Ferroptosis is a form of programmed cell death that is pathogenic to several acute and chronic diseases and executed via oxygenation of polyunsaturated phosphatidylethanolamines (PE) by 15-lipoxygenases (15-LO) that normally use free polyunsaturated fatty acids as substrates. Mechanisms of the altered 15-LO substrate specificity are enigmatic. We sought a common ferroptosis regulator for 15LO. We discovered that PEBP1, a scaffold protein inhibitor of protein kinase cascades, complexes with two 15LO isoforms, 15LO1 and 15LO2, and changes their substrate competence to generate hydroperoxy-PE. Inadequate reduction of hydroperoxy-PE due to insufficiency or dysfunction of a selenoperoxidase, GPX4, leads to ferroptosis. We demonstrated the importance of PEBP1-dependent regulatory mechanisms of ferroptotic death in airway epithelial cells in asthma, kidney epithelial cells in renal failure, and cortical and hippocampal neurons in brain trauma. As master regulators of ferroptotic cell death with profound implications for human disease, PEBP1/15LO complexes represent a new target for drug discovery.

中文翻译：

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PEBP1通过使脂质死亡信号产生脂氧合酶来预防肥大症。

Ferroptosis是程序性细胞死亡的一种形式，对几种急性和慢性疾病均具有致病性，并且通过15-脂氧合酶（15-LO）氧化多不饱和磷脂酰乙醇胺（PE）来执行，通常以游离多不饱和脂肪酸为底物。改变15-LO底物特异性的机理是神秘的。我们寻求15LO的通用促铁调节剂。我们发现PEBP1，一种蛋白激酶级联的支架蛋白抑制剂，与两种15LO亚型15LO1和15LO2形成复合物，并改变了它们的底物能力以生成氢过氧-PE。硒过氧化物酶GPX4不足或功能异常导致氢过氧化物-PE的还原不足会导致肥大症。我们证明了哮喘患者气道上皮细胞中PEBP1依赖的铁通性死亡的调控机制的重要性，肾上皮细胞在肾功能衰竭，而皮层和海马神经元在脑外伤。作为对人类疾病具有深远影响的肥大细胞死亡的主要调节者，PEBP1 / 15LO复合物代表了药物发现的新目标。