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PDZ and LIM domain protein 1 (PDLIM1) is a cytoskeletal protein and is associated with the malignant pathological features of several tumors. However, the prognostic value of PDLIM1 and the molecular mechanisms by which it is involved in the metabolism and progression in gastric cancer (GC) are still unclear. The GEPIA database was used to predict the expression and prognosis of PDLIM1 in GC. qRT-PCR and western blot assays were applied to detect the mRNA and protein expression in GC tissues and cells. Loss- and gain-of-function experiments were performed to evaluate the biological role of PDLIM1 in GC cells. The Warburg effect was detected by a battery of glycolytic indicators. The interaction of PDLIM1 and hexokinase 2 (HK2) was determined by a co-immunoprecipitation assay. Furthermore, the modulatory effects of PDLIM1 and HK2 on Wnt/β-catenin signaling were assessed. The results showed that PDLIM1 expression was upregulated in GC tissues and cells and was associated with a poor prognosis for GC patients. PDLIM1 inhibition reduced GC cell proliferation, migration and invasion and promoted cell apoptosis. In the glucose deprivation (GLU-D) condition, the PDLIM1 level was reduced and PDLIM1 overexpression led to an increase in glycolysis. Besides, mechanistic investigation showed that PDLIM1 interacted with HK2 to mediate biological behaviors and the glycolysis of GC through Wnt/β-catenin signaling under glucose deprivation. In conclusion, PDLIM1 interacts with HK2 to promote gastric cancer progression by enhancing the Warburg effect via Wnt/β-catenin signaling. [ABSTRACT FROM AUTHOR]