铁死亡是由铁依赖性磷脂过氧化引发的受调节的细胞死亡过程，主要受到 GPX4 依赖性和 FSP1 依赖性监视机制的抑制。然而，在癌症发展过程中如何调节铁死亡监测系统仍然很大程度上未知。在此，我们报道 YTHDC1 介导的 m6A 对 FSP1 的表观遗传调控减轻了 FSP1 依赖性铁死亡抑制，这在一定程度上有助于 YTHDC1 在肺癌进展中的肿瘤抑制作用。 YTHDC1敲除促进了肺癌进展并上调了FSP1蛋白水平，导致肺癌细胞铁死亡抵抗。沉默 FSP1 消除了 YTHDC1 敲低诱导的增殖增加和铁死亡抵抗。从机制上讲，YTHDC1 与 FSP1 3'-UTR 中的 m6A 位点结合，招募了替代多聚腺苷酸化调节因子 CSTF3，以生成不太稳定的包含 FSP1 mRNA 的较短 3'-UTR，而 YTHDC1 下调则生成包含 FSP1 mRNA 的较长 3'-UTR，即RNA结合蛋白HuR稳定，从而导致FSP1蛋白水平增强。因此，我们的研究结果将 YTHDC1 确定为肺癌中的肿瘤进展抑制剂，并通过调节 FSP1 mRNA 稳定性作为铁死亡调节剂，从而为 YTHDC1 高肺癌提出了与铁死亡相关的治疗选择。© 2023。作者，拥有独家许可ADMC 细胞差异与死亡协会。

Ferroptosis is a regulated cell death process initiated by iron-dependent phospholipid peroxidation and is mainly suppressed by GPX4-dependent and FSP1-dependent surveillance mechanisms. However, how the ferroptosis surveillance system is regulated during cancer development remains largely unknown. Here, we report that the YTHDC1-mediated m6A epigenetic regulation of FSP1 alleviates the FSP1-dependent ferroptosis suppression that partially contributes to the tumor suppressive role of YTHDC1 in lung cancer progression. YTHDC1 knockdown promoted the lung tumor progression and upregulated FSP1 protein level that resulted in ferroptosis resistance of lung cancer cells. Silencing FSP1 abrogated YTHDC1 knockdown-induced proliferation increase and ferroptosis resistance. Mechanistically, YTHDC1 binding to the m6A sites in the FSP1 3'-UTR recruited the alternative polyadenylation regulator CSTF3 to generate a less stable shorter 3'-UTR contained FSP1 mRNA, whereas YTHDC1 downregulation generated the longer 3'-UTR contained FSP1 mRNA that is stabilized by RNA binding protein HuR and thus led to the enhanced FSP1 protein level. Therefore, our findings identify YTHDC1 as a tumor progression suppressor in lung cancer and a ferroptosis regulator through modulating the FSP1 mRNA stability and thus suggest a ferroptosis-related therapeutic option for YTHDC1high lung cancer.© 2023. The Author(s), under exclusive licence to ADMC Associazione Differenziamento e Morte Cellulare.