Ferroptosis is a unique modality of regulated cell death that is driven by iron-dependent phospholipid peroxidation. N6-methyladenosine (m6A) RNA modification participates in varieties of cellular processes. However, it remains elusive whether m6A reader Fragile X Mental Retardation Protein (FMRP) are involved in the modulation of ferroptosis in breast cancer (BC). In this study, we found that FMRP expression was elevated and associated with poor prognosis and pathological stage in BC patients. Overexpression of FMRP induced ferroptosis resistance and exerted oncogenic roles by positively regulating a critical ferroptosis defense gene SLC7A11. Mechanistically, upregulated FMRP catalyzes m6A modification of SLC7A11 mRNA and further influences the SLC7A11 translation through METTL3-dependent manner. Further studies revealed that FMRP interacts with splicing factor hnRNPM to recognize the splice site and then modulated the exon skip splicing event of SLC7A11 transcript. Interestingly, SLC7A11-S splicing variant can effectively promote FMRP overexpression-induced ferroptosis resistance in BC cells. Moreover, our clinical data suggested that FMRP/hnRNPM/SLC7A11 expression were significantly increased in the tumor tissues, and this signal axis was important evaluation factors closely related to the worse survival and prognosis of BC patients. Overall, our results uncovered a novel regulatory mechanism by which high FMRP expression protects BC cells from undergoing ferroptosis. Targeting the FMRP–SLC7A11 axis has a dual effect of inhibiting ferroptosis resistance and tumor growth, which could be a promising therapeutic target for treating BC.

中文翻译：

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FMRP 通过与 hnRNPM 相互作用促进选择性剪接SLC7A11从而保护乳腺癌细胞免受铁死亡


铁死亡是一种独特的调节细胞死亡方式，由铁依赖性磷脂过氧化驱动。N6-甲基腺苷 （m6A） RNA 修饰参与多种细胞过程。然而，m6A 阅读器脆性 X 智力低下蛋白 （FMRP） 是否参与乳腺癌 （BC） 铁死亡的调节仍然难以捉摸。在这项研究中，我们发现 FMRP 表达升高，并与 BC 患者的不良预后和病理分期相关。FMRP 的过表达诱导铁死亡抗性，并通过正向调节关键的铁死亡防御基因SLC7A11发挥致癌作用。从机制上讲，上调的 FMRP 催化 SLC7A11 mRNA 的 m6A 修饰，并通过 METTL3 依赖性方式进一步影响 SLC7A11 翻译。进一步研究显示，FMRP 与剪接因子 hnRNPM 相互作用以识别剪接位点，然后调节 SLC7A11 转录本的外显子跳跃剪接事件。有趣的是，SLC7A11-S 剪接变体可以有效促进 FMRP 过表达诱导的 BC 细胞铁死亡耐药。此外，我们的临床数据表明，FMRP/hnRNPM/SLC7A11 在肿瘤组织中的表达显著增加，该信号轴是与 BC 患者较差的生存和预后密切相关的重要评价因素。总体而言，我们的结果揭示了一种新的调节机制，通过该机制，高 FMRP 表达保护 BC 细胞免受铁死亡。靶向 FMRP-SLC7A11 轴具有抑制铁死亡耐药和肿瘤生长的双重作用，这可能是治疗 BC 的一个有前途的治疗靶点。