MicroRNAs (miRNAs) are small regulatory molecules playing important roles in different physiological and pathological processes, but only several miRNAs were functionally characterized in Merkel cell carcinoma (MCC). We previously identified miR-150-5p as one of the differentially expressed miRNAs between MCC metastases and primary tumors. In the present study, we further investigated the functional role of miR-150-5p in MCC progression. Our results revealed that miR-150-5p suppresses the migratory and invasive properties of MCC cells. We identified RNA N6-methyladenosine (m6A) demethylase FTO as a direct target of miR-150-5p. Functionally, we showed that FTO enhances proliferative, migratory and invasive properties of MCC cells, and rescued the antitumor effects induced by miR-150-5p. Mechanistically, we demonstrated that FTO stabilizes CTNNB1 transcripts via its m6A demethylation activity. Silencing the m6A reader YTHDF2 increased, while its overexpression decreased CTNNB1 mRNA and protein levels. Furthermore, the RNA immunoprecipitation assays demonstrated the interaction between CTNNB1 mRNA and YTHDF2. Together, these results suggest that FTO stabilizes CTNNB1 in an m6A-dependent manner. In conclusion, our findings uncover the role of miR-150-5p and its target FTO in MCC progression, suggesting the potential of targeting FTO signaling for MCC therapy.© 2025 Wiley Periodicals LLC.