Targeting Aurora kinase B regulates cholesterol metabolism and enhances chemoimmunotherapy in cholangiocarcinoma.

IF 25.8 1区医学 Q1 GASTROENTEROLOGY & HEPATOLOGY

Gut Pub Date : 2025-07-31 DOI:10.1136/gutjnl-2025-335291

Furong Liu,Wei Chen,Ze Zhang,Weifeng Zeng,Haofan Hu,Shangwu Ning,Zhibin Liao,Yachong Liu,Hongwei Zhang,Qinggang Fu,Bixiang Zhang,Xiaoping Chen,Wanguang Zhang,Zhanguo Zhang

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引用次数: 0

Abstract

BACKGROUND Cholangiocarcinoma (CCA) is a highly lethal malignant tumour with increasing incidence. Current therapies exhibit limited benefits, which urgently demand the identification of novel therapeutic targets. OBJECTIVE We aimed to identify potential therapeutic targets for CCA and broaden current therapies. DESIGN Potential therapeutic targets for CCA were identified by sgRNA library screening and validated in preclinical models. Multi-omics sequencing and various experimental approaches were performed to validate the mechanism by which Aurora kinase B (AURKB) regulates CCA progression and the immune microenvironment, supported by clinical samples from public data sets and Tongji Hospital cohorts. The translational therapy was comprehensively validated in CCA organoid, patient-derived xenograft and preclinical murine models. RESULTS AURKB was identified as a highly expressed and targetable kinase in CCA. Knockout of AURKB significantly inhibited CCA progression, reduced CD8+ T cell exhaustion and enhanced antitumour response. Mechanistically, AURKB promoted the generation of histone H3 lysine 9 tri-methylation (H3K9me3)/serine 10 phosphorylation, leading to a decrease in the enrichment of H3K9me3 at the neutral cholesterol ester hydrolase 1 (NCEH1) promoter, thereby increasing NCEH1 expression and cholesterol levels in tumours. High AURKB expression in clinical samples predicted poorer outcomes in patients with CCA undergoing neoadjuvant chemoimmunotherapy and was associated with cholesterol accumulation within tumours. AURKB inhibitor or simvastatin can suppress CCA progression and significantly enhance sensitivity to chemoimmunotherapy. CONCLUSIONS AURKB regulates cholesterol levels and immune microenvironment in tumours, highlighting that targeting AURKB or adopting cholesterol-reducing strategy holds promise for CCA treatment, especially in conjunction with first-line chemoimmunotherapy.

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靶向极光激酶B调节胆管癌的胆固醇代谢并增强化疗免疫治疗。

背景胆管癌（CCA）是一种高致死性恶性肿瘤，发病率增高。目前的治疗方法显示出有限的益处，这迫切需要确定新的治疗靶点。目的：我们旨在确定CCA的潜在治疗靶点，并拓宽目前的治疗方法。设计通过sgRNA文库筛选确定CCA的潜在治疗靶点，并在临床前模型中进行验证。在公共数据集和同济医院队列的临床样本的支持下，通过多组学测序和各种实验方法验证极光激酶B （Aurora kinase B， AURKB）调控CCA进展和免疫微环境的机制。转化疗法在CCA类器官、患者来源的异种移植物和临床前小鼠模型中得到了全面验证。结果在CCA中发现了高表达的靶向性激酶tsaurkb。敲除AURKB可显著抑制CCA进展，减少CD8+ T细胞耗竭，增强抗肿瘤反应。在机制上，AURKB促进组蛋白H3赖氨酸9三甲基化(H3K9me3)/丝氨酸10磷酸化的产生，导致H3K9me3在中性胆固醇酯水解酶1 （NCEH1）启动子处的富集减少，从而增加肿瘤中NCEH1的表达和胆固醇水平。临床样本中AURKB的高表达预示着CCA患者接受新辅助化疗免疫治疗的预后较差，并且与肿瘤内胆固醇积累有关。AURKB抑制剂或辛伐他汀可抑制CCA进展并显著提高对化学免疫治疗的敏感性。结论：AURKB调节肿瘤中的胆固醇水平和免疫微环境，强调靶向AURKB或采用降胆固醇策略有望用于CCA治疗，特别是与一线化学免疫治疗相结合。

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

Gut 医学-胃肠肝病学

CiteScore

45.70

自引率

2.40%

发文量

284

审稿时长

1.5 months

期刊介绍： Gut is a renowned international journal specializing in gastroenterology and hepatology, known for its high-quality clinical research covering the alimentary tract, liver, biliary tree, and pancreas. It offers authoritative and current coverage across all aspects of gastroenterology and hepatology, featuring articles on emerging disease mechanisms and innovative diagnostic and therapeutic approaches authored by leading experts. As the flagship journal of BMJ's gastroenterology portfolio, Gut is accompanied by two companion journals: Frontline Gastroenterology, focusing on education and practice-oriented papers, and BMJ Open Gastroenterology for open access original research.