Sarcosine sensitizes lung adenocarcinoma to chemotherapy by dual activation of ferroptosis via PDK4/PDHA1 signaling and NMDAR-mediated iron export.

IF 9.4 1区医学 Q1 HEMATOLOGY

Experimental Hematology & Oncology Pub Date : 2025-04-24 DOI:10.1186/s40164-025-00657-0

Guangyao Shan, Yunyi Bian, Shencheng Ren, Zhengyang Hu, Binyang Pan, Dejun Zeng, Zhaolin Zheng, Hong Fan, Guoshu Bi, Guangyu Yao, Cheng Zhan

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Abstract

Background: Ferroptosis, a regulated cell death driven by iron-dependent lipid peroxidation, is associated with chemoresistance in lung adenocarcinoma (LUAD). This study aims to investigate the role of sarcosine in ferroptosis and its underlying mechanisms.

Methods: An RSL3-induced ferroptosis model was used to screen a library of 889 human endogenous metabolites and metabolomic profiling was harnessed to identify metabolites associated with ferroptosis. Cell viability, lipid-reactive oxygen species (ROS), ferrous iron, malondialdehyde (MDA), and mitochondrial integrity were assessed to evaluate sarcosine's effects on ferroptosis. Metabolic fate was studied using ¹⁵N-labeled sarcosine. Next, we used untargeted metabolomic profiling and next-generation sequencing to dissect metabolic and transcriptomic changes upon sarcosine supplementation. The effects of sarcosine on ferroptosis and chemotherapy were further validated in patient-derived organoids (PDOs), xenograft models, and LUAD tissues.

Results: Sarcosine emerged as a potent ferroptosis inducer in the metabolic library screening, which was further confirmed via cell viability, lipid-ROS, ferrous iron, and MDA measurements. Metabolic flux analysis showed limited conversion of sarcosine to other metabolites in LUAD cells, while untargeted metabolomic profiling and seahorse assays indicated a metabolic shift from glycolysis to oxidative phosphorylation. Sarcosine enhanced pyruvate dehydrogenase activity to generate more ROS by interacting with PDK4, reducing PDHA1 phosphorylation. As a co-activator of N-methyl-D-aspartate receptor (NMDAR), sarcosine also exerted its pro-ferroptosis effect via regulating ferrous export through the NMDAR/MXD3/SLC40A1 axis. Given the significance of ferroptosis in chemotherapy, we validated that sarcosine enhanced the sensitization of cisplatin by promoting ferroptosis in LUAD cells, PDOs, and xenograft models.

Conclusion: Sarcosine promotes ferroptosis and enhances chemosensitivity, suggesting its potential as a therapeutic agent in treating LUAD.

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sarcos通过PDK4/PDHA1信号和nmda介导的铁输出双重激活铁下沉，使肺腺癌对化疗增敏。

背景：肺腺癌（LUAD）中铁依赖性脂质过氧化导致的细胞死亡与化疗耐药有关。本研究旨在探讨肌氨酸在铁下垂中的作用及其潜在机制。方法：利用rsl3诱导的铁下垂模型筛选889种人类内源性代谢物，并利用代谢组学分析鉴定与铁下垂相关的代谢物。通过评估细胞活力、脂质活性氧（ROS）、亚铁、丙二醛（MDA）和线粒体完整性来评估肌氨酸对铁下垂的影响。用15n标记的肌氨酸研究代谢命运。接下来，我们使用非靶向代谢组学分析和下一代测序来解剖补充肌氨酸后的代谢和转录组学变化。肌氨酸对铁下垂和化疗的影响在患者源性类器官（PDOs）、异种移植模型和LUAD组织中得到进一步验证。结果：在代谢文库筛选中，肌氨酸是一种有效的铁下垂诱导剂，通过细胞活力、脂质- ros、亚铁和MDA测量进一步证实了这一点。代谢通量分析显示，LUAD细胞中肌氨酸向其他代谢物的转化有限，而非靶向代谢组学分析和海马分析表明，代谢从糖酵解向氧化磷酸化转变。肌氨酸增强丙酮酸脱氢酶活性，通过与PDK4相互作用产生更多ROS，减少PDHA1磷酸化。作为n -甲基- d -天冬氨酸受体（NMDAR）的共激活剂，肌氨酸也通过NMDAR/MXD3/SLC40A1轴调节铁输出发挥其促铁凋亡作用。考虑到铁下垂在化疗中的重要性，我们验证了肌氨酸通过促进LUAD细胞、PDOs和异种移植模型中的铁下垂来增强顺铂的致敏性。结论：肌氨酸促进铁下垂，增强化疗敏感性，提示其作为LUAD治疗药物的潜力。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Experimental Hematology & Oncology Medicine-Oncology

CiteScore

12.60

自引率

7.30%

发文量

审稿时长

6 weeks

期刊介绍： Experimental Hematology & Oncology is an open access journal that encompasses all aspects of hematology and oncology with an emphasis on preclinical, basic, patient-oriented and translational research. The journal acts as an international platform for sharing laboratory findings in these areas and makes a deliberate effort to publish clinical trials with 'negative' results and basic science studies with provocative findings. Experimental Hematology & Oncology publishes original work, hypothesis, commentaries and timely reviews. With open access and rapid turnaround time from submission to publication, the journal strives to be a hub for disseminating new knowledge and discussing controversial topics for both basic scientists and busy clinicians in the closely related fields of hematology and oncology.