Noguchi Noriko, Saito Yoshiro, Niki Etsuo
The Systems Life Sciences Laboratory, Department of Medical Life Systems, Faculty of Life and Medical Sciences, Doshisha University, Kyotanabe, Japan.
Laboratory of Molecular Biology and Metabolism, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
Free Radic Biol Med. 2025 Sep;237:228-238. doi: 10.1016/j.freeradbiomed.2025.05.393. Epub 2025 May 13.
The discovery and conceptualization of ferroptosis as regulated, iron-catalyzed cell death driven by excessive lipid peroxidation triggered re-evaluation of lipid hydroperoxides in connection with health and disease. Free and ester forms of polyunsaturated fatty acids (PUFAs) are oxidized in vivo by multiple oxidizing species to produce lipid hydroperoxides as primary products, some purposely while others unintentionally. The detailed analysis of isomer distribution of lipid hydroperoxides enables us to identify the responsible oxidants. Linoleates, the most abundant PUFA in humans, are oxidized to give multiple isomers of hydroperoxyoctadecadienoates (H(p)ODEs) as primary major products, racemic trans, trans-9- and 13-H(p)ODEs, 13(S)-cis, trans-H(p)ODE, and 10- and 12-H(p)ODEs being specific biomarker for the oxidation by free radicals, lipoxygenase (LOX), and singlet oxygen, respectively. Cholesterol is another important lipid and its hydroperoxides are produced solely by non-enzymatic oxidation, the major products being cholesterol 7-hydroperoxide and 5-hydroperoxide by free radicals and singlet oxygen, respectively. The available data obtained from human samples show that lipid hydroperoxides are produced in vivo primarily by free radical mediated lipid peroxidation and that the contribution of LOXs and singlet oxygen is small. Multiple antioxidants having different functions play their respective roles in the physiological defense network against detrimental lipid peroxidation and ferroptosis. The fact that lipid hydroperoxides are produced in vivo mainly by free radical mediated lipid peroxidation suggests that radical scavenging antioxidants act as essential ferroptosis inhibitors, which was substantiated by many studies. Considering the reactivity and physiological concentrations, it may be said that vitamins E and C play the primary roles as biological radical scavenging antioxidants against ferroptosis by synergistic interactions. Novel synthetic antioxidants with higher reactivity than natural antioxidants have been reported and their biological effects should be assessed. The factors that determine antioxidant effects in vivo are critically reviewed.
铁死亡作为一种由过量脂质过氧化驱动的、受调控的铁催化细胞死亡方式的发现和概念化，引发了对脂质氢过氧化物与健康和疾病关系的重新评估。体内多不饱和脂肪酸（PUFAs）的游离形式和酯形式会被多种氧化物种氧化，产生脂质氢过氧化物作为主要产物，有些是有意产生的，有些则是无意产生的。对脂质氢过氧化物异构体分布的详细分析使我们能够识别出相应的氧化剂。亚油酸是人类中最丰富的多不饱和脂肪酸，被氧化后产生多种氢过氧化十八碳二烯酸（H(p)ODEs）异构体作为主要主要产物，外消旋反式、反式 - 9 - 和13 - H(p)ODEs、13(S)-顺式、反式 - H(p)ODE以及10 - 和12 - H(p)ODEs分别是自由基、脂氧合酶（LOX）和单线态氧氧化的特异性生物标志物。胆固醇是另一种重要的脂质，其氢过氧化物仅通过非酶氧化产生，主要产物分别是自由基和单线态氧产生的胆固醇7 - 氢过氧化物和5 - 氢过氧化物。从人体样本获得的现有数据表明，脂质氢过氧化物在体内主要由自由基介导的脂质过氧化产生，而脂氧合酶和单线态氧的贡献较小。多种具有不同功能的抗氧化剂在抵御有害脂质过氧化和铁死亡的生理防御网络中发挥各自的作用。脂质氢过氧化物在体内主要由自由基介导的脂质过氧化产生这一事实表明，自由基清除抗氧化剂作为重要的铁死亡抑制剂，这一点已被许多研究所证实。考虑到反应性和生理浓度，可以说维生素E和C通过协同相互作用在对抗铁死亡的生物自由基清除抗氧化剂中起主要作用。已经报道了具有比天然抗氧化剂更高反应性的新型合成抗氧化剂，其生物学效应应进行评估。对体内决定抗氧化作用的因素进行了批判性综述。
