Abstract:
Ferroptosis is an iron-dependent regulated cell death that suppresses tumor growth. It is activated by extensive peroxidation of membrane phospholipids caused by oxidative stress. GPX4, an antioxidant enzyme, reduces these peroxidized membrane phospholipids thereby inhibiting ferroptosis. This enzyme has two distinct subcellular localization; the cytosol and mitochondria. Dihydroorotate dehydrogenase (DHODH) complements mitochondrial GPX4 in reducing peroxidized membrane phospholipids. It is the rate-limiting enzyme in de novo pyrimidine nucleotide biosynthesis. Its role in ferroptosis inhibition suggests that DHODH inhibitors could have two complementary mechanisms of action against tumors; inhibiting de novo pyrimidine nucleotide biosynthesis and enhancing ferroptosis. However, the link between mitochondrial function and ferroptosis, and the involvement of DHODH in the ETC suggests that its role in ferroptosis could be modulated by the Warburg effect. Therefore, we reviewed relevant literature to get an insight into the possible effect of this metabolic reprogramming on the role of DHODH in ferroptosis. Furthermore, an emerging link between DHODH and cellular GSH pool has also been highlighted. These insights could contribute to the rational design of ferroptosis-based anticancer drugs. Video Abstract.
摘要:
铁凋亡是一种铁依赖性调节的细胞死亡,抑制肿瘤生长。它被氧化应激引起的膜磷脂的广泛过氧化激活。GPX4,一种抗氧化酶,减少这些过氧化膜磷脂,从而抑制铁凋亡。该酶具有两种不同的亚细胞定位;胞质溶胶和线粒体。二氢乳清酸脱氢酶(DHODH)在减少过氧化膜磷脂中补充线粒体GPX4。它是嘧啶核苷酸从头生物合成中的限速酶。其在铁凋亡抑制中的作用表明DHODH抑制剂可能具有两种互补的抗肿瘤作用机制;抑制从头嘧啶核苷酸生物合成和增强铁凋亡。然而,线粒体功能和铁死亡之间的联系,DHODH在ETC中的参与表明其在铁凋亡中的作用可能受到Warburg效应的调节。因此,我们回顾了相关文献,以了解这种代谢重编程对DHODH在铁凋亡中的作用的可能影响。此外,还强调了DHODH和蜂窝GSH池之间的新兴联系。这些见解可能有助于合理设计基于铁凋亡的抗癌药物。视频摘要。