谷氨酰胺饥饿通过AMPK/PDZD8介导的铁蛋白吞噬诱导非小细胞肺癌的铁蛋白沉积
Glutamine Starvation Induces Ferroptosis in NSCLC via AMPK/PDZD8-Mediated Ferritinophagy.
摘要(中文译文)
非小细胞肺癌（NSCLC）对谷氨酰胺的依赖性使得靶向谷氨酰胺代谢成为一种有吸引力的治疗策略。饮食干预越来越多地被考虑作为癌症的辅助治疗手段。本研究旨在探讨非小细胞肺癌中谷氨酰胺饥饿与铁死亡之间的关系，并阐明其潜在的分子机制。在A549和H460非小细胞肺癌细胞系中以及利用SCID小鼠异种移植模型的体内实验中，评估了谷氨酰胺饥饿的影响。评估内容包括细胞活力、迁移能力、克隆形成能力以及关键蛋白的表达。为了深入探究机制，对AMPK进行了过表达或抑制处理，并分析了铁蛋白自噬的关键标志物（包括ULK1、BECN1、NCOA4和LC3-II/I）以及铁死亡的关键标志物（如ACSL4、GPX4和xCT）。谷氨酰胺饥饿在体外和体内环境中均显著抑制了肿瘤生长，同时还降低了培养细胞的迁移能力和克隆形成能力。该干预激活了AMPK，表现为总量和磷酸化形式的增加，并上调了PDZD8的表达。在机制上，AMPK激活在驱动铁蛋白自噬和铁死亡中发挥了关键作用——对AMPK的调控一致性地改变了这些过程的关键标志物。此外，AMPK水平影响了PDZD8蛋白的表达。值得注意的是，单独过表达PDZD8即足以促进铁蛋白自噬和铁死亡，表明PDZD8作为AMPK在该通路中的关键下游介质发挥作用。我们的研究结果揭示了谷氨酰胺饥饿通过AMPK/PDZD8信号通路介导的铁蛋白自噬激活，触发非小细胞肺癌中的铁死亡。这些结果支持将饮食限制谷氨酰胺作为非小细胞肺癌新型治疗方法的潜力。
Abstract
: The dependence of non-small cell lung cancer (NSCLC) on glutamine has made targeting glutamine metabolism an attractive therapeutic approach. Dietary interventions are increasingly considered as adjuvant cancer therapies. This study aims to explore the relationship between glutamine starvation and ferroptosis in NSCLC and to elucidate the underlying molecular mechanisms. : The effects of glutamine starvation were evaluated both in A549 and H460 NSCLC cell lines and in vivo using xenograft models in SCID mice. Assessments included cell viability, migration, clonogenic capacity, and the expression of key proteins. To gain mechanistic insight, AMPK was either overexpressed or inhibited, and key markers of ferritinophagy (including ULK1, BECN1, NCOA4, and LC3-II/I) and ferroptosis (such as ACSL4, GPX4, and xCT) were analyzed. : Glutamine starvation markedly suppressed tumor growth in both in vitro and in vivo settings, while also reducing cell migration and clonogenicity in cultured cells. This intervention activated AMPK, as indicated by increases in both total and phosphorylated forms, and upregulated PDZD8 expression. Mechanistically, AMPK activation played a critical role in driving ferritinophagy and ferroptosis-manipulation of AMPK consistently altered key markers of these processes. Furthermore, AMPK levels influenced PDZD8 protein expression. Notably, overexpressing PDZD8 alone was sufficient in promoting both ferritinophagy and ferroptosis, indicating that PDZD8 acts as a critical downstream mediator of AMPK in this pathway. : Our findings reveal that glutamine starvation triggers ferroptosis in NSCLC via activation of ferritinophagy, mediated by the AMPK/PDZD8 signaling pathway. These results support the potential of dietary glutamine restriction as a novel therapeutic approach for NSCLC.
如何引用
AMA
Hong Chen, Xiaoying Wu, Manting Zhu, Ying Cheng, Qing Feng. Glutamine Starvation Induces Ferroptosis in NSCLC via AMPK/PDZD8-Mediated Ferritinophagy.. Nutrients. 2026; doi:10.3390/nu18101596.
APA
Hong Chen, Xiaoying Wu, Manting Zhu, Ying Cheng, Qing Feng (2026). Glutamine Starvation Induces Ferroptosis in NSCLC via AMPK/PDZD8-Mediated Ferritinophagy.. Nutrients. https://doi.org/10.3390/nu18101596
GB/T 7714
Hong Chen, Xiaoying Wu, Manting Zhu, Ying Cheng, Qing Feng. Glutamine Starvation Induces Ferroptosis in NSCLC via AMPK/PDZD8-Mediated Ferritinophagy.[J]. Nutrients, 2026 doi:10.3390/nu18101596.
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