The study investigates the role of IDH1 mutations in gliomas, a common type of brain tumor. Heterozygous mutations in the *IDH1* gene, which encodes isocitrate dehydrogenase-1, are found in certain human brain tumors but their mechanism in tumor development is unclear. The researchers found that these mutations impair the enzyme's ability to bind to its substrate, isocitrate, and form inactive heterodimers with wild-type IDH1, thereby inhibiting its activity. Forced expression of mutant IDH1 reduces the production of α-ketoglutarate (α-KG), a key intermediate, and increases the levels of HIF-1α, a transcription factor that promotes tumor growth under hypoxic conditions. The rise in HIF-1α levels was reversible by an α-KG derivative. HIF-1α levels were higher in gliomas with *IDH1* mutations compared to those without. These findings suggest that IDH1 functions as a tumor suppressor and that its inactivation through mutation contributes to tumorigenesis by activating the HIF-1 pathway. The study also highlights the potential of α-KG derivatives as therapeutic agents for gliomas with *IDH1* mutations.The study investigates the role of IDH1 mutations in gliomas, a common type of brain tumor. Heterozygous mutations in the *IDH1* gene, which encodes isocitrate dehydrogenase-1, are found in certain human brain tumors but their mechanism in tumor development is unclear. The researchers found that these mutations impair the enzyme's ability to bind to its substrate, isocitrate, and form inactive heterodimers with wild-type IDH1, thereby inhibiting its activity. Forced expression of mutant IDH1 reduces the production of α-ketoglutarate (α-KG), a key intermediate, and increases the levels of HIF-1α, a transcription factor that promotes tumor growth under hypoxic conditions. The rise in HIF-1α levels was reversible by an α-KG derivative. HIF-1α levels were higher in gliomas with *IDH1* mutations compared to those without. These findings suggest that IDH1 functions as a tumor suppressor and that its inactivation through mutation contributes to tumorigenesis by activating the HIF-1 pathway. The study also highlights the potential of α-KG derivatives as therapeutic agents for gliomas with *IDH1* mutations.