Targeting PDK1: A novel approach to combat hypoxia-induced epithelial-mesenchymal transition in chronic rhinosinusitis with nasal polyps

IF 4.6 2区医学 Q2 ALLERGY

Clinical and Translational Allergy Pub Date : 2025-04-02 DOI:10.1002/clt2.70048

Sicen Pan, Mengyan Zhuang, Xiangdong Wang, Qinqin Zhang, Ting He, Ying Li, Jian Jiao, Luo Zhang

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引用次数: 0

Abstract

Background

Hypoxia is a prevalent pathological process in chronic rhinosinusitis with nasal polyps (CRSwNP), leading to a cascade of pathological events, including epithelial-mesenchymal transition (EMT). However, the mechanisms underlying hypoxia-induced EMT remain unclear. This study aims to elucidate the mechanisms driving EMT under hypoxic conditions in CRSwNP.

Methods

Transcriptome and proteome analyses of hypoxia-treated human nasal epithelial cells (HNECs) were performed to identify key molecules and pathways. The expression of hypoxia-inducible factor-1α (HIF-1α), pyruvate dehydrogenase kinase (PDK1), lactate dehydrogenase A (LDHA), and EMT markers was assessed in nasal tissues from CRSwNP patients. In vitro, cultured HNECs were exposed to hypoxia and lactate, or overexpressed PDK1, to evaluate changes in EMT markers.

Results

Hypoxia activated the glycolysis-related pathway in HNECs, with PDK1 and LDHA identified as significantly upregulated glycolysis-related enzymes. The expression of PDK1 and LDHA was closely correlated with HIF-1α and EMT markers in nasal tissues. Hypoxia induced an increase in PDK1 and LDHA expression, lactate production, and EMT occurrence in HNECs. PDK1 overexpression or lactate stimulation also triggered EMT, while PDK1 inhibition attenuated hypoxia-induced EMT in HNECs.

Conclusions

This study is the first to reveal that hypoxia-induced activation of PDK1 plays a critical role in regulating EMT by promoting lactate production, thereby providing a potential therapeutic target for CRSwNP.

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靶向PDK1：对抗缺氧诱导的慢性鼻窦炎伴鼻息肉的上皮-间质转化的新方法

缺氧是慢性鼻窦炎伴鼻息肉（CRSwNP）的一个普遍病理过程，导致一系列病理事件，包括上皮-间质转化（EMT）。然而，缺氧诱发EMT的机制尚不清楚。本研究旨在阐明CRSwNP缺氧条件下EMT的驱动机制。方法对缺氧处理的人鼻上皮细胞（HNECs）进行转录组学和蛋白质组学分析，确定关键分子和通路。检测CRSwNP患者鼻组织中缺氧诱导因子-1α (HIF-1α)、丙酮酸脱氢酶激酶（PDK1）、乳酸脱氢酶A （LDHA）和EMT标志物的表达。在体外，培养的hnec暴露于缺氧和乳酸或过表达PDK1中，以评估EMT标志物的变化。结果缺氧激活了nec的糖酵解相关途径，PDK1和LDHA被鉴定为糖酵解相关酶的显著上调。PDK1和LDHA的表达与鼻组织HIF-1α和EMT标志物密切相关。缺氧诱导HNECs中PDK1和LDHA表达增加、乳酸生成和EMT发生。PDK1过表达或乳酸刺激也会引发EMT，而PDK1抑制会减弱缺氧诱导的nec中EMT。本研究首次揭示了缺氧诱导的PDK1激活通过促进乳酸生成在调节EMT中起关键作用，从而为CRSwNP提供了一个潜在的治疗靶点。

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

Clinical and Translational Allergy Immunology and Microbiology-Immunology

CiteScore

7.50

自引率

4.50%

发文量

117

审稿时长

12 weeks

期刊介绍： Clinical and Translational Allergy, one of several journals in the portfolio of the European Academy of Allergy and Clinical Immunology, provides a platform for the dissemination of allergy research and reviews, as well as EAACI position papers, task force reports and guidelines, amongst an international scientific audience. Clinical and Translational Allergy accepts clinical and translational research in the following areas and other related topics: asthma, rhinitis, rhinosinusitis, drug hypersensitivity, allergic conjunctivitis, allergic skin diseases, atopic eczema, urticaria, angioedema, venom hypersensitivity, anaphylaxis, food allergy, immunotherapy, immune modulators and biologics, animal models of allergic disease, immune mechanisms, or any other topic related to allergic disease.