Ferroptosis is a form of regulated cell death that is induced by inhibiting glutathione peroxidase 4 (GPX4), which eliminates lipid peroxidation. Ferroptosis induction is influenced by the cell environment. However, the cellular states altering ferroptosis susceptibility remain largely unknown. We found that melanoma cell lines became resistant to ferroptosis as cell density increased. Comparative transcriptome and metabolome analyses revealed that cell density-dependent ferroptosis resistance was coupled with a shift toward a lipogenic phenotype accompanied by strong induction of stearoyl-CoA desaturase (SCD). Database analysis of gene dependency across hundreds of cancer cell lines uncovered a negative correlation between GPX4 and SCD dependency. Importantly, SCD inhibition, either pharmacologically or through genetic knockout, sensitized melanoma cells to GPX4 inhibition, thereby attenuating ferroptosis resistance in cells at high density. Our findings indicate that transition to an SCD-inducing, lipogenic cell state produces density-dependent resistance to ferroptosis, which may provide a therapeutic strategy against melanoma.

中文翻译：

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硬脂酰辅酶A去饱和酶的诱导赋予黑色素瘤细胞密度依赖性铁死亡抗性

铁死亡是一种受调节的细胞死亡形式，通过抑制谷胱甘肽过氧化物酶 4 (GPX4) 诱导，从而消除脂质过氧化。铁死亡诱导受到细胞环境的影响。然而，改变铁死亡易感性的细胞状态仍然很大程度上未知。我们发现，随着细胞密度的增加，黑色素瘤细胞系对铁死亡具有抵抗力。比较转录组和代谢组分析表明，细胞密度依赖性铁死亡抗性与向脂肪生成表型的转变相结合，并伴有硬脂酰辅酶A去饱和酶（SCD）的强烈诱导。对数百个癌细胞系的基因依赖性的数据库分析发现GPX4和SCD依赖性之间存在负相关。重要的是，SCD 抑制，无论是药理学上的还是通过基因敲除，都使黑色素瘤细胞对 GPX4 抑制敏感，从而减弱了高密度细胞的铁死亡抵抗力。我们的研究结果表明，向 SCD 诱导的脂肪生成细胞状态的转变会产生密度依赖性的铁死亡抵抗力，这可能提供一种针对黑色素瘤的治疗策略。