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Abstract：
Ferroptosis, a new type of programmed cell death discovered in recent years, plays an important role in many neurodegenerative diseases. N2L is a novel lipoic acid-niacin dimer regulating lipid metabolism with multifunction, including antioxidant effect. It also exerts neuroprotective effects against glutamate- or β-amyloid (Aβ) -induced cell death. Because reactive oxygen species (ROS) play an essential role in ferroptosis, we hypothesize that N2L might protect cells from ferroptosis. Here, we investigated the protective effect of N2L and the underlying mechanism(s) under RAS-selective lethality 3 (RSL3) treatment in HT22 cells. RSL3 decreased the cell viability and induced excessive accumulation of ROS in HT22 cells. N2L pretreatment effectively protected HT22 cells against lipid peroxidation. What\'s more, N2L recovered glutathione peroxidase 4 (GPX4) expression and blocked the increase of Cyclooxygenase-2 (cox-2) and acyl-CoA synthetase long-chain family member 4 (ACSL4) protein expressions. Moreover, N2L also significantly prevented Ferritin Heavy Chain 1 (FTH1) from downregulation and maintained iron homeostasis. Finally, N2L pretreatment could decrease c-Jun N-terminal kinase (JNK) / extracellular regulated protein kinases (ERK) activation induced by RSL3. Taken together, our results showed that N2L could protect HT22 cells from RSL3-induced ferroptosis through decreasing lipid peroxidation and JNK/ERK activation. And N2L could be a ferroptosis inhibitor for the therapy of ferroptosis-related diseases, such as Alzheimer\'s disease.
摘要：
Ferroptosis,近年来发现的一种新型的程序性细胞死亡，在许多神经退行性疾病中起着重要作用。N2L是一种新型的硫辛酸-烟酸二聚体,具有调节脂质代谢的多功能,包括抗氧化作用。它还对谷氨酸或β-淀粉样蛋白（Aβ）诱导的细胞死亡发挥神经保护作用。因为活性氧（ROS）在铁死亡中起着至关重要的作用，我们假设N2L可能保护细胞免受铁凋亡。这里,我们研究了在RAS选择性致死性3(RSL3)处理下N2L在HT22细胞中的保护作用和潜在机制。RSL3降低了HT22细胞的活力并诱导了ROS的过度积累。N2L预处理有效保护HT22细胞免受脂质过氧化。更重要的是，N2L恢复了谷胱甘肽过氧化物酶4（GPX4）的表达，并阻断了环氧合酶2（cox-2）和酰基辅酶A合成酶长链家族成员4（ACSL4）蛋白表达的增加。此外，N2L还显著阻止铁蛋白重链1(FTH1)下调并维持铁稳态。最后,N2L预处理可以降低RSL3诱导的c-Jun氨基末端激酶（JNK）/细胞外调节蛋白激酶（ERK）的激活。一起来看,我们的结果表明，N2L可以通过降低脂质过氧化和JNK/ERK激活来保护HT22细胞免受RSL3诱导的铁凋亡。N2L可能是一种铁凋亡抑制剂，用于治疗铁凋亡相关疾病，如老年痴呆症。
