铁过氧化物死亡与癌症转移之间的互作机制尚不清楚。在这里，我们确定AMER1是铁过氧化物死亡的关键调节因子。AMER1缺失导致结直肠癌（CRC）细胞对铁过氧化物死亡的抗性。有趣的是，AMER1缺陷的CRC细胞更倾向于形成远处转移灶，而AMER1天然型的CRC细胞主要侵袭淋巴结。此外，铁过氧化物抑制剂liproxstatin-1有效促进了AMER1天然型细胞的血液转移。机械上，AMER1与SLC7A11和铁蛋白轻链（FTL）结合，并招募β-TrCP1/2，通过泛素化降解SLC7A11和FTL。因此，AMER1缺陷增加了细胞的半胱氨酸水平，但减少了不稳定游离铁的池，从而增强了CRC细胞对铁过氧化物死亡的抗性。因此，AMER1缺失增加了CRC细胞在高氧化应激条件下在血液中的存活，并促进了CRC的血液转移。总之，AMER1介导了铁过氧化物死亡与癌症转移之间的互作机制，为具有AMER1突变的转移性结直肠癌患者的治疗提供了机遇。版权所有© 2023作者。由Elsevier Inc.发表，保留所有权利。

The crosstalk between ferroptosis and cancer metastasis remains unclear. Here, we identify AMER1 as a key regulator of ferroptosis. AMER1 loss causes resistance to ferroptosis in colorectal cancer (CRC) cells. Interestingly, AMER1-deficient CRC cells preferentially form distant metastases, while AMER1-naive CRC cells mainly invade lymph nodes. Moreover, the ferroptosis inhibitor liproxstatin-1 effectively promotes hematogenous transfer of AMER1-naive cells. Mechanistically, AMER1 binds to SLC7A11 and ferritin light chain (FTL) and recruits β-TrCP1/2, which degrade SLC7A11 and FTL by ubiquitination. Therefore, AMER1 deficiency increases cellular cystine levels but decreases the pool of labile free iron, thereby enhancing resistance to ferroptosis in CRC cells. Thus, AMER1 deficiency increases the survival of CRC cells in the blood under conditions of high oxidative stress and then promotes hematogenous metastasis of CRC. In conclusion, AMER1 mediates the crosstalk between ferroptosis and cancer metastasis, which provides a window of opportunity for treating metastatic colorectal cancer patients with AMER1 mutations.Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.