The relationship between patterns of RNA modifications and gastric cancer (GC) liver metastasis (GCLM) remains unclear. Here, by single-cell sequencing, clinical sample analysis, and mouse model studies, an abnormal increase in the expression of the RNA acetyltransferase N-acetyltransferase 10 (NAT10) in liver metastatic GC cells is identified. NAT10-mediated N4-acetylcytidine modification of CXCL2 and KLF5 mRNA increases their stability. Then, secreted CXCL2 is found to promote the infiltration and polarization of M2-like macrophages to produce oncostatin M, which transcriptionally activates NAT10 expression via STAT3 signaling. In addition, organoid models confirm that NAT10 promotes the adhesion of GC cells to hepatocytes. Mechanistically, KLF5 transcriptionally activates ITGαV, facilitating GC cell attachment to hepatocytes. Intriguingly, high expression of NAT10/KLF5 axis is associated with poor prognosis of GC patients and targeting this axis significantly reduces GCLM in preclinical murine models. Collectively, these findings suggest the clinical significance of NAT10 in developing targeted therapies for GC patients with liver metastasis.