Ferroptosis is a form of cell death caused by lipid peroxidation that is emerging as a target for cancer therapy, highlighting the need to identify factors that govern ferroptosis susceptibility. Lipid peroxidation occurs primarily on phospholipids containing polyunsaturated fatty acids (PUFAs). Here, we show that even though extracellular lipid limitation reduces cellular PUFA levels, lipid-starved cancer cells are paradoxically more sensitive to ferroptosis. Using mass spectrometry-based lipidomics with stable isotope fatty acid labeling, we show that lipid limitation induces a fatty acid trafficking pathway in which PUFAs are liberated from triglycerides to synthesize highly unsaturated PUFAs such as arachidonic and adrenic acid. These PUFAs then accumulate in phospholipids, including ether phospholipids, to promote ferroptosis sensitivity. Therefore, PUFA levels within cancer cells do not necessarily correlate with ferroptosis susceptibility. Rather, how cancer cells respond to extracellular lipid levels by trafficking PUFAs into proper phospholipid pools contributes to their sensitivity to ferroptosis.

中文翻译：

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脂质可用性通过调节多不饱和脂肪酸运输来影响癌细胞的铁死亡敏感性


铁死亡是一种由脂质过氧化引起的细胞死亡形式，正在成为癌症治疗的靶点，这凸显了确定控制铁死亡易感性的因素的必要性。脂质过氧化主要发生在含有多不饱和脂肪酸 （PUFA） 的磷脂上。在这里，我们表明，尽管细胞外脂质限制降低了细胞 PUFA 水平，但脂质饥饿的癌细胞对铁死亡更敏感。使用基于质谱的脂质组学和稳定同位素脂肪酸标记，我们表明脂质限制诱导脂肪酸运输途径，其中 PUFA 从甘油三酯中释放出来，合成高度不饱和的 PUFA，例如花生四烯酸和肾上腺酸。然后，这些 PUFA 在磷脂（包括醚磷脂）中积累，以促进铁死亡敏感性。因此，癌细胞内的 PUFA 水平不一定与铁死亡易感性相关。相反，癌细胞如何通过将 PUFA 运输到适当的磷脂库中来响应细胞外脂质水平，这导致了它们对铁死亡的敏感性。