Energy stress depletes ATP and induces cell death. Here we identify an unexpected inhibitory role of energy stress on ferroptosis, a form of regulated cell death induced by iron-dependent lipid peroxidation. We found that ferroptotic cell death and lipid peroxidation can be inhibited by treatments that induce or mimic energy stress. Inactivation of AMP-activated protein kinase (AMPK), a sensor of cellular energy status, largely abolishes the protective effects of energy stress on ferroptosis in vitro and on ferroptosis-associated renal ischaemia-reperfusion injury in vivo. Cancer cells with high basal AMPK activation are resistant to ferroptosis and AMPK inactivation sensitizes these cells to ferroptosis. Functional and lipidomic analyses further link AMPK regulation of ferroptosis to AMPK-mediated phosphorylation of acetyl-CoA carboxylase and polyunsaturated fatty acid biosynthesis. Our study demonstrates that energy stress inhibits ferroptosis partly through AMPK and reveals an unexpected coupling between ferroptosis and AMPK-mediated energy-stress signalling.

中文翻译：

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能量压力介导的AMPK激活抑制肥大症。

能量应激会耗尽ATP并诱导细胞死亡。在这里，我们确定了能量应激对肥大症的意外抑制作用，肥大症是铁依赖性脂质过氧化作用诱导的调控细胞死亡的一种形式。我们发现诱导或模拟能量应激的治疗可以抑制肥大细胞的死亡和脂质过氧化。AMP活化蛋白激酶（AMPK）（一种细胞能量状态的传感器）的失活在很大程度上消除了能量应激对体外受精和与受精相关的肾脏缺血再灌注损伤的保护作用。具有高基础AMPK活化作用的癌细胞对肥大病具有抵抗力，而AMPK失活会使这些细胞对肥大症敏感。功能和脂质组学分析进一步将肥大症的AMPK调节与乙酰辅酶A羧化酶的AMPK介导的磷酸化和多不饱和脂肪酸的生物合成联系起来。我们的研究表明，能量应激部分通过AMPK抑制了肥大症，并揭示了肥大症与AMPK介导的能量应激信号之间的意外耦合。