MUC1通过src介导的FSP1去泛素化和肉豆蔻酰化驱动ICC的铁凋亡抗性。

IF 6.8 1区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Clinical and Translational Medicine Pub Date : 2025-10-09 DOI:10.1002/ctm2.70495

Yuqiao Zhao, Shifeng Yang, Lei Huang, Xuyun Liu, Qixiang Han, Qichao Niu, Siyi Li, Chuanlie Zhou, Boshi Sun, Yanmei Yang, Xinyu Zhang

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引用次数: 0

摘要

背景：肝内胆管癌（ICC）预后差，治疗选择有限。上睑下垂是一种很有前景的治疗策略，但耐药性机制仍然知之甚少。本研究探讨了粘蛋白1 （MUC1）在ICC中调节铁下垂敏感性的作用。方法：对GEO和TCGA数据集进行生物信息学分析，确定ICC中铁中毒的相关因素。MUC1在ICC细胞系和临床标本中均有表达。通过rsl3诱导的细胞死亡试验、脂质过氧化测定和铁检测来评估铁下垂敏感性。机制研究采用免疫沉淀-质谱，共免疫沉淀，激酶测定和去泛素化测定。采用皮下肿瘤模型评价体内疗效。结果：MUC1在ICC中被鉴定为关键的铁下垂抑制因子。MUC1过表达通过抑制脂质过氧化和减少亚铁积累而赋予RSL3抗性，独立于gpx4 -谷胱甘肽途径。MUC1募集Src激酶，其磷酸化去泛素化酶泛素特异性蛋白酶10 （USP10）在酪氨酸359和364位点，增强铁沉抑制蛋白1 （FSP1）在赖氨酸246位点的去泛素化，并稳定FSP1蛋白。同时，Src在酪氨酸41位点磷酸化n -肉豆蔻酰基转移酶1 (NMT1)，通过肉豆蔻酰基化增强FSP1膜定位。这一双重机制增强了FSP1-辅酶Q10 （CoQ10）抗氧化系统。MUC1敲低可显著增强小鼠体外对铁的敏感性，抑制体内肿瘤生长。结论：MUC1通过Src-USP10/NMT1-FSP1轴调控ICC对铁下沉的抵抗。针对这一信号级联代表了克服ICC铁下垂耐药性的潜在治疗策略。MUC1通过src介导的翻译后修饰抑制ICC中的铁下垂。Src磷酸化USP10通过去除k48连接的多泛素来稳定FSP1。Src激活NMT1，增强FSP1肉豆肉酰化和膜定位。

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MUC1 drives ferroptosis resistance in ICC via Src-mediated FSP1 deubiquitination and myristoylation

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MUC1 drives ferroptosis resistance in ICC via Src-mediated FSP1 deubiquitination and myristoylation

Background

Intrahepatic cholangiocarcinoma (ICC) exhibits poor prognosis and limited therapeutic options. Ferroptosis represents a promising therapeutic strategy, yet resistance mechanisms remain poorly understood. This study investigated the role of mucin 1 (MUC1) in regulating ferroptosis sensitivity in ICC.

Methods

Bioinformatic analyses of GEO and TCGA datasets identified ferroptosis-related factors in ICC. MUC1 expression was validated in ICC cell lines and clinical specimens. Ferroptosis sensitivity was assessed through RSL3-induced cell death assays, lipid peroxidation measurements, and iron detection. Mechanistic studies employed immunoprecipitation-mass spectrometry, co-immunoprecipitation, kinase assays, and deubiquitination assays. In vivo efficacy was evaluated using subcutaneous tumor models.

Results

MUC1 was identified as a critical ferroptosis suppressor in ICC. MUC1 overexpression conferred RSL3 resistance by inhibiting lipid peroxidation and reducing ferrous iron accumulation, independent of the GPX4-glutathione pathway. Mechanistically, MUC1 recruited Src kinase, which phosphorylated deubiquitinating enzyme ubiquitin-specific protease 10 (USP10) at tyrosines 359 and 364, enhancing ferroptosis suppressor protein 1 (FSP1) deubiquitination at lysine 246 and stabilizing FSP1 protein. Concurrently, Src phosphorylated N-myristoyltransferase 1 (NMT1) at tyrosine 41, augmenting FSP1 membrane localization through myristoylation. This dual mechanism potentiated the FSP1- coenzyme Q10 (CoQ10) antioxidant system. MUC1 knockdown significantly enhanced ferroptotic sensitivity in vitro and suppressed tumor growth in vivo.

Conclusions

MUC1 orchestrates ferroptosis resistance in ICC through the Src-USP10/NMT1-FSP1 axis. Targeting this signaling cascade represents a potential therapeutic strategy for overcoming ferroptosis resistance in ICC.

Key points

MUC1 suppresses ferroptosis in ICC via Src-mediated post-translational modifications.
Src phosphorylation of USP10 stabilizes FSP1 by removing K48-linked polyubiquitin.
Src activates NMT1 to enhance FSP1 myristoylation and membrane localization.

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来源期刊

Clinical and Translational Medicine Multiple-

CiteScore

15.90

自引率

1.90%

发文量

450

审稿时长

4 weeks

期刊介绍： Clinical and Translational Medicine (CTM) is an international, peer-reviewed, open-access journal dedicated to accelerating the translation of preclinical research into clinical applications and fostering communication between basic and clinical scientists. It highlights the clinical potential and application of various fields including biotechnologies, biomaterials, bioengineering, biomarkers, molecular medicine, omics science, bioinformatics, immunology, molecular imaging, drug discovery, regulation, and health policy. With a focus on the bench-to-bedside approach, CTM prioritizes studies and clinical observations that generate hypotheses relevant to patients and diseases, guiding investigations in cellular and molecular medicine. The journal encourages submissions from clinicians, researchers, policymakers, and industry professionals.