Glioma are tumors that often arise from glial cells and mostly start in the brain. It can be classified by the specific cell types including astrocytomas and oligodendrogliomas or by histopathological and clinical criteria from WHO grade I to grade IV gliomas. Low-grade gliomas tended to exhibit benign tendencies and portend a better prognosis for the patients while high grade gliomas are mostly malignant and cause worse prognosis. The current treatment is combination of the radiation therapy and oral administration of chemotherapy drug temozolomide (TMZ). It has been reported that several gene mutations can influence glioma progression. Among them, isocitrate dehydrogenases (IDH) mutation lost the normal function of α-ketoglutarate (α-KG) production and convert to 2-hydroxyglutarate (2-HG) and was reported to prolong the gliomas survival rate. The neo-enzyme 2HG is regarded as an oncometabolite through the inhibition of α-KG dependent enzymes and induction of cell transformation in tumor initiation. However, the role of D-2HG in tumor progression is still controversial and need to be further investigated. In our study, we presented the novel target proteins of 2-HG by using AETHIC, which can dissect the interaction of small molecules and proteins. We identified Signal transducer and activator of transcription 3 (STAT-3) as the target protein by screening the functional outcomes and protein changes in the overexpressed mutant IDH1 glioma cells. Furthermore, we used the in vitro binding assay to investigate the interaction between STAT-3 and 2-HG, the results confirmed that 2-HG can directly bind to STAT-3. Clinically, the survival rate and the expression level of STAT-3 downstream target genes also validated the importance of 2-HG affects prognosis through STAT-3. We hope to provide a new point of view on the better therapeutic target of glioma patients.