三重谷胱甘肽耗竭增强二硫化物和脂质过氧化物蓄积以强化二硫死亡和铁死亡
Triple glutathione depletion-augmented disulfide and lipid peroxide accumulation to potentiate disulfidptosis and ferroptosis.
文献信息
| PMID | 42909876 |
|---|---|
| 原文 | 在 PubMed 查看原文 ↗ |
| 发表日期 | 2026 |
| 作者 | Shulin Du |
| 作者单位 | Joint Laboratory of Opto-Functional Theranostics in Medicine and Chemistry, Institute of Translational Medicine, The First Hospital of Jilin University, Changchun 130021, P. R. China. |
| 期刊 | Theranostics |
| SCI 分区 | Q1 |
| IF | 15.4 |
| 研究类型 | 基础研究 · 基础／转化 |
| 所属专科 | 鼻科 |
中文摘要
未标注： 异常氧化还原稳态的适应性调节赋予肿瘤细胞强大的生存能力，其中谷胱甘肽（GSH）作为抗氧化基石之一，显著削弱了许多调控性细胞死亡相关疗法的疗效，包括二硫死亡和铁死亡。
方法： 在此，构建了负载金纳米点的铁-二硫代二乙醇酸（SS）纳米颗粒（FeSS@Au NPs），通过三重GSH耗竭增强二硫死亡和铁死亡用于肿瘤治疗。FeSS NPs通过FeCl3与SS之间主导的配位驱动自组装预先制备。FeSS@Au NPs通过在FeSS NPs上原位生长金纳米点制备。对FeSS@Au NPs进行了系统评价，包括结构、特性、稳定性和抗肿瘤活性。
结果： FeSS@Au NPs中的Fe3+可通过氧化还原反应将GSH氧化为谷胱甘肽二硫化物（GSSG）。SS可通过硫醇-二硫化物交换耗竭GSH。金纳米点可通过其类葡萄糖氧化酶活性减弱烟酰胺腺嘌呤二核苷酸磷酸的补充，从而破坏胱氨酸向半胱氨酸的转化，进而通过提供较少的半胱氨酸下调GSH合成。由于GSH耗竭，蓄积的二硫化物（包括GSSG和胱氨酸）可触发二硫死亡。同时，谷胱甘肽过氧化物酶4活性受抑制以及通过Fenton反应升高的·OH可促进脂质过氧化物蓄积，从而增强铁死亡。
结论： 通过三重GSH耗竭策略，FeSS@Au NPs通过诱导二硫死亡和铁死亡实现强效的肿瘤生长抑制，为高效肿瘤治疗提供了一种有前景的治疗方法。
英文摘要
UNLABELLED: The adaptive regulation of abnormal redox homeostasis endows tumor cells with robust survival capabilities, with glutathione (GSH) serving as one of the antioxidant cornerstones, which significantly impairs the efficacy of many regulated cell death-related therapies, including disulfidptosis and ferroptosis.
METHODS: Herein, Au nanodot-loaded iron-dithiodiglycolic acid (SS) nanoparticles (FeSS@Au NPs) were engineered to potentiate disulfidptosis and ferroptosis via triple GSH depletion for oncotherapy. FeSS NPs were pre-prepared by dominant coordination-driven self-assembly between FeCl3 and SS. FeSS@Au NPs were prepared through the in situ growth of Au nanodots on FeSS NPs. FeSS@Au NPs were systematically evaluated, including the structure, characteristics, stability and antitumor activity.
RESULTS: Fe3+ in FeSS@Au NPs can oxidize GSH into glutathione (GSSG) through redox reaction. SS can deplete GSH through thiol-disulfide exchange. Au nanodots can disrupt cystine-to-cysteine transformation by attenuating nicotinamide adenine dinucleotide phosphate supplement with its glucose oxidase-like activity, thus downregulating GSH synthesis by providing less cysteine. Resulting from GSH depletion, the accumulated disulfides, including GSSG and cystine, can trigger disulfidptosis. Meanwhile, the inhibited glutathione peroxidase 4 activity and elevated ·OH via Fenton reaction can promote lipid peroxide accumulation, thereby boosting ferroptosis.
CONCLUSIONS: Through a triple GSH depletion strategy, FeSS@Au NPs achieve robust tumor growth inhibition by inducing disulfidptosis and ferroptosis, providing a promising therapeutic approach for efficient tumor treatments.