SLC7A11 是一种胱氨酸转运蛋白和铁死亡抑制剂。 E3 连接酶和去泛素化酶 (DUB) 如何协调调节 SLC7A11 的稳定性以响应环境胱氨酸仍然是个谜。在此，我们报告 neddylation 抑制剂 MLN4924 通过灭活 Cullin-RING 连接酶 3 (CRL-3)，引起 SLC7A11 积累，从而增加胱氨酸的摄取。我们确定 KCTD10 是 SLC7A11 泛素化的 CRL-3 底物识别亚基，USP18 是 SLC7A11 去泛素化酶。胱氨酸剥夺后，KCTD10 或 USP18 的蛋白水平分别降低或升高，从而促进 SLC7A11 积累。通过破坏或稳定 SLC7A11、KCTD10 或 USP18，反向调节胱氨酸摄取和铁死亡。从生物学角度来看，MLN4924 与 SLC7A11 抑制剂咪唑酮 Erastin (IKE) 组合可增强对肿瘤生长的抑制。在人乳腺肿瘤组织中，SLC7A11水平分别与KCTD10或USP18呈负相关或正相关。总的来说，我们的研究定义了 SLC7A11 和铁死亡如何受 CRL3KCTD10/E3-USP18/DUB 轴协调调节，并为药物组合增强抗癌功​​效提供了合理的理论依据。

SLC7A11 is a cystine transporter and ferroptosis inhibitor. How the stability of SLC7A11 is coordinately regulated in response to environmental cystine by which E3 ligase and deubiquitylase (DUB) remains elusive. Here, we report that neddylation inhibitor MLN4924 increases cystine uptake by causing SLC7A11 accumulation, via inactivating Cullin-RING ligase-3 (CRL-3). We identified KCTD10 as the substrate-recognizing subunit of CRL-3 for SLC7A11 ubiquitylation, and USP18 as SLC7A11 deubiquitylase. Upon cystine deprivation, the protein levels of KCTD10 or USP18 are decreased or increased, respectively, contributing to SLC7A11 accumulation. By destabilizing or stabilizing SLC7A11, KCTD10, or USP18 inversely regulates the cystine uptake and ferroptosis. Biologically, MLN4924 combination with SLC7A11 inhibitor Imidazole Ketone Erastin (IKE) enhanced suppression of tumor growth. In human breast tumor tissues, SLC7A11 levels were negatively or positively correlated with KCTD10 or USP18, respectively. Collectively, our study defines how SLC7A11 and ferroptosis is coordinately regulated by the CRL3KCTD10/E3-USP18/DUB axis, and provides a sound rationale of drug combination to enhance anticancer efficacy.