Abstract

Background Metabolic reprogramming is a hallmark of gastric cancer and is essential for sustaining rapid proliferation and malignant progression. The serine synthesis pathway (SSP), a key branch of glycolysis coupled to one-carbon metabolism (OCM), plays a central role in nucleotide biosynthesis, redox homeostasis, and epigenetic regulation. Although aberrant SSP activation has been implicated in gastric cancer, its upstream regulatory mechanisms remain poorly defined. Long non-coding RNAs (lncRNAs) have emerged as critical modulators of oncogenic signaling and metabolism. This study aimed to elucidate the role of the lncRNA SNHG12 in gastric cancer progression and to determine whether it drives metabolic reprogramming through the Wnt/β-catenin–SSP axis. Methods SNHG12 expression and clinical relevance were analyzed using public datasets, clinical gastric cancer specimens, and cell lines. Gain- and loss-of-function experiments were performed to assess the effects of SNHG12 on proliferation, apoptosis, migration, and invasion. Transcriptomic profiling, targeted metabolomics, and integrative multi-omics analyses were used to characterize metabolic alterations. Pharmacological inhibition of SSP (NCT503) and Wnt/β-catenin signaling (IWR-1) was applied in vitro and in vivo. A subcutaneous xenograft mouse model was used to validate tumor-promoting effects and therapeutic responses. Results SNHG12 was significantly upregulated in gastric cancer tissues and cell lines and was associated with poor overall and progression-free survival. Functionally, SNHG12 promoted gastric cancer cell proliferation, migration, and invasion while suppressing apoptosis. Transcriptomic and targeted metabolomic analyses revealed broad metabolic alterations associated with SNHG12, including changes in serine/one-carbon metabolism, purine biosynthesis, and glutathione-related pathways.