Background <p>Epiphycan (EPYC) has been confirmed to play an oncogenic role in many cancers. However, its role and mechanism in gastric cancer (GC) progression has not been explored.</p> Methods <p>The levels of EPYC and NOP2/Sun domain 2 (NSUN2) were detected by qRT-PCR and western blot. Cell proliferation, apoptosis, migration and invasion were determined by cell counting kit 8 assay, colony formation assay, flow cytometry, wound healing assay and transwell assay. Fe²⁺ and iron levels were examined to assess cell ferroptosis. Actinomycin D assay was used to detect the effect of NSUN2 knockdown on EPYC mRNA stability, and methylated RNA immunoprecipitation (MeRIP) assay was performed to determine the effect of NSUN2 silencing on 5-methylcytosine (m5C) level of EPYC. Xenograft tumors were constructed to explore the regulation of NSUN2 knockdown on GC tumorigenesis in vivo.</p> Results <p>EPYC was abnormally higher expressed in GC tissues and cells. Knockdown of EPYC restrained GC cell proliferation, migration and invasion, while enhanced apoptosis and ferroptosis. NSUN2 had elevated expression in GC, which could increase the mRNA stability and expression of EPYC through m5C modification. NSUN2 silencing inhibited GC cell proliferation, metastasis, promoted apoptosis and ferroptosis, while these effects were reversed by EPYC overexpression. In vivo experiments revealed that NSUN2 downregulation reduced GC tumorigenesis by decreasing EPYC level in vivo.</p> Conclusion <p>NSUN2-mediated m5C modification of EPYC contributed to GC cell growth and metastasis, which provided a novel regulatory axis for understanding the pathogenesis of GC.</p>