Background Gastric cancer ranks as one of the most prevalent malignant tumors worldwide, holding the fifth-highest incidence and third-highest mortality rate. Despite advancements in treatment, the absence of effective therapeutic targets continues to result in a relatively poor prognosis for gastric cancer patients. Therefore, a deeper understanding of the etiology and mechanisms underlying gastric cancer cell development is crucial. This could lead to the identification of novel diagnostic and prognostic molecular markers, as well as new molecular targets of clinical significance, improving treatment outcomes and overall survival rates. Epigenetic modifications, particularly RNA modifications, are key in regulating cellular functions.m5C RNA modification is catalyzed by the NOL1/NOP2/SUN (NSUN) family and DNA methyltransferase 2 (DNMT2). NSUN5, a key member of the M5C methylation family, specifically methylates ribosomes, influencing protein synthesis. It plays a significant role in crucial biological processes like cell proliferation and differentiation. Yet, its function and mechanisms in gastric cancer are not fully understood.

Methods This study involved analyzing NSUN5’s differential expression in gastric cancer versus normal tissues, survival trends, associated signaling pathways, and immune infiltration using the TCGA database. We then employed immunohistochemistry experiments to assess NSUN5 expression in gastric cancer tissues. To investigate the impact of NSUN5 on the proliferation, stemness, and migratory capabilities of gastric cancer cells, as well as on the expression of key proteins in relevant signaling pathways, we conducted functional gain and loss experiments.

Results The study revealed that NSUN5 is highly expressed in gastric cancer tissues, with a positive correlation to tumor stage and a negative correlation to patient prognosis. NSUN5 promotes in vitro proliferation, stemness, and migration of gastric cancer cells, and in vivo tumor growth, primarily via the WNT/β-catenin signaling pathway. Additionally, NSUN5 appears to decrease the infiltration of CD8+ T cells in gastric cancer, contributing to immune escape.

Conclusions In conclusion, our research suggests that NSUN5 acts as a proto-oncogene in gastric cancer development and could potentially serve as a novel therapeutic target.