Pan Sicen, Zhuang Mengyan, Wang Xiangdong, Zhang Qinqin, He Ting, Li Ying, Jiao Jian, Zhang Luo
Department of Otolaryngology Head and Neck Surgery, Beijing TongRen Hospital, Capital Medical University, Beijing, China.
Beijing Laboratory of Allergic Diseases, Beijing Municipal Education Commission, Beijing Key Laboratory of Nasal Diseases, Key Laboratory of Otolaryngology Head and Neck Surgery, Beijing Institute of Otolaryngology, Ministry of Education, Capital Medical University, Beijing, China.
Clin Transl Allergy. 2025 Apr;15(4):e70048. doi: 10.1002/clt2.70048.
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.
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.
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.
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.
缺氧是慢性鼻-鼻窦炎伴鼻息肉（CRSwNP）中普遍存在的病理过程，会引发一系列病理事件，包括上皮-间质转化（EMT）。然而，缺氧诱导EMT的机制仍不清楚。本研究旨在阐明CRSwNP中缺氧条件下驱动EMT的机制。
对缺氧处理的人鼻上皮细胞（HNECs）进行转录组和蛋白质组分析，以确定关键分子和通路。评估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，将培养的HNECs暴露于缺氧和乳酸环境中，或过表达PDK1，以评估EMT标志物的变化。
缺氧激活了HNECs中与糖酵解相关的通路，PDK1和LDHA被确定为显著上调的糖酵解相关酶。鼻组织中PDK1和LDHA的表达与HIF-1α和EMT标志物密切相关。缺氧导致HNECs中PDK1和LDHA表达增加、乳酸生成增加以及EMT发生。PDK1过表达或乳酸刺激也引发EMT，而PDK1抑制则减弱了HNECs中缺氧诱导的EMT。
本研究首次揭示缺氧诱导的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。
