The mechanisms underlying the dynamic remodelling of cellular membrane phospholipids to prevent phospholipid peroxidation-induced membrane damage and evade ferroptosis, a non-apoptotic form of cell death driven by iron-dependent lipid peroxidation, remain poorly understood. Here we show that lysophosphatidylcholine acyltransferase 1 (LPCAT1) plays a critical role in ferroptosis resistance by increasing membrane phospholipid saturation via the Lands cycle, thereby reducing membrane levels of polyunsaturated fatty acids, protecting cells from phospholipid peroxidation-induced membrane damage and inhibiting ferroptosis. Furthermore, the enhanced in vivo tumour-forming capability of tumour cells is closely associated with the upregulation of LPCAT1 and emergence of a ferroptosis-resistant state. Combining LPCAT1 inhibition with a ferroptosis inducer synergistically triggers ferroptosis and suppresses tumour growth. Therefore, our results unveil a plausible role for LPCAT1 in evading ferroptosis and suggest it as a promising target for clinical intervention in human cancer.

细胞膜磷脂动态重塑以防止磷脂过氧化诱导的膜损伤并避免铁死亡（一种由铁依赖性脂质过氧化驱动的非凋亡形式的细胞死亡）的机制仍知之甚少。在这里，我们发现溶血磷脂酰胆碱酰基转移酶 1 (LPCAT1) 通过 Lands 循环增加膜磷脂饱和度，从而降低膜上多不饱和脂肪酸的水平，保护细胞免受磷脂过氧化诱导的膜损伤并抑制铁死亡，从而在抗铁死亡中发挥关键作用。此外，肿瘤细胞体内致瘤能力的增强与LPCAT1的上调和铁死亡抵抗状态的出现密切相关。将 LPCAT1 抑制与铁死亡诱导剂相结合可协同触发铁死亡并抑制肿瘤生长。因此，我们的结果揭示了 LPCAT1 在避免铁死亡方面的合理作用，并表明它是人类癌症临床干预的一个有希望的靶点。