Iron overload-induced oxidative stress is implicated in various neurodegenerative disorders. Given the numerous adverse effects associated with current iron chelators, natural antioxidants are being explored as alternative therapeutic options. Dithiolethiones found in cruciferous vegetables have emerged as promising candidates against a wide range of toxicants owing to their lipophilic and cytoprotective properties. Here, we test the dithiolethiones 3H-1,2-dithiole-3-thione (D3T) and 5-amino-3-thioxo-3H-(1,2) dithiole-4-carboxylic acid ethyl ester (ACDT) against ferric ammonium citrate (FAC)-induced toxicity in U-87 MG astrocytoma cells. Exposure to 15 mM FAC for 24 h resulted in 54% cell death. A 24-h pretreatment with 50 μM D3T and ACDT prevented this cytotoxicity. Both dithiolethiones exhibited antioxidant effects by activating the nuclear factor erythroid 2-related factor-2 (Nrf2) transcription factor and upregulating levels of intracellular glutathione (GSH). This resulted in the successful inhibition of FAC-induced reactive oxygen species, lipid peroxidation, and cell death. Additionally, D3T and ACDT upregulated expression of the Nrf2-mediated iron storage protein ferritin which consequently reduced the total labile iron pool. A 24-h pretreatment with D3T and ACDT also prevented cell death induced by the ferroptosis inducer erastin by upregulating the transmembrane cystine/glutamate antiporter (xCT) expression. The resulting increase in intracellular GSH and alleviation of lipid peroxidation was comparable to that caused by ferrostatin-1, a specific ferroptosis inhibitor. Collectively, our findings demonstrate that dithiolethiones may show promise as potential therapeutic options for the treatment of iron overload disorders.

铁过载诱导的氧化应激与各种神经退行性疾病有关。鉴于与当前铁螯合剂相关的众多副作用，正在探索天然抗氧化剂作为替代治疗选择。在十字花科蔬菜中发现的二硫硫酮由于其亲脂性和细胞保护特性，已成为对抗多种毒物的有希望的候选物。在这里，我们测试了二硫硫酮 3H-1,2-dithiole-3-thione (D3T) 和 5-amino-3-thioxo-3H-(1,2) dithiole-4-carboxylic acid ethyl ester (ACDT) 对抗铁铵柠檬酸盐 (FAC) 诱导的 U-87 MG 星形细胞瘤细胞毒性。暴露于 15 mM FAC 24 小时导致 54% 的细胞死亡。使用 50 μM D3T 和 ACDT 进行 24 小时预处理可防止这种细胞毒性。两种二硫硫酮均通过激活核因子红细胞 2 相关因子 2 (Nrf2) 转录因子和上调细胞内谷胱甘肽 (GSH) 水平来发挥抗氧化作用。这导致成功抑制 FAC 诱导的活性氧、脂质过氧化和细胞死亡。此外，D3T 和 ACDT 上调了 Nrf2 介导的铁储存蛋白铁蛋白的表达，从而减少了总不稳定铁库。用 D3T 和 ACDT 进行 24 小时预处理还可以通过上调跨膜胱氨酸/谷氨酸逆向转运蛋白 (xCT) 表达来防止铁死亡诱导剂 erastin 诱导的细胞死亡。由此产生的细胞内 GSH 增加和脂质过氧化的减轻与 ferrostatin-1（一种特定的铁死亡抑制剂）引起的相当。总的来说，