biostudies-literatureChen CEthics Committee of the First Affiliated Hospital of Anhui Medical UniversityYouth Talents Project of Jiangyin Health CommitteeEthics Committee of Nanjing Drum Tower HospitalGeneral Program of Wuxi Health CommitteeNanjing Special Foundation for Health Science and Technology Development, Distinguished Young ProgramResearch Fund of the Anhui Institute of Translational MedicineNatural Science Foundation of Anhui ProvinceOutstanding Youth Scientific Research Projects in Colleges and Universities of Anhui ProvinceNational Natural Science Foundation of ChinaChina Postdoctoral Science Foundatione2410263https://www.ebi.ac.uk/biostudies/studies/S-EPMC12005778biostudies-literatureUnknown12(15)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.Advanced science (Weinheim, Baden-Wurttemberg, Germany)NAT10 Promotes Gastric Cancer Liver Metastasis by Modulation of M2 Macrophage Polarization and Metastatic Tumor Cell Hepatic Adhesion.PMC120057782021-187-01820731142022AH0301152022zhyx-C218210326620230472408085Y04082102984JQX21005U24A207208227315782473107819030852408085QH23582372755JYOYT202310M2022282024M760032Xu LLin QWang BZhou SFu YMa ZZhang MDing QChen CLi MXu JZhao XWang MQian YBao LWang QWang SWang ZfalseNAT10 Promotes Gastric Cancer Liver Metastasis by Modulation of M2 Macrophage Polarization and Metastatic Tumor Cell Hepatic Adhesion.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.2025-01-01T00:00:00Z2025 Apr2025-07-08T03:11:32.844Z2025-07-08T03:11:32.844ZS-EPMC120057783998526910.1002/advs.202410263