated intracellular AMP, leading to the activation of AMP-activated protein kinase (AMPK), a master regulator of energy metabolism. AMPK activation subsequently inhibits acetyl-CoA carboxylase (ACC), suppressing cellular lipid synthesis. Through these mechanisms, AK4 limits IR-induced ferroptosis and contributes to radioresistance. Notably, we demonstrate that entinostat, a class I histone deacetylase (HDAC) inhibitor, downregulates AK4 expression and enhances the sensitivity of GBM cells to IR both in vitro and in vivo. In conclusion, our study reveals that AK4 promotes radioresistance in GBM by coordinating mitochondrial redox regulation and AMPK-mediated lipid metabolism, highlighting AK4 as a promising therapeutic target for overcoming GBM radioresistance.</p> Graphical abstract <p></p>

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Adenylate kinase 4 promotes radioresistance by suppressing radiation-induced ferroptosis through metabolic regulation in glioblastoma

  • 期刊论文

  • 发表日期：

    2026年3月5日

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  • Byeongsoo Kim,
  • Hyunkoo Kang,
  • Junhyeong Park,
  • Sujin Park,
  • HyeSook Youn,
  • BuHyun Youn

摘要

Primary solid tumors often exhibit accelerated glucose metabolism yet generate limited ATP due to reduced flux through the tricarboxylic acid (TCA) cycle. However, how these distinct metabolic alterations contribute to therapeutic resistance—and whether they represent targetable metabolic vulnerabilities—remains unclear. Here, we identify adenylate kinase 4 (AK4), a mitochondrial regulator of adenylate homeostasis, as a key mediator of radioresistance in glioblastoma (GBM) cells. We found that AK4 is upregulated in radioresistant GBM cells, where it suppresses mitochondrial oxidative phosphorylation to maintain redox homeostasis and promote cell survival following ionizing radiation (IR). Moreover, AK4 maintains elevated intracellular AMP, leading to the activation of AMP-activated protein kinase (AMPK), a master regulator of energy metabolism. AMPK activation subsequently inhibits acetyl-CoA carboxylase (ACC), suppressing cellular lipid synthesis. Through these mechanisms, AK4 limits IR-induced ferroptosis and contributes to radioresistance. Notably, we demonstrate that entinostat, a class I histone deacetylase (HDAC) inhibitor, downregulates AK4 expression and enhances the sensitivity of GBM cells to IR both in vitro and in vivo. In conclusion, our study reveals that AK4 promotes radioresistance in GBM by coordinating mitochondrial redox regulation and AMPK-mediated lipid metabolism, highlighting AK4 as a promising therapeutic target for overcoming GBM radioresistance.

Graphical abstract