靶向NOTCH1-KEAP1轴通过调节NRF2的稳定延缓慢性肝损伤和肝癌进展。

IF 12.8 1区 医学 Q1 ONCOLOGY
Chunxiao Chang, Meng Wang, Jia Li, Sihao Qi, Xiaojuan Yu, Jun Xu, Shengbin Shi
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引用次数: 0

摘要

背景:慢性肝损伤是肝细胞癌(HCC)、脂肪性肝炎(NASH)、乙型和丙型病毒性肝炎(HBV、HCV)等疾病的关键因素。了解其分子机制对有效治疗至关重要。NOTCH1信号通路虽然尚未完全了解,但与肝损伤有关,可能是潜在的治疗靶点。方法:通过一系列生化试验、分子分析方法和靶向信号通路试验等,对临床HCC、HBV、HCV和NASH样本及其他体外和体内表现进行验证,确认NOTCH1及其下游靶点的作用。结果:本研究首次证实了脂肪性肝炎、HCC、HBV、HCV患者和小鼠模型肝细胞中NOTCH1的异常升高。至关重要的是,我们发现肝细胞特异性NOTCH1敲除可减少慢性肝脏炎症和HCC小鼠模型中的肝细胞损伤,而腺相关病毒血清型8 (AAV8)介导的NOTCH1在肝细胞中过表达会加剧肝损伤相关的表型设置。在机制上,我们发现NOTCH1在控制肝细胞铁凋亡和氧化损伤中具有新的作用。它与kelch样ech相关蛋白1 (KEAP1)相互作用,并通过其胞内结构域(NICD1)直接募集。此外,NOTCH1募集的KEAP1阻碍了KEAP1- nfe2与BZIP转录因子2 (Nrf2)的结合稳定性,促进了KEAP1与Nrf2的分离,从而降低了Nrf2的稳定性,阻碍了Nrf2泛素化相关的蛋白酶体降解。至关重要的是,我们还发现NOTCH1的ANK结构域对于NICD1-KEAP1接触和信号激活至关重要。具有ANK结构域突变体的NOTCH1 (ΔANK)无法与KEAP1连接并增加其表达,这强调了ANK结构域在KEAP1- nrf2信号传导中的重要性。通过逆转KEAP1的下调和NRF2的过表达,ANK功能与铁下垂和ROS积累有关。靶向ANK结构域可能减缓HCC和肝损伤的进程。结论:这些研究结果支持靶向NOTCH1-KEAP1-NRF2轴作为一种可能的慢性肝损伤治疗方法,这些发现表明NOTCH1-KEAP1是一种加速肝损伤进展的NRF2抑制因子。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Targeting NOTCH1-KEAP1 axis retards chronic liver injury and liver cancer progression via regulating stabilization of NRF2.

Background: Chronic liver injury is a key factor in diseases like hepatocellular carcinoma (HCC), steatohepatitis (NASH), and viral hepatitis type B and C (HBV, HCV). Understanding its molecular mechanisms is crucial for effective treatment. The NOTCH1 signaling pathway, though not fully understood, is implicated in liver injury and may be a potential therapeutic target.

Methods: Clinical HCC, HBV, HCV and NASH samples and additional in vitro and in vivo performances were subjected to confirm the role of NOTCH1 and its downstream targets via a series of biochemical assays, molecular analysis approaches and targeted signaling pathway assay, etc. RESULTS: The present study first verified the abnormal elevation of NOTCH1 in hepatocytes from patients with steatohepatitis, HCC, HBV, HCV, and mouse models. Crucially, we discovered that hepatocyte-specific NOTCH1 knockout reduces hepatocellular damage in chronic liver inflammation and HCC mouse models, whereas adeno-associated virus serotype 8 (AAV8)-mediated NOTCH1 overexpression in hepatocytes exacerbates liver injury-related phenotype on-setting. Mechanistically, we showed that NOTCH1 has a new role in controlling ferroptosis and oxidative damage in hepatocytes. It interacts with Kelch-like ECH-associated protein 1 (KEAP1) and is directly recruited through its intracellular domain (NICD1). Additionally, the KEAP1 recruited by NOTCH1 impeded the binding stability of KEAP1-NFE2 like BZIP transcription factor 2 (Nrf2), promote the separation of KEAP1 and Nrf2, thereby reducing the stability of Nrf2 and hindering the ubiquitination-related proteasome degradation of Nrf2. Crucially, we also discovered that NOTCH1's ANK domain is essential for NICD1-KEAP1 contacts and signaling activation. The inability of NOTCH1 with ANK domain mutants (ΔANK) to connect with KEAP1 and increase its expression emphasizes the importance of the ANK domain in KEAP1-NRF2 signaling. By reversing the downregulation of KEAP1 and the overexpression of NRF2, ANK function is linked to ferroptosis and ROS buildup. ANK domain targeting may slow the course of HCC and liver damage.

Conclusions: Targeting the NOTCH1-KEAP1-NRF2 axis as a possible chronic hepatic injury therapy is supported by these findings, which identify NOTCH1-KEAP1 as an NRF2 suppressor that accelerates the progression of liver injury.

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来源期刊
CiteScore
18.20
自引率
1.80%
发文量
333
审稿时长
1 months
期刊介绍: The Journal of Experimental & Clinical Cancer Research is an esteemed peer-reviewed publication that focuses on cancer research, encompassing everything from fundamental discoveries to practical applications. We welcome submissions that showcase groundbreaking advancements in the field of cancer research, especially those that bridge the gap between laboratory findings and clinical implementation. Our goal is to foster a deeper understanding of cancer, improve prevention and detection strategies, facilitate accurate diagnosis, and enhance treatment options. We are particularly interested in manuscripts that shed light on the mechanisms behind the development and progression of cancer, including metastasis. Additionally, we encourage submissions that explore molecular alterations or biomarkers that can help predict the efficacy of different treatments or identify drug resistance. Translational research related to targeted therapies, personalized medicine, tumor immunotherapy, and innovative approaches applicable to clinical investigations are also of great interest to us. We provide a platform for the dissemination of large-scale molecular characterizations of human tumors and encourage researchers to share their insights, discoveries, and methodologies with the wider scientific community. By publishing high-quality research articles, reviews, and commentaries, the Journal of Experimental & Clinical Cancer Research strives to contribute to the continuous improvement of cancer care and make a meaningful impact on patients' lives.
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