NANS suppresses NF-κB signaling to promote ferroptosis by perturbing iron homeostasis.

IF 7.5 1区生物学 Q1 CELL BIOLOGY

Cell reports Pub Date : 2025-05-09 DOI:10.1016/j.celrep.2025.115701

Ziyang Wang, Yuqin Di, Lvlan Ye, Wenzheng Fang, Xiangqiong Wen, Xiang Zhang, Jiale Qin, Youpeng Wang, Kunhua Hu, Zhenxin Zhu, Weiling He, Ying Chen

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引用次数: 0

Abstract

Metastatic colorectal cancer (CRC) cells endure survival challenges, including treatment-induced ferroptosis. While adaptation to ferroptosis stress facilitates metastasis, reciprocal regulatory mechanisms remain unclear. Here, a CRISPR-Cas9 screen identifies N-acetylneuraminate synthase (NANS) as a ferroptosis promoter in CRC, regardless of its metabolic function. NANS expression is downregulated and correlates with poor prognosis in patients with CRC. Under ferroptotic stress, cyclin-dependent kinase 1 (CDK1) phosphorylates NANS at serine 275 (S275), triggering its dissociation from TAK1. Phosphorylated NANS is ubiquitinated by UBE2N at K246, leading to degradation, which activates TAK1-NF-κB signaling and upregulates the ferroptosis inhibitor FTH1, enabling metastasis via ferroptosis resistance. NANS pS275 levels are associated with tumor aggressiveness and clinical outcomes in patients with CRC. These findings indicate that NANS suppresses CRC metastasis by enhancing ferroptosis susceptibility, while CDK1-mediated phosphorylation at S275 drives adaptive resistance. Targeting this phosphorylation axis may improve ferroptosis-inducing therapies to restrict metastatic progression in CRC.

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NANS通过干扰铁稳态抑制NF-κB信号，促进铁凋亡。

转移性结直肠癌（CRC）细胞面临生存挑战，包括治疗诱导的铁下垂。虽然对铁下垂应激的适应促进了转移，但相互调节机制尚不清楚。在这里，CRISPR-Cas9筛选鉴定了n -乙酰神经氨酸合酶（NANS）在CRC中作为铁凋亡启动子，而不管其代谢功能如何。在结直肠癌患者中，NANS表达下调并与预后不良相关。在紧铁胁迫下，细胞周期蛋白依赖性激酶1 （CDK1）磷酸化NANS的丝氨酸275 (S275)，触发其与TAK1分离。磷酸化的NANS在K246位点被UBE2N泛素化，导致降解，激活TAK1-NF-κB信号并上调铁亡抑制剂FTH1，从而通过铁亡抗性实现转移。NANS pS275水平与结直肠癌患者的肿瘤侵袭性和临床结果相关。这些发现表明，NANS通过增强铁凋亡易感性来抑制结直肠癌转移，而cdk1介导的S275磷酸化驱动适应性耐药。靶向这个磷酸化轴可能会改善诱导铁凋亡的治疗方法，以限制结直肠癌的转移进展。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cell reports CELL BIOLOGY-

CiteScore

13.80

自引率

1.10%

发文量

1305

审稿时长

77 days

期刊介绍： Cell Reports publishes high-quality research across the life sciences and focuses on new biological insight as its primary criterion for publication. The journal offers three primary article types: Reports, which are shorter single-point articles, research articles, which are longer and provide deeper mechanistic insights, and resources, which highlight significant technical advances or major informational datasets that contribute to biological advances. Reviews covering recent literature in emerging and active fields are also accepted. The Cell Reports Portfolio includes gold open-access journals that cover life, medical, and physical sciences, and its mission is to make cutting-edge research and methodologies available to a wide readership. The journal's professional in-house editors work closely with authors, reviewers, and the scientific advisory board, which consists of current and future leaders in their respective fields. The advisory board guides the scope, content, and quality of the journal, but editorial decisions are independently made by the in-house scientific editors of Cell Reports.