Dietary lipids impact development, homeostasis, and disease, but links between specific dietary fats and cell fates are poorly understood. Ferroptosis is an iron-dependent form of nonapoptotic cell death associated with oxidized polyunsaturated phospholipids. Here, we show that dietary ingestion of the polyunsaturated fatty acid (PUFA) dihomogamma-linolenic acid (DGLA; 20:3n-6) can trigger germ-cell ferroptosis and sterility in the nematode Caenorhabditis elegans. Exogenous DGLA is also sufficient to induce ferroptosis in human cells, pinpointing this omega-6 PUFA as a conserved metabolic instigator of this lethal process. In both C. elegans and human cancer cells, ether-lipid synthesis protects against ferroptosis. These results establish C. elegans as a powerful animal model to study the induction and modulation of ferroptosis by dietary fats and indicate that endogenous ether lipids act to prevent this nonapoptotic cell fate.

膳食脂质影响发育、体内平衡和疾病，但对特定膳食脂肪与细胞命运之间的联系知之甚少。铁死亡是与氧化多不饱和磷脂相关的铁依赖性非凋亡细胞死亡形式。在这里，我们表明饮食摄入多不饱和脂肪酸 (PUFA) 二高伽玛亚麻酸 (DGLA; 20:3n-6) 可以引发线虫秀丽隐杆线虫的生殖细胞铁死亡和不育。外源性 DGLA 也足以在人类细胞中诱导铁死亡，将这种 omega-6 PUFA 确定为这一致命过程的保守代谢始动因素。在秀丽隐杆线虫和人类癌细胞中，醚-脂质合成可防止铁死亡。这些结果确定了秀丽隐杆线虫 作为研究膳食脂肪诱导和调节铁死亡的强大动物模型，并表明内源性醚脂质可防止这种非凋亡细胞命运。