Ferroptosis is a form of cell death that has received considerable attention not only as a means to eradicate defined tumour entities but also because it provides unforeseen insights into the metabolic adaptation that tumours exploit to counteract phospholipid oxidation^1,2. Here, we identify proferroptotic activity of 7-dehydrocholesterol reductase (DHCR7) and an unexpected prosurvival function of its substrate, 7-dehydrocholesterol (7-DHC). Although previous studies suggested that high concentrations of 7-DHC are cytotoxic to developing neurons by favouring lipid peroxidation³, we now show that 7-DHC accumulation confers a robust prosurvival function in cancer cells. Because of its far superior reactivity towards peroxyl radicals, 7-DHC effectively shields (phospho)lipids from autoxidation and subsequent fragmentation. We provide validation in neuroblastoma and Burkitt’s lymphoma xenografts where we demonstrate that the accumulation of 7-DHC is capable of inducing a shift towards a ferroptosis-resistant state in these tumours ultimately resulting in a more aggressive phenotype. Conclusively, our findings provide compelling evidence of a yet-unrecognized antiferroptotic activity of 7-DHC as a cell-intrinsic mechanism that could be exploited by cancer cells to escape ferroptosis.

铁死亡是细胞死亡的一种形式，它不仅作为根除特定肿瘤实体的一种手段而受到广泛关注，而且还因为它为肿瘤利用代谢适应来抵消磷脂氧化提供了不可预见的见解^1,2 。在这里，我们鉴定了 7-脱氢胆固醇还原酶 (DHCR7) 的促凋亡活性及其底物​​ 7-脱氢胆固醇 (7-DHC) 的意外促存活功能。尽管之前的研究表明高浓度的 7-DHC 通过促进脂质过氧化而对发育中的神经元具有细胞毒性³ ，但我们现在表明 7-DHC 的积累赋予癌细胞强大的促生存功能。由于其对过氧自由基的反应性远超优异，7-DHC 可有效保护（磷酸）脂质免遭自动氧化和随后的碎裂。我们在神经母细胞瘤和伯基特淋巴瘤异种移植物中进行了验证，证明 7-DHC 的积累能够诱导这些肿瘤向铁死亡抵抗状态转变，最终导致更具侵袭性的表型。总之，我们的研究结果提供了令人信服的证据，证明 7-DHC 具有尚未被认识的抗铁死亡活性，作为一种细胞内在机制，癌细胞可以利用该机制来逃避铁死亡。