三阴性乳腺癌（TNBC）患者的治疗选择有限，导致转移复发率高且预后不良。铁死亡是一种由铁依赖性脂质过氧化引起的细胞死亡，并被硒蛋白 GPX4 的抗氧化活性所抵消。在这里，我们发现，TNBC 细胞在高细胞密度培养时在细胞外环境中分泌抗铁死亡因子，但在低密度形成集落时容易发生铁死亡。我们发现，抗铁死亡因子（被确定为含有脂质的单不饱和脂肪酸（MUFA））的分泌以及单细胞铁死亡的脆弱性取决于与细胞密度成正比的硬脂酰辅酶A去饱和酶（SCD）的低表达。最后，我们表明，抑制 Sec-tRNAsec 生物合成（硒蛋白生产的重要步骤）会导致铁死亡并损害循环 TNBC 细胞的肺播种，这些细胞不再受到原发肿瘤富含 MUFA 的环境的保护。© 2024。作者。

The limited availability of therapeutic options for patients with triple-negative breast cancer (TNBC) contributes to the high rate of metastatic recurrence and poor prognosis. Ferroptosis is a type of cell death caused by iron-dependent lipid peroxidation and counteracted by the antioxidant activity of the selenoprotein GPX4. Here, we show that TNBC cells secrete an anti-ferroptotic factor in the extracellular environment when cultured at high cell densities but are primed to ferroptosis when forming colonies at low density. We found that secretion of the anti-ferroptotic factors, identified as monounsaturated fatty acid (MUFA) containing lipids, and the vulnerability to ferroptosis of single cells depends on the low expression of stearyl-CoA desaturase (SCD) that is proportional to cell density. Finally, we show that the inhibition of Sec-tRNAsec biosynthesis, an essential step for selenoprotein production, causes ferroptosis and impairs the lung seeding of circulating TNBC cells that are no longer protected by the MUFA-rich environment of the primary tumour.© 2024. The Author(s).