Ferroptosis, an iron-dependent nonapoptotic cell death, is a highly regulated tumor suppressing process. However, functions and mechanisms of RNA-binding proteins in regulation of evasion of ferroptosis during lung cancer progression are still largely unknown. Here, we report that the RNA-binding protein RBMS1 participates in lung cancer development via mediating ferroptosis evasion. Through an shRNA-mediated systematic screen, we discovered that RBMS1 is a key ferroptosis regulator. Clinically, RBMS1 was elevated in lung cancer and its high expression was associated with reduced patient survival. Conversely, depletion of RBMS1 inhibited lung cancer progression both in vivo and in vitro. Mechanistically, RBMS1 interacted with the translation initiation factor eIF3d directly to bridge the 3′- and 5′-UTR of SLC7A11. RBMS1 ablation inhibited the translation of SLC7A11, reduced SLC7A11-mediated cystine uptake, and promoted ferroptosis. In a drug screen that targeted RBMS1, we further uncovered that nortriptyline hydrochloride decreased the level of RBMS1, thereby promoting ferroptosis. Importantly, RBMS1 depletion or inhibition by nortriptyline hydrochloride sensitized radioresistant lung cancer cells to radiotherapy. Our findings established RBMS1 as a translational regulator of ferroptosis and a prognostic factor with therapeutic potential and clinical value.

中文翻译：

---

RBMS1通过SLC7A11的翻译控制调节肺癌铁死亡

铁死亡是一种铁依赖性非凋亡性细胞死亡，是一种高度调节的肿瘤抑制过程。然而，RNA结合蛋白在肺癌进展过程中调节铁死亡逃避的功能和机制仍然很大程度上未知。在这里，我们报告了 RNA 结合蛋白 RBMS1 通过介导铁死亡逃避参与肺癌的发展。通过 shRNA 介导的系统筛选，我们发现 RBMS1 是一个关键的铁死亡调节因子。临床上，RBMS1 在肺癌中升高，其高表达与患者生存率降低有关。相反，RBMS1的消耗在体内和体外都抑制了肺癌的进展。机制上，RBMS1 与翻译起始因子 eIF3d 直接相互作用以桥接 3 ' - 和 5' -SLC7A11 的UTR。RBMS1 消融抑制 SLC7A11 的翻译，减少 SLC7A11 介导的胱氨酸摄取，并促进铁死亡。在针对 RBMS1 的药物筛选中，我们进一步发现去甲替林盐酸盐降低了 RBMS1 的水平，从而促进了铁死亡。重要的是，去甲替林盐酸盐的 RBMS1 消耗或抑制使抗辐射肺癌细胞对放射治疗敏感。我们的研究结果确立了 RBMS1 作为铁死亡的转化调节因子和具有治疗潜力和临床价值的预后因素。