ALKBH5 facilitates tumor progression via an m6A-YTHDC1-dependent mechanism in glioma

N⁶-methyladenosine (m6A) methylation, is a well-known epigenetic modification involved in various biological processes, including tumorigenesis. However, the role of AlkB homolog 5 (ALKBH5), a critical component of m6A modification, remains unclear in glioma. This study investigates the function of ALKBH5 in glioma progression and its potential as a therapeutic target. We found that ALKBH5 expression was dramatically increased in glioma, and high expression of ALKBH5 predicted poor prognosis. Overexpression of ALKBH5 promotes cell proliferation, migration, and invasion in vitro and accelerates tumor growth in vivo. Furthermore, m6A-MeRIP-seq, MeRIP-qPCR, RNA pulldown, and immunoprecipitation assays revealed that the transcription factor, forkhead box protein O1 (FOXO1), was the potential target of ALKBH5. Mechanistically, ALKBH5 facilitates glioma progression by demethylating m6A-modified FOXO1 mRNA, thereby destroying FOXO1 stability and expression through a YTHDC1-dependent pathway. The downregulated FOXO1 interacts with β-catenin, increasing its nuclear accumulation and thus promoting oncogenic Wnt/β-catenin signaling. Our findings suggest that targeting the ALKBH5/FOXO1 axis may provide a novel therapeutic strategy for glioma treatment.