SNHG12 drives gastric cancer progression by activating the Wnt/β-catenin-mediated serine synthesis pathway.

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. Mechanistically, SNHG12 increased Wnt/β-catenin reporter activity, promoted β-catenin nuclear accumulation, and was accompanied by increased expression of key SSP-associated enzymes, including PHGDH, PSAT1, and SHMT2. Pharmacological inhibition of SSP or Wnt/β-catenin signaling partially reversed SNHG12-induced malignant phenotypes in vitro and suppressed tumor growth in xenograft models. CONCLUSIONS: This study identifies SNHG12 as an important regulator of metabolic reprogramming in gastric cancer. Our data support a model in which SNHG12 promotes gastric cancer cell proliferation, invasion, and migration through SSP regulation, and suggest that its effects on the SSP may be mediated, at least in part, through modulation of SSP-associated enzymes via the Wnt/β-catenin pathway. These findings support SNHG12 as a candidate biomarker and a potential therapeutic target for combined metabolic and signaling-based interventions in gastric cancer.