Triple-negative breast cancer (TNBC) has limited therapeutic options, is highly metastatic and characterized by early recurrence. Lipid metabolism is generally deregulated in TNBC and might reveal vulnerabilities to be targeted or used as biomarkers with clinical value. Ferroptosis is a type of cell death caused by iron-dependent lipid peroxidation which is facilitated by the presence of polyunsaturated fatty acids (PUFA). Here we identify fatty acid desaturases 1 and 2 (FADS1/2), which are responsible for PUFA biosynthesis, to be highly expressed in a subset of TNBC with a poorer prognosis. Lipidomic analysis, coupled with functional metabolic assays, showed that FADS1/2 high-expressing TNBC are susceptible to ferroptosis-inducing agents and that targeting FADS1/2 by both genetic interference and pharmacological approach renders those tumors ferroptosis-resistant while unbalancing PUFA/MUFA ratio by the supplementation of exogenous PUFA sensitizes resistant tumors to ferroptosis induction. Last, inhibiting lipid droplet (LD) formation and turnover suppresses the buffering capacity of LD and potentiates iron-dependent cell death. These findings have been validated in vitro and in vivo in mouse- and human-derived clinically relevant models and in a retrospective cohort of TNBC patients.

中文翻译：

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FADS1/2 控制三阴性乳腺癌的脂质代谢和铁死亡易感性。


三阴性乳腺癌 （TNBC） 的治疗选择有限，高度转移，以早期复发为特征。TNBC 中的脂质代谢通常失调，可能会揭示成为目标或用作具有临床价值的生物标志物的脆弱性。铁死亡是一种由铁依赖性脂质过氧化引起的细胞死亡，多不饱和脂肪酸 （PUFA） 的存在会促进这种过氧化。在这里，我们确定了负责 PUFA 生物合成的脂肪酸去饱和酶 1 和 2 （FADS1/2） 在预后较差的 TNBC 亚群中高度表达。脂质组学分析与功能代谢测定相结合，表明 FADS1/2 高表达 TNBC 对铁死亡诱导剂敏感，并且通过遗传干扰和药理学方法靶向 FADS1/2 使这些肿瘤对铁死亡产生抵抗力，而通过补充外源性 PUFA 破坏 PUFA/MUFA 比率使耐药肿瘤对铁死亡诱导敏感。最后，抑制脂滴 （LD） 的形成和周转会抑制 LD 的缓冲能力并增强铁依赖性细胞死亡。这些发现已在小鼠和人源性临床相关模型以及 TNBC 患者的回顾性队列中得到体外和体内验证。