铁死亡是由铁依赖性脂质过氧化引起的一种独特的非凋亡性细胞死亡，在肿瘤抑制中具有潜在的生理功能，但其潜在机制尚未完全阐明。在这里，我们报告长链非编码RNA（lncRNA）LncFASA增加了三阴性乳腺癌（TNBC）对铁死亡的易感性。作为一种肿瘤抑制因子，LncFASA 驱动含有过氧化物酶家族成员过氧化还原蛋白 1 (PRDX1) 的液滴的形成，从而通过 SLC7A11-GPX4 轴导致脂质过氧化的积累。从机制上讲，LncFASA 直接与 PRDX1 的 Ahpc-TSA 结构域结合，通过驱动液-液相分离来抑制其过氧化物酶活性，从而破坏细胞内 ROS 稳态。值得注意的是，高 LncFASA 表达表明乳腺癌个体总体生存良好，并且 LncFASA 通过调节铁死亡来损害乳腺异种移植肿瘤的生长。总之，我们的研究结果说明了这种 lncRNA 在铁死亡介导的癌症发展中的关键作用，并为乳腺癌的治疗策略提供了新的见解。© 2023。中国科学出版社。

Ferroptosis, a unique type of non-apoptotic cell death resulting from iron-dependent lipid peroxidation, has a potential physiological function in tumor suppression, but its underlying mechanisms have not been fully elucidated. Here, we report that the long non-coding RNA (lncRNA) LncFASA increases the susceptibility of triple-negative breast cancer (TNBC) to ferroptosis. As a tumor suppressor, LncFASA drives the formation of droplets containing peroxiredoxin1 (PRDX1), a member of the peroxidase family, resulting in the accumulation of lipid peroxidation via the SLC7A11-GPX4 axis. Mechanistically, LncFASA directly binds to the Ahpc-TSA domain of PRDX1, inhibiting its peroxidase activity by driving liquid-liquid phase separation, which disrupts intracellular ROS homeostasis. Notably, high LncFASA expression indicates favorable overall survival in individuals with breast cancer, and LncFASA impairs the growth of breast xenograft tumors by modulating ferroptosis. Together, our findings illustrate the crucial role of this lncRNA in ferroptosis-mediated cancer development and provide new insights into therapeutic strategies for breast cancer.© 2023. Science China Press.