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Experimental Hematology & Oncology

Experimental Hematology & Oncology

IF: 13.5
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Sarcosine sensitizes lung adenocarcinoma to chemotherapy by dual activation of ferroptosis via PDK4/PDHA1 signaling and NMDAR-mediated iron export

Published:24 April 2025 DOI: 10.1186/s40164-025-00657-0 PMID: 40275333
Guangyao Shan,?Yunyi Bian,?Shencheng Ren,?Zhengyang Hu,?Binyang Pan,?Dejun Zeng,?Zhaolin Zheng,?Hong Fan,?Guoshu Bi,?Guangyu Yao,?Cheng Zhan

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.

Substances (50)

Materials
Procduct Name CAS Molecular Formula Supplier Price
Rapamycin 53123-88-9 C51H79NO13 1043 suppliers $9.00-$6160.00
Rapamycin 53123-88-9 C51H79NO13 1043 suppliers $9.00-$6160.00
Rapamycin 53123-88-9 C51H79NO13 1043 suppliers $9.00-$6160.00
Rapamycin 53123-88-9 C51H79NO13 1043 suppliers $9.00-$6160.00
Cisplatin 15663-27-1 Cl2H6N2Pt 926 suppliers $14.00-$7570.00
Cisplatin 15663-27-1 Cl2H6N2Pt 926 suppliers $14.00-$7570.00
Cisplatin 15663-27-1 Cl2H6N2Pt 926 suppliers $14.00-$7570.00
Cisplatin 15663-27-1 Cl2H6N2Pt 926 suppliers $14.00-$7570.00
Sarcosine 107-97-1 C3H7NO2 765 suppliers $5.00-$5321.75
Sarcosine 107-97-1 C3H7NO2 765 suppliers $5.00-$5321.75

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