Costa Inês, Barbosa Daniel José, Benfeito Sofia, Silva Vera, Chavarria Daniel, Borges Fernanda, Remião Fernando, Silva Renata
Associate Laboratory i4HB - Institute for Health and Bioeconomy, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal; UCIBIO - Applied Molecular Biosciences Unit, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal.
TOXRUN - Toxicology Research Unit, Department of Sciences, University Institute of Health Sciences, CESPU, CRL, 4585-116 Gandra, Portugal; Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, 4200-135 Porto, Portugal.
Pharmacol Ther. 2023 Apr;244:108373. doi: 10.1016/j.pharmthera.2023.108373. Epub 2023 Mar 8.
Ferroptosis is a type of regulated cell death characterized by intracellular accumulation of iron and reactive oxygen species, inhibition of system Xc-, glutathione depletion, nicotinamide adenine dinucleotide phosphate oxidation and lipid peroxidation. Since its discovery and characterization in 2012, many efforts have been made to reveal the underlying mechanisms, modulating compounds, and its involvement in disease pathways. Ferroptosis inducers include erastin, sorafenib, sulfasalazine and glutamate, which, by inhibiting system Xc-, prevent the import of cysteine into the cells. RSL3, statins, Ml162 and Ml210 induce ferroptosis by inhibiting glutathione peroxidase 4 (GPX4), which is responsible for preventing the formation of lipid peroxides, and FIN56 and withaferin trigger GPX4 degradation. On the other side, ferroptosis inhibitors include ferrostatin-1, liproxstatin-1, α-tocopherol, zileuton, FSP1, CoQ10 and BH4, which interrupt the lipid peroxidation cascade. Additionally, deferoxamine, deferiprone and N-acetylcysteine, by targeting other cellular pathways, have also been classified as ferroptosis inhibitors. Increased evidence has established the involvement of ferroptosis in distinct brain diseases, including Alzheimer's, Parkinson's and Huntington's diseases, amyotrophic lateral sclerosis, multiple sclerosis, and Friedreich's ataxia. Thus, a deep understanding of how ferroptosis contributes to these diseases, and how it can be modulated, can open a new window of opportunities for novel therapeutic strategies and targets. Other studies have shown a sensitivity of cancer cells with mutated RAS to ferroptosis induction and that chemotherapeutic agents and ferroptosis inducers synergize in tumor treatment. Thus, it is tempting to consider that ferroptosis may arise as a target mechanistic pathway for the treatment of brain tumors. Therefore, this work provides an up-to-date review on the molecular and cellular mechanisms of ferroptosis and their involvement in brain diseases. In addition, information on the main ferroptosis inducers and inhibitors and their molecular targets is also provided.
铁死亡是一种程序性细胞死亡，其特征在于细胞内铁和活性氧的积累、系统Xc-的抑制、谷胱甘肽耗竭、烟酰胺腺嘌呤二核苷酸磷酸氧化和脂质过氧化。自2012年被发现和表征以来，人们已做出诸多努力来揭示其潜在机制、调控化合物及其在疾病途径中的作用。铁死亡诱导剂包括埃拉司亭、索拉非尼、柳氮磺胺吡啶和谷氨酸，它们通过抑制系统Xc-，阻止半胱氨酸进入细胞。RSL3、他汀类药物、Ml162和Ml210通过抑制谷胱甘肽过氧化物酶4（GPX4）诱导铁死亡，GPX4负责阻止脂质过氧化物的形成，而FIN56和牛膝甾酮触发GPX4降解。另一方面，铁死亡抑制剂包括铁抑素-1、脂氧素他汀-1、α-生育酚、齐留通、FSP1、辅酶Q10和四氢生物蝶呤，它们中断脂质过氧化级联反应。此外，去铁胺、去铁酮和N-乙酰半胱氨酸通过靶向其他细胞途径，也被归类为铁死亡抑制剂。越来越多的证据表明铁死亡参与了多种脑部疾病，包括阿尔茨海默病、帕金森病和亨廷顿病、肌萎缩侧索硬化症、多发性硬化症以及弗里德赖希共济失调。因此，深入了解铁死亡如何导致这些疾病以及如何对其进行调控，可为新型治疗策略和靶点打开新的机遇之窗。其他研究表明，具有RAS突变的癌细胞对铁死亡诱导敏感，并且化疗药物和铁死亡诱导剂在肿瘤治疗中具有协同作用。因此，人们不禁认为铁死亡可能成为治疗脑肿瘤的一种靶向机制途径。因此，这项工作对铁死亡的分子和细胞机制及其在脑部疾病中的作用进行了最新综述。此外，还提供了关于主要铁死亡诱导剂和抑制剂及其分子靶点的信息。
