Gastric cancer is the second most common cancer worldwide and has poor prognosis. To determine the mechanism of adaptation to metabolic stress in cancer cell, we use gastric cancer as a model system to reveal the potential signaling pathways involved. 2-DE, coupled with ESI-Q-TOF MS/MS analysis was used to identify differentially expressed proteins between gastric tumor tissues and the corresponding noncancerous tissues. In total, 107 spots with significant alteration (± over 2-fold, p < 0.05) were positively identified by MS/MS analysis. Altered expression of representative proteins was validated by RT-PCR and Western blotting. Cluster analysis of the changed proteins revealed an interesting group of metabolic proteins, which suggested accumulation of triiodothyronine (T3, major functional component of thyroid hormone) and over-expression of hypoxia induced factor (HIF) in gastric carcinoma. These observations were further confirmed by ECLI assay and immunohistochemistry. T3-induced expression of HIF1-alpha and VEGF was further verified using a gastric cancer cell line and in vivo mouse model. Since the early accumulation of HIF1-alpha was found to be independent of de novo transcription, we also found the involvement of a cytosolic cascade PI3K/Akt pathway sensitive to T3 stimulus was involved. Furthermore, we demonstrated that T3-induced over-expression of HIF1-alpha was mediated by fumarate accumulation, and could be enhanced by FUMH inactivation whilst inhibited by 2-oxoglutarate. These results provide evidence for alteration of metabolic proteins and dysfunction of thyroid hormone (TH) regulation in gastric tumors, and a novel thyroid hormone mediated tumorigenic signaling pathway is proposed. Our findings are considered a significant step towards a better understanding of adaptations to metabolic stress in gastric carcinogenesis.