Ferroptosis is a form of regulated necrotic cell death controlled by glutathione peroxidase 4 (GPX4). At present, mechanisms that could predict sensitivity and/or resistance and that may be exploited to modulate ferroptosis are needed. We applied two independent approaches—a genome-wide CRISPR-based genetic screen and microarray analysis of ferroptosis-resistant cell lines—to uncover acyl-CoA synthetase long-chain family member 4 (ACSL4) as an essential component for ferroptosis execution. Specifically, Gpx4–Acsl4 double-knockout cells showed marked resistance to ferroptosis. Mechanistically, ACSL4 enriched cellular membranes with long polyunsaturated ω6 fatty acids. Moreover, ACSL4 was preferentially expressed in a panel of basal-like breast cancer cell lines and predicted their sensitivity to ferroptosis. Pharmacological targeting of ACSL4 with thiazolidinediones, a class of antidiabetic compound, ameliorated tissue demise in a mouse model of ferroptosis, suggesting that ACSL4 inhibition is a viable therapeutic approach to preventing ferroptosis-related diseases.

Ferroptosis是谷胱甘肽过氧化物酶4（GPX4）控制的坏死细胞死亡的一种调节形式。当前，需要可以预测敏感性和/或抗性并且可以被利用来调节铁锈病的机制。我们应用了两种独立的方法，即基于全基因组CRISPR的遗传筛选和抗铁锈病细胞株的微阵列分析，以发现酰基辅酶A合成酶长链家族成员4（ACSL4）作为铁锈病执行的必要组成部分。具体来说，Gpx4 – Acsl4双敲除细胞对铁锈病表现出明显的抗性。从机理上讲，ACSL4用长的多不饱和ω6脂肪酸丰富了细胞膜。此外，ACSL4优先在一组基底样乳腺癌细胞系中表达，并预测它们对肥大症的敏感性。用噻唑烷二酮（一种抗糖尿病化合物）对ACSL4进行药理学靶向治疗，可改善肥大症小鼠模型中的组织死亡，这表明ACSL4抑制是预防与肥大症相关疾病的可行治疗方法。