FKBP9 Enhances IGF2BP1 Mediated m6A Recognition and Promotes Hepatocellular Carcinoma Progression

Hepatocellular carcinoma (HCC) is one of the most prevalent and lethal malignancies worldwide, with intricate molecular mechanisms driving its progression. Among various post-transcriptional regulatory mechanisms, N6-methyladenosine (m6A) modification has emerged as a critical factor influencing mRNA stability and translation, thereby impacting tumorigenesis. FK506-binding protein 9 (FKBP9), a peptidyl-prolyl isomerase (PPIase), has been implicated in several cancers; however, its specific role in HCC remains largely unexplored, and existing studies have not fully elucidated the molecular interactions and downstream effects of FKBP9 in HCC. In this study, we employed a combination of biochemical, molecular, and cellular techniques, including immunoprecipitation, RNA immunoprecipitation, luciferase reporter assays, and in vivo tumor models, to investigate the functional relationship between FKBP9 and the m6A reader protein Insulin like growth factor 2 mRNA binding protein 1 (IGF2BP1). Our findings demonstrate that FKBP9 directly interacts with IGF2BP1, enhancing its recognition of m6A-modified transcripts, particularly oncogenes such as MYC and Platelet-Derived Growth Factor Subunit B (PDGFB). Functional assays revealed that FKBP9 promotes HCC cell proliferation, migration, and invasion by stabilizing m6A-tagged oncogenic mRNAs. Furthermore, in vivo experiments confirmed that FKBP9 overexpression accelerates tumor growth, whereas MYC inhibition mitigates this effect. This study provides novel insights into the oncogenic role of FKBP9 in HCC by uncovering its regulatory influence on IGF2BP1-mediated m6A RNA recognition. These findings suggest that targeting the FKBP9-IGF2BP1 axis could be a promising therapeutic strategy for HCC.