Production of oxidized biomass, which requires regeneration of the cofactor NAD⁺, can be a proliferation bottleneck that is influenced by environmental conditions. However, a comprehensive quantitative understanding of metabolic processes that may be affected by NAD⁺ deficiency is currently missing. Here, we show that de novo lipid biosynthesis can impose a substantial NAD⁺ consumption cost in proliferating cancer cells. When electron acceptors are limited, environmental lipids become crucial for proliferation because NAD⁺ is required to generate precursors for fatty acid biosynthesis. We find that both oxidative and even net reductive pathways for lipogenic citrate synthesis are gated by reactions that depend on NAD⁺ availability. We also show that access to acetate can relieve lipid auxotrophy by bypassing the NAD⁺ consuming reactions. Gene expression analysis demonstrates that lipid biosynthesis strongly anti-correlates with expression of hypoxia markers across tumor types. Overall, our results define a requirement for oxidative metabolism to support biosynthetic reactions and provide a mechanistic explanation for cancer cell dependence on lipid uptake in electron acceptor-limited conditions, such as hypoxia.

氧化生物质的生产需要辅助因子 NAD ⁺的再生，这可能是受环境条件影响的增殖瓶颈。然而，目前尚缺乏对可能受 NAD ^{+缺乏影响的代谢过程的全面定量了解。}在这里，我们证明从头脂质生物合成可以在增殖的癌细胞中施加大量 NAD ^{+消耗成本。}当电子受体有限时，环境脂质对于增殖变得至关重要，因为需要 NAD ⁺来生成脂肪酸生物合成的前体。我们发现，脂肪生成柠檬酸合成的氧化途径甚至净还原途径都受到依赖于 NAD ^{+的反应的控制。}可用性。我们还表明，获取乙酸盐可以通过绕过 NAD ⁺消耗反应来缓解脂质营养缺陷型。基因表达分析表明，脂质生物合成与肿瘤类型中缺氧标志物的表达强烈反相关。总体而言，我们的结果定义了氧化代谢支持生物合成反应的要求，并为癌细胞在电子受体限制条件（例如缺氧）下依赖脂质摄取提供了机制解释。