ObjectiveTo investigate the expression of phosphoglycerate dehydrogenase (PHGDH) in gastric cancer and its role in resistance to the chemotherapy drug oxaliplatin.MethodsPHGDH-overexpressing and knockdown gastric cancer cell-derived organoid models were established. The half maximal inhibitory concentration (IC50) values of oxaliplatin in organoids with differential PHGDH expression were determined using the cell counting kit-8 (CCK-8) assay. DNA damage was assessed via Western blotting analysis of γ-H2AX (Ser139) levels. Oxidative stress levels were evaluated by measuring GSH/GSSG and NADPH/NADP+ ratios and reactive oxygen species (ROS) level. Cell migration assays and subcutaneous xenograft tumor experiments in BALB/c nude mice were conducted to assess the effects of PHGDH expression on oxaliplatin resistance. Additionally, survival prognosis in gastric cancer patients with differential PHGDH expression was analyzed using TCGA data.ResultsExperimental results showed that elevated PHGDH expression was significantly associated with the oxaliplatin resistance of gastric cancer cells. Stimulation of gastric cancer organoids with oxaliplatin significantly reduced the phosphorylation level of H2AX (P<0.000 1), thereby diminishing the DNA damage caused by oxaliplatin, while knockdown of PHGDH enhanced cellular sensitivity to oxaliplatin (P<0.000 1), inhibiting gastric cancer cell proliferation and migration capabilities (P<0.000 1). High expression of PHGDH leaded to an increase in the intracellular GSH/GSSG and NADPH/NADP⁺ ratios in gastric cancer cells (P<0.000 1, P<0.001), along with a decrease in ROS levels (P<0.000 1). In vivo experiments further confirmed that under oxaliplatin stimulation, the volume of PHGDH overexpressing patient-derived organoids xenografts (PDOX) was significantly larger than that in the control group (P<0.01). Analysis of the TCGA database revealed that patients with high PHGDH expression experienced significantly shorter disease-specific survival and progression-free survival than those with lower expression of PHGDH (HR=2.23, 95% CI: 1.43-3.47, P<0.001; HR=1.70, 95%CI: 1.19-2.44, P=0.004), with consistent results observed across different stages and grades of gastric cancer.ConclusionPHGDH plays a pivotal role in regulating oxaliplatin resistance in gastric cancer cells, suggesting its potential as a therapeutic target and prognostic biomarker.