nnos介导的TCOF1的s -亚硝基化调节KRAS蛋白抑制肝母细胞瘤的进展。

IF 11.9 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Redox Biology Pub Date : 2025-09-20 DOI:10.1016/j.redox.2025.103870

Meng Wang, Yupeng Wang, Yue Qian, Ziyan Luo, Siqi Dong, Zhuoyan Li, Lingling Wu, Fang Yu, Zihua Lin, Lin Qiu, Hua Jiang, Linna Yu

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引用次数: 0

摘要

神经元型一氧化氮合酶（nNOS）在肿瘤发生中起双重作用，但其在肝母细胞瘤（HB）中的功能尚不清楚。30例临床HB样本分析显示nNOS显著下调，与肿瘤恶性相关。在体外和体内，过表达nNOS抑制HB细胞增殖和肿瘤生长。多组学分析发现MAPK通路是一个关键靶点，KRAS蛋白水平显著降低。在机制上，nNOS诱导TCOF1在半胱氨酸644处的s -亚硝基化，破坏TCOF1与KRAS的相互作用，从而加速KRAS蛋白的降解。这些发现证实了nNOS-TCOF1-KRAS轴是HB进展的关键调节因子，并提出了一种新的基于no的kras驱动型癌症治疗策略。

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nNOS-mediated S-nitrosylation of TCOF1 regulates KRAS proteostasis to suppress hepatoblastoma progression.

Neuronal nitric oxide synthase (nNOS) plays dual roles in tumorigenesis, but its function in hepatoblastoma (HB) remains unclear. Analysis of 30 clinical HB samples reveals significant nNOS downregulation, correlating with tumor malignancy. Overexpression of nNOS inhibits HB cell proliferation and tumor growth in vitro and in vivo. Multi-omics analysis identifies the MAPK pathway as a key target, with KRAS protein levels most prominently reduced. Mechanistically, nNOS induces S-nitrosylation of TCOF1 at cysteine 644, disrupting TCOF1-KRAS interaction and thereby accelerating KRAS protein degradation. These findings establish the nNOS-TCOF1-KRAS axis as a critical regulator of HB progression and propose a novel NO-based therapeutic strategy for KRAS-driven cancers.

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来源期刊

Redox Biology BIOCHEMISTRY & MOLECULAR BIOLOGY-

CiteScore

19.90

自引率

3.50%

发文量

318

审稿时长

25 days

期刊介绍： Redox Biology is the official journal of the Society for Redox Biology and Medicine and the Society for Free Radical Research-Europe. It is also affiliated with the International Society for Free Radical Research (SFRRI). This journal serves as a platform for publishing pioneering research, innovative methods, and comprehensive review articles in the field of redox biology, encompassing both health and disease. Redox Biology welcomes various forms of contributions, including research articles (short or full communications), methods, mini-reviews, and commentaries. Through its diverse range of published content, Redox Biology aims to foster advancements and insights in the understanding of redox biology and its implications.