FTO-mediated m6A demethylation of BCL6 promotes gastric cancer progression by suppressing ferroptosis.

B-cell lymphoma 6 (BCL6) functions in various cancers, but its role and regulation in gastric cancer (GC) remain unclear. N6-methyladenosine (m6A) modification is critical for tumorigenesis, and the demethylase FTO (highly expressed in GC) may regulate target gene stability via m6A. This study explored FTO's regulation of BCL6 m6A modification and its impact on GC progression through ferroptosis. qPCR assessed BCL6 expression in GC cells. BCL6 overexpression models were used to evaluate cell viability, apoptosis, and ferroptosis (via ROS, Fe2+, MDA, LDH, and ferroptosis-related proteins). RIP-PCR, MeRIP-qPCR, and mRNA stability assays examined FTO-BCL6 mRNA interaction and m6A effects. YTHDF2 knockdown validated its role, and co-silencing FTO/BCL6 clarified the axis's function. BCL6 was downregulated in GC cells. Its overexpression inhibited cell viability, promoted apoptosis, and induced ferroptosis. FTO bound BCL6 mRNA, removed m6A, and reduced its stability. YTHDF2 mediated FTO's negative regulation of BCL6. FTO knockdown enhanced ferroptosis and impaired GC cell function, partially reversed by BCL6 silencing. FTO suppresses BCL6 via m6A demethylation, inhibiting ferroptosis to promote GC progression. The FTO/BCL6 axis is a potential therapeutic target for GC.