Halogenated quinones are representative metabolites of persistent organic pollutants. Tetrachlorobenzoquinone (TCBQ) is a reactive metabolite of the widely used fungicide hexachlorobenzene (HCB) and wood preservative pentachlorophenol (PCP). Our previous studies have demonstrated that TCBQ induced neuron-like cell apoptosis in a reactive oxygen species (ROS)-dependent manner. Here, we found that TCBQ caused lipid peroxidation and cellular morphological changes including shrinked mitochondrial size, suggesting the involvement of a recently uncovered form of programmed cell death (PCD), ferroptosis. Indeed, we then identified that ferroptosis is a novel PCD driven by TCBQ, which was correlated with a decrease in glutathione peroxidase 4 (GPX4) level and iron accumulation by altering iron metabolism. Notably, nuclear factor erythroid-derived 2-like 2 (Nrf2) is a negative regulator in modulating the outcomes of ferroptosis as an adaptive cellular defense response. Nrf2 activation enhanced iron storage capacity and GPX4 activity by elevating ferritin heavy chain 1 (FTH1) expression and glutathione (GSH) level, respectively. On the contrary, Nfe2l2 (Nrf2) deficiency enhanced PC12 cells susceptibility to ferroptosis.

卤代醌是持久性有机污染物的代表性代谢产物。四氯苯醌（TCBQ）是广泛使用的杀菌剂六氯苯（HCB）和木材防腐剂五氯苯酚（PCP）的反应性代谢产物。我们以前的研究表明，TCBQ以活性氧（ROS）依赖性方式诱导神经元样细胞凋亡。在这里，我们发现TCBQ引起脂质过氧化和细胞形态变化，包括线粒体大小缩小，提示参与了最近发现的程序性细胞死亡（PCD）形式的肥大症。的确，我们然后确定了肥大症是由TCBQ驱动的新型PCD，其与谷胱甘肽过氧化物酶4（GPX4）水平的降低和通过改变铁代谢而引起的铁蓄积有关。值得注意的是 核因子类红细胞衍生的2样2（Nrf2）是负调节因子，可调节肥大症作为适应性细胞防御反应的结果。Nrf2激活分别通过提高铁蛋白重链1（FTH1）表达和谷胱甘肽（GSH）水平来增强铁的储存能力和GPX4活性。反之，Nfe2l2（Nrf2）缺乏症增强了PC12细胞对肥大症的敏感性。