MR Promotes Ferroptosis in Gastric Cancer by Regulating FANCD2 Expression Mediated by m6A Modification

Area of Science:

• Oncology
• Molecular Biology
• Cell Biology

Background:

• Methionine restriction (MR) inhibits gastric cancer progression.
• Ferroptosis, a form of regulated cell death, exhibits anti-tumor effects.
• The ferroptosis inhibitor FA complementation group D2 protein (FANCD2) plays a role in tumor growth.

Purpose of the Study:

• To investigate if MR treatment induces ferroptosis in gastric cancer cells by regulating FANCD2 expression.
• To determine the effect of MR-induced ferroptosis on gastric cancer progression.

Main Methods:

• Gastric cancer cells and patient-derived organoids were cultured under MR conditions.
• Ferroptosis was assessed by measuring lipid ROS, ACSL4, malondialdehyde (MDA), and 4-hydroxy-2-nonenal (4-HNE).
• FANCD2 and METTL3 (methyltransferase-like 3) expression, m6A methylation, and mRNA stability were analyzed.
• In vivo studies involved MR diet and lentivirus-mediated gene overexpression in mouse models.
• Tumor volume and organoid diameter were measured.

Main Results:

• MR treatment significantly increased ferroptosis markers and reduced gastric cancer cell proliferation and tumor volume in vivo.
• MR decreased FANCD2 expression, m6A abundance, and mRNA stability, while FANCD2 overexpression reversed these effects.
• MR down-regulated METTL3 expression, which in turn reduced FANCD2 m6A methylation and stability, promoting ferroptosis.

Conclusions:

• MR inhibits gastric cancer progression by promoting ferroptosis.
• The mechanism involves MR-induced down-regulation of METTL3, leading to decreased FANCD2 m6A modification and stability.
• This study highlights MR as a potential therapeutic strategy for gastric cancer by modulating ferroptosis through the METTL3-FANCD2 pathway.