PDF(Pubmed)
Abstract：
The activation of ferroptosis is being pursued in cancer research as a strategy to target apoptosis-resistant cells. By contrast, in various diseases that affect the cardiovascular system, kidneys, liver, and central and peripheral nervous systems, attention is directed toward interventions that prevent ferroptotic cell death. Mechanistic insights into both research areas stem largely from studies using cellular in vitro models. However, intervention strategies that show promise in cellular test systems often fail in clinical trials, which raises concerns regarding the predictive validity of the utilized in vitro models. In this study, the human LUHMES cell line, which serves as a model for human dopaminergic neurons, was used to characterize factors influencing the activation of ferroptosis. Erastin and RSL-3 induced cell death that was distinct from apoptosis. Parameters such as the differentiation state of LUHMES cells, cell density, and the number and timing of medium changes were identified as determinants of sensitivity to ferroptosis activation. In differentiated LUHMES cells, interventions at mechanistically divergent sites (iron chelation, coenzyme Q10, peroxidase mimics, or inhibition of 12/15-lipoxygenase) provide almost complete protection from ferroptosis. LUHMES cells allowed the experimental modulation of intracellular iron concentrations and demonstrated a correlation between intracellular iron levels, the rate of lipid peroxidation, as well as the sensitivity of the cells to ferroptotic cell death. These findings underscore the importance of understanding the various factors that influence ferroptosis activation and highlight the need for well-characterized in vitro models to enhance the reliability and predictive value of observations in ferroptosis research, particularly when translating findings into in vivo contexts.
摘要：
在癌症研究中，铁凋亡的激活被视为靶向抗凋亡细胞的策略。相比之下,在影响心血管系统的各种疾病中，肾脏，肝脏,中枢和周围神经系统，注意力集中在防止铁细胞死亡的干预措施上。对这两个研究领域的机制见解主要来自使用细胞体外模型的研究。然而,在细胞测试系统中显示出希望的干预策略通常在临床试验中失败，这引起了人们对所用体外模型预测有效性的担忧。在这项研究中,人类LUHMES细胞系，作为人类多巴胺能神经元的模型，用于表征影响铁凋亡激活的因素。Erastin和RSL-3诱导的细胞死亡与细胞凋亡不同。LUHMES细胞的分化状态等参数，细胞密度，培养基变化的数量和时间被确定为对铁凋亡激活敏感性的决定因素。在分化的LUHMES细胞中，在机械上不同的部位进行干预(铁螯合，辅酶Q10，过氧化物酶模拟物，或抑制12/15-脂氧合酶）提供几乎完全的铁中毒保护。LUHMES细胞允许细胞内铁浓度的实验调节，并证明了细胞内铁水平之间的相关性，脂质过氧化的速率，以及细胞对铁细胞死亡的敏感性。这些发现强调了理解影响铁凋亡激活的各种因素的重要性，并强调了需要充分表征的体外模型，以增强铁凋亡研究中观察结果的可靠性和预测价值。特别是当将发现转化为体内环境时。
