通过锰基纳米平台调控细胞能量供应和氧化还原稳态诱发二硫死亡增强的线粒体自噬
Provoking disulfidptosis-enhanced mitophagy by manganese-based nanoplatform via regulating cellular energy supply and redox homeostasis.
摘要(中文译文)
在非小细胞肺癌（NSCLC）中，肿瘤的代谢重编程及氧化还原防御机制的强化仍是氧化应激疗法的主要障碍。为应对这些障碍，我们策略性地靶向了在细胞氧化还原稳态中发挥核心作用的胱氨酸转运体SLC7A11。在此，基于bulk RNA测序（RNA-seq）分析的指导，我们发现同时激活SLC7A11并抑制葡萄糖转运体GLUT1可协同延缓NSCLC进展。我们提出了一种有效策略，通过同时靶向SLC7A11和GLUT1实现协同的化学动力学治疗（CDT）与二硫死亡。我们构建了一种由RNA-seq指导的纳米平台，该平台以中空结构的二氧化锰（HMnO）为载体并负载GLUT1抑制剂Bay876（HMnO@Bay）。肿瘤细胞摄取后，HMnO通过类Fenton反应持续产生细胞毒性羟自由基并激活SLC7A11的表达。纳米平台释放的Bay876阻断葡萄糖摄取，下调NADPH补充，并破坏SLC7A11介导的GSH合成抗氧化通路。这通过增加胱氨酸蓄积促进二硫死亡，同时通过减弱GSH介导的ROS耗竭增强CDT。此外，RNA-seq探究了HMnO@Bay处理肿瘤细胞的转录组变化，揭示CDT与二硫死亡的协同治疗促进肿瘤细胞线粒体自噬。全面的体外和体内评价表明，该治疗有效抑制肿瘤生长且全身毒性极低。本研究通过同时靶向氧化与葡萄糖稳态失衡，提供了一种有前景的NSCLC治疗范式，可诱导二硫死亡增强的线粒体自噬。
Abstract
Metabolic reprogramming and reinforcing redox defense mechanisms in tumors remains major obstacles to oxidative stress therapies in Non-small cell lung cancer (NSCLC). To address these obstacles, we strategically targeted cystine transporter SLC7A11, which plays a central role in cellular redox homeostasis. Herein, guided by bulk RNA-sequencing (RNA-seq) analysis, we identified that concurrent activation of SLC7A11 and inhibition of glucose transporter GLUT1 synergistically delays NSCLC progression. We introduced an effective strategy to effectively target SLC7A11 and GLUT1 for synergistic chemodynamic therapy (CDT) and disulfidptosis. A RNA-seq-guided nanoplatform was constructed from manganese dioxide (HMnO) with hollow structures and loaded with GLUT1 inhibitor Bay876 (HMnO@Bay). Upon tumor cell uptake, HMnO continuously generates cytotoxic hydroxyl radicals through Fenton-like reaction and activates the expression of SLC7A11. The Bay876 released from the nanoplatform blocks glucose uptake, downregulates NADPH supplementation, and disrupts the SLC7A11-mediated GSH synthesis antioxidant pathway. This boosts disulfidptosis via increased cystine accumulation while concurrently enhancing CDT through the attenuation of GSH-mediated ROS exhaustion. Additionally, RNA-seq explored changes in the transcriptome of tumor cells treated with HMnO@Bay, revealing that the synergistic therapy of CDT and disulfidptosis promotes mitophagy in tumor cells. Comprehensive in vitro and in vivo evaluations reveal the treatment effectively suppresses tumor growth with minimal systemic toxicity. This study provides a promising NSCLC therapy paradigm to induce disulfidptosis-enhanced mitophagy by simultaneously targeting oxidative and glucose dyshomeostasis.
如何引用
AMA
Zhenying Diao, Bin Feng, Yanfei Fu, Youcheng Liang, Long Qiu, Jianbo Sun, et al. Provoking disulfidptosis-enhanced mitophagy by manganese-based nanoplatform via regulating cellular energy supply and redox homeostasis.. Materials today. Bio. 2026; doi:10.1016/j.mtbio.2026.103249.
APA
Zhenying Diao, Bin Feng, Yanfei Fu, Youcheng Liang, Long Qiu, Jianbo Sun, et al (2026). Provoking disulfidptosis-enhanced mitophagy by manganese-based nanoplatform via regulating cellular energy supply and redox homeostasis.. Materials today. Bio. https://doi.org/10.1016/j.mtbio.2026.103249
GB/T 7714
Zhenying Diao, Bin Feng, Yanfei Fu, Youcheng Liang, Long Qiu, Jianbo Sun, et al. Provoking disulfidptosis-enhanced mitophagy by manganese-based nanoplatform via regulating cellular energy supply and redox homeostasis.[J]. Materials today. Bio, 2026 doi:10.1016/j.mtbio.2026.103249.
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