Ferroptosis is a recently characterized form of cell death that has gained attention for its roles in both pathological and physiological contexts. The existence of multiple anti-ferroptotic pathways in both neoplastic and healthy cells, along with the critical regulation of iron metabolism involved in lipid peroxides (lipid-ROS) production—the primary mediators of this cell death process—underscores the necessity of precisely controlling or preventing accidental/unwanted ferroptosis. Conversely, dysregulated iron metabolism and alterations in the expression or activity of key anti-ferroptotic components are linked to the development and progression of various human diseases, including multiple sclerosis (MS). In MS, the improper activation of ferroptosis has been associated with the progressive loss of myelinating oligodendrocytes (myOLs). Our study demonstrates that the physiological and maturation-dependent increase in iron accumulation within oligodendrocytes acts as a pro-ferroptotic signal, countered by the concurrent expression of AKR1C1. Importantly, MS-related neuroinflammation contributes to the down-regulation of AKR1C1 through miRNA-mediated mechanisms, rendering mature oligodendrocytes more vulnerable to ferroptosis. Together, these findings highlight the role of ferroptosis in MS-associated oligodendrocyte loss and position AKR1C1 as a potential therapeutic target for preserving oligodendrocyte integrity and supporting neuronal function in MS patients.

中文翻译：

---

AKR 赋予少突胶质细胞对分化刺激的铁死亡的抵抗力


铁死亡是一种最近表征的细胞死亡形式，因其在病理和生理环境中的作用而受到关注。肿瘤细胞和健康细胞中存在多种抗铁死亡途径，以及脂质过氧化物 （脂质-ROS） 产生中涉及的铁代谢的关键调节——该细胞死亡过程的主要介质——强调了精确控制或预防意外/不需要的铁死亡的必要性。相反，铁代谢失调和关键抗铁死亡成分表达或活性的改变与各种人类疾病的发生和发展有关，包括多发性硬化症 （MS）。在 MS 中，铁死亡的不当激活与髓鞘少突胶质细胞 （myOLs） 的进行性丢失有关。我们的研究表明，少突胶质细胞内铁积累的生理性和成熟依赖性增加充当促铁死亡信号，与 AKR1C1 的并发表达相抵消。重要的是，MS 相关神经炎症通过 miRNA 介导的机制有助于下调 AKR1C1，使成熟的少突胶质细胞更容易受到铁死亡的影响。总之，这些发现强调了铁死亡在 MS 相关少突胶质细胞丢失中的作用，并将 AKR1C1 定位为保持少突胶质细胞完整性和支持 MS 患者神经元功能的潜在治疗靶点。