This study investigates the role of reductive glutamine metabolism in lipid synthesis under hypoxic conditions. The authors found that human cells, particularly those grown under hypoxia, rely on the reductive carboxylation of glutamine-derived alpha-ketoglutarate (αKG) to synthesize acetyl coenzyme A (AcCoA) for lipid synthesis. This process is primarily mediated by isocitrate dehydrogenase 1 (IDH1). The study used stable isotopic tracers and metabolic flux analysis to demonstrate that reductive glutamine metabolism contributes significantly to the de novo lipogenesis in various cell lines, including cancer cells. Under hypoxic conditions, cells preferentially use glutamine-derived carbon for lipid synthesis, accounting for approximately 80% of the carbon used for palmitate synthesis in A549 cells. The authors also found that the von Hippel-Lindau (VHL) tumor suppressor protein plays a crucial role in regulating this metabolic pathway, as VHL-deficient renal cell carcinoma (RCC) cells preferentially utilize reductive glutamine metabolism even under normal oxygen levels. Additionally, hypoxia-induced stabilization of HIF-1α and HIF-2α leads to increased PDK1 activity, which inhibits pyruvate dehydrogenase (PDH) and promotes reductive glutamine metabolism. These findings highlight the importance of reductive TCA metabolism in cell proliferation and provide potential therapeutic targets for mitigating hypoxic tumor growth.This study investigates the role of reductive glutamine metabolism in lipid synthesis under hypoxic conditions. The authors found that human cells, particularly those grown under hypoxia, rely on the reductive carboxylation of glutamine-derived alpha-ketoglutarate (αKG) to synthesize acetyl coenzyme A (AcCoA) for lipid synthesis. This process is primarily mediated by isocitrate dehydrogenase 1 (IDH1). The study used stable isotopic tracers and metabolic flux analysis to demonstrate that reductive glutamine metabolism contributes significantly to the de novo lipogenesis in various cell lines, including cancer cells. Under hypoxic conditions, cells preferentially use glutamine-derived carbon for lipid synthesis, accounting for approximately 80% of the carbon used for palmitate synthesis in A549 cells. The authors also found that the von Hippel-Lindau (VHL) tumor suppressor protein plays a crucial role in regulating this metabolic pathway, as VHL-deficient renal cell carcinoma (RCC) cells preferentially utilize reductive glutamine metabolism even under normal oxygen levels. Additionally, hypoxia-induced stabilization of HIF-1α and HIF-2α leads to increased PDK1 activity, which inhibits pyruvate dehydrogenase (PDH) and promotes reductive glutamine metabolism. These findings highlight the importance of reductive TCA metabolism in cell proliferation and provide potential therapeutic targets for mitigating hypoxic tumor growth.