〔Abstract〕 Objective To study the molecular mechanism of fat mass and obesity-associated protein(FTO) regulating hepatocellular carcinoma(HCC). Methods HepG2 cells of knock-down FTO were constructed, HepG2 cells of knock-down FTO and HepG2 cells were collected, and high-throughput sequencing was performed using Illumina Hiseq platform to screen the gene expression differences between the two groups. Through GO and KEGG enrichment analysis of these differential genes, FTO regulatory pathways were studied and downstream target genes of FTO were screened. The role of FTO downstream target gene in HCC was revealed by bioinformatic analysis and cell experiments. Results Transcriptome sequencing showed that 386 genes were differentially expressed between HepG2 cells of knock-down FTO and HepG2 cells, and they were involved in biological processes such as response to interferon-gamma. The expression of IFIT2, one of the most responsive interferon-stimulating genes, was up-regulated after FTO knockdown. Potential m6A methylation occurred at multiple sites of IFIT2. The survival of HCC patients with high expression of IFIT2 was significantly prolonged, and knock-down of IFIT2 promoted the growth and migration of HepG2 cells. Conclusion FTO may regulate IFIT2 by mediating m6A, and further promote the occurrence and development of HCC.