FKBP9 enhances IGF2BP1-mediated m⁶A recognition to promote hepatocellular carcinoma progression

N⁶-methyladenosine (m⁶A) modification regulates mRNA stability and translation to promote cancer progression. FK506-binding protein 9 (FKBP9), a peptidyl-prolyl isomerase, is associated with carcinogenesis, but its role in m⁶A modification remains unclear. In this study we aimed to explore how FKBP9 regulates m⁶A modification during the development of hepatocellular carcinoma (HCC).

The expression of FKBP9 in HCC was profiled by reverse-transcription quantitative PCR, western blot, ELISA, and immunohistochemistry. Cell proliferation, migration, invasion, apoptosis, and mRNA stability were examined using CCK-8, colony formation, flow cytometry, and cycloheximide treatment. An orthotopic allograft tumor model was constructed for in vivo analysis. Immunoprecipitation, mass spectrometry, methylated RNA immunoprecipitation sequencing, and RNA sequencing were performed to elucidate underlying mechanisms.

FKBP9 was significantly upregulated in both HCC tissues and serum (p <0.05) and correlated with unfavorable clinical outcomes in patients (p <0.05). Its overexpression enhanced HCC cell proliferation and metastasis, while its depletion triggered cell cycle arrest and apoptosis. Mechanistically, FKBP9 interacted with the KH3-4 domains of IGF2BP1 through its peptidyl-prolyl isomerase domain, thereby stabilizing the binding of IGF2BP1 to m⁶A-modified MYC and PDGFB. Clinical analysis further confirmed that FKBP9 expression was positively associated with the expression of MYC and PDGFB at both the mRNA and protein levels (p <0.05). Co-overexpression of FKBP9 with MYC or PDGFB was linked to a worse prognosis (p <0.05).

FKBP9 promotes HCC progression by facilitating IGF2BP1 recognition of m6A-modified transcripts, thereby stabilizing MYC and PDGFB. The FKBP9-IGF2BP1 axis represents a potential therapeutic target in HCC.

This study highlights the critical role of FKBP9 in hepatocellular carcinoma progression by regulating IGF2BP1-mediated m6A RNA recognition, thereby enhancing the stability of key oncogenic transcripts such as MYC and PDGFB. These findings provide new insights into the molecular mechanisms driving hepatocellular carcinoma and identify potential therapeutic opportunities for patients with poor prognosis linked to high FKBP9 expression. The FKBP9-IGF2BP1 axis may serve as both a biomarker and a therapeutic target to guide the development of new treatment strategies. Further studies are warranted to validate these results in larger patient cohorts and to assess the clinical feasibility of targeting this pathway.