Niclosamide suppresses gastric cancer progression through YTHDF2 inhibition-affected lactate metabolic reprogramming

Area of Science:

• Oncology
• Metabolomics
• Molecular Biology

Background:

• Gastric cancer (GC) is an aggressive malignancy characterized by significant mortality.
• Metabolic reprogramming, affecting glucose, lipid, and amino acid pathways, is a hallmark of GC.
• Lactate metabolism and the lactate shuttle play a crucial role in GC progression.

Purpose of the Study:

• To comprehensively analyze metabolic alterations in GC using multi-omics approaches.
• To investigate the role of the lactate shuttle in GC tumorigenesis.
• To evaluate the therapeutic potential of niclosamide and its mechanism involving YTHDF2 in GC.

Main Methods:

• Non-targeted metabolomics and transcriptomics on GC patient samples.
• Single-cell RNA sequencing to analyze intercellular metabolic dynamics.
• In vitro and in vivo experiments to assess niclosamide and YTHDF2 effects on GC cells.

Main Results:

• Identified significant metabolic reprogramming and upregulated lactate metabolism in GC.
• Dissected lactate shuttle dynamics between tumor epithelial and endothelial cells.
• Demonstrated that niclosamide suppresses GC by targeting YTHDF2, a key regulator of metabolic genes.

Conclusions:

• Upregulated lactate metabolism via the lactate shuttle is a key driver of gastric cancer.
• Niclosamide exerts anti-tumor effects by disrupting metabolic reprogramming through YTHDF2-mediated regulation of metabolic genes.
• YTHDF2 is a critical modulator of GC metabolism, presenting niclosamide as a potential therapeutic agent for gastric cancer.