Ferroptosis represents a recently identified form of programmed cell death that depends on iron and is triggered by lipid peroxidation. Nevertheless, its precise mechanisms and therapeutic relevance in cancer, particularly at the level of post-transcriptional regulation, remain largely unclear. In this study, we demonstrated that AKT inhibition markedly triggered GPX4-dependent ferroptosis and effectively restrained colorectal cancer progression both in vitro and in vivo. This process was accompanied by suppression of the demethylase FTO, leading to elevated m6A modification of GPX4 mRNA, which was then recognized by YTHDF2 and subsequently degraded. Bioinformatic prediction identified three putative methylation sites (193/647/766), among which site 193 was confirmed as the functional locus, being demethylated by FTO and recognized by YTHDF2. Meanwhile, inhibition of AKT promoted reactive oxygen species (ROS) accumulation, which exerted negative feedback regulation on GPX4 expression. Furthermore, MK2206 treatment initiated a protective autophagy response, whereas autophagy blockade further intensified ferroptosis and significantly potentiated the antitumor efficacy of MK2206. Overall, AKT suppression activated ferroptosis via the FTO/YTHDF2/GPX4 axis to inhibit colon cancer development, highlighting FTO and GPX4 as promising biomarkers and therapeutic targets in colorectal cancer management.
