ALYREF promotes tumor progression by regulating SLC2A3-mediated glycolysis in gastric cancer

Gastric cancer (GC) remains one of the leading causes of cancer-related mortality worldwide, and the molecular mechanisms driving its progression are not fully understood. ALYREF, an RNA-binding protein implicated in mRNA export and stability, has recently emerged as a potential oncogenic factor in several malignancies; however, its role in GC remains unclear. In this study, we investigated the clinical significance and biological function of ALYREF in GC. Immunohistochemical analysis of a tissue microarray demonstrated that ALYREF expression was significantly elevated in GC tissues compared with adjacent non-tumorous tissues and was positively associated with lymphatic metastasis, advanced pathological stage, and poor overall survival. These findings were further validated using TCGA and GEO datasets. Functional assays revealed that ALYREF depletion suppressed GC cell proliferation and migration while promoting apoptosis in vitro , whereas ALYREF overexpression exerted the opposite effects. Mechanistically, quantitative proteomic analysis identified SLC2A3 as a downstream target of ALYREF. We demonstrated that ALYREF interacted with SLC2A3 and enhanced its protein stability by promoting USP3-mediated deubiquitination, thereby preventing proteasomal degradation. Rescue experiments confirmed that SLC2A3 mediated the tumor-promoting effects of ALYREF both in vitro and in vivo . Furthermore, ALYREF enhanced glycolytic activity in GC cells by up-regulating SLC2A3, as evidenced by increased glucose uptake, lactate production, and extracellular acidification rate, effects that were reversed by SLC2A3 knockdown or glycolytic inhibition. Collectively, our findings reveal that ALYREF promotes GC progression through a USP3-dependent stabilization of SLC2A3 and subsequent enhancement of glycolysis. The ALYREF–USP3–SLC2A3 axis may represent a novel therapeutic target for GC.