FTO‐mediated m6A demethylation regulates IGFBP3 expression and AKT activation through IMP3‐dependent P‐body re‐localisation in lung cancer

作者：Haiyang Wang, Hui Peng, Zhenzhen Zhang, Yilimunuer Abulimiti, Jiayi Hu, Yongxin Zhou, Ping Ji, Dong Li · 发表于：Clinical and Translational Medicine · 年份：2025 · DOI：10.1002/ctm2.70392 · 被引用次数：10 · 研究领域：RNA modifications and cancer、Cancer-related gene regulation、HVDC Systems and Fault Protection

Abstract Lung cancer remains one of the leading causes of cancer‐related deaths worldwide, and a growing body of evidence suggests that RNA modifications, including methylation, play a critical role in its progression. In this study, we investigated the role of the RNA demethylase fat mass and obesity‐associated protein (FTO) in lung cancer progression and determined the underlying molecular mechanisms. FTO expression was significantly upregulated in LUAD and correlated with poor prognosis. FTO knockdown in lung patient‐derived organoids and LUAD cell lines reduced their proliferation, invasion, and migration, and FTO knockdown in a Kras G12D mouse model reduced the growth of lung tumours. Mechanistically, FTO demethylated m 6 A sites in the insulin‐like growth factor‐binding protein 3 (IGFBP3) 3′UTR, preventing IMP3 binding. The ribonuclear protein IMP3 was identified as a crucial functional reader that interacted with m 6 A‐modified sites in the IGFBP3 3′UTR, thereby promoting IGFBP3 mRNA localisation to P‐bodies and suppressing its translation. Elevated IGFBP3 activated AKT signalling and promoted tumour progression. Collectively, we revealed that FTO drives lung cancer progression via m 6 A‐dependent sequestration of IGFBP3 mRNA into P‐bodies by IMP3, which suppresses translation and activates AKT signalling. The FTO–IGFBP3–AKT axis thus represents a promising therapeutic target. Key points FTO regulates the translation of IGFBP3 by demethylating m6A sites in the 3′‐untra...