Glutamine Starvation Induces Ferroptosis in NSCLC via AMPK/PDZD8-Mediated Ferritinophagy

作者：Hong Chen, Xiaoying Wu, Meng Zhu, Ying Cheng, Qing Feng · 发表于：Nutrients · 年份：2026 · DOI：10.3390/nu18101596 · 研究领域：Ferroptosis and cancer prognosis、Cancer, Hypoxia, and Metabolism、Immune cells in cancer

Objectives: 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. Methods: 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. Results: 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, indi...