Ryan Sean K, Ugalde Cathryn L, Rolland Anne-Sophie, Skidmore John, Devos David, Hammond Timothy R
Sanofi, Rare and Neurologic Diseases, Cambridge, MA, USA.
The ALBORADA Drug Discovery Institute, University of Cambridge, Island Research Building, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0AH, UK.
Trends Pharmacol Sci. 2023 Oct;44(10):674-688. doi: 10.1016/j.tips.2023.07.007. Epub 2023 Aug 30.
Iron accumulation has been associated with the etiology and progression of multiple neurodegenerative diseases (NDDs). The exact role of iron in these diseases is not fully understood, but an iron-dependent form of regulated cell death called ferroptosis could be key. Although there is substantial preclinical and clinical evidence that ferroptosis plays a role in NDD, there are still questions regarding how to target ferroptosis therapeutically, including which proteins to target, identification of clinically relevant biomarkers, and which patients might benefit most. Clinical trials of iron- and ferroptosis-targeted therapies are beginning to provide some answers, but there is growing interest in developing new ferroptosis inhibitors. We describe newly identified ferroptosis targets, opportunities, and challenges in NDD, as well as key considerations for progressing new therapeutics to the clinic.
铁蓄积与多种神经退行性疾病（NDDs）的病因和进展相关。铁在这些疾病中的确切作用尚未完全明确，但一种名为铁死亡的铁依赖性调节性细胞死亡形式可能是关键所在。尽管有大量临床前和临床证据表明铁死亡在神经退行性疾病中起作用，但在如何以铁死亡为靶点进行治疗方面仍存在问题，包括靶向哪些蛋白质、识别临床相关生物标志物以及哪些患者可能受益最大。针对铁和铁死亡的靶向治疗的临床试验开始提供一些答案，但人们对开发新的铁死亡抑制剂的兴趣与日俱增。我们描述了在神经退行性疾病中新发现的铁死亡靶点、机遇和挑战，以及将新疗法推进到临床的关键考虑因素。
