Tian Zhen, Zheng Hongyan, Fan Yan, Li Boyu, Huang Zhenli, Wang Meijia, Zhang Jixian, Zhao Jianping, Wang Shanshan, Xie Jungang
Department of Respiratory and Critical Care Medicine, National Clinical Research Center of Respiratory Disease, Key Laboratory of Pulmonary Diseases of Health Ministry, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
Department of Respiratory and Critical Care Medicine, Hubei Province Integrated Traditional Chinese and Western Medicine Hospital, Wuhan 430015, China.
Cells. 2025 Jul 1;14(13):1004. doi: 10.3390/cells14131004.
Hexokinase catalyzes the first rate-limiting step glycolysis. However, the roles of hexokinase 2 (HK2) in asthma remain incompletely understood. This study aimed to investigate metabolic alterations in asthma, focusing on the expression, function and regulation of HK2. In this study, non-targeted metabolomics analysis of 20 asthma patients and 15 healthy controls identified metabolic alterations in asthma, particularly in the glycolytic pathways. Consistently, HK2 expression was elevated in both asthma individuals and mice with allergic airway inflammation. Airway epithelium-specific HK2 knockdown and pharmacological inhibition with 2-deoxy-D-glucose (2-DG) significantly attenuated airway inflammation and hyperresponsiveness in mice induced by ovalbumin/ lipopolysaccharide. Mechanistic analyses demonstrated that HK2 regulates epithelial apoptosis and inflammation via interaction with peptidylprolyl isomerase F (PPIF), independent of voltage-dependent anion channel 1 (VDAC1). Asthma is associated with metabolic reprogramming, characterized by alterations in lipid and glucose metabolism. These findings establish HK2 plays a crucial role in asthma pathogenesis by promoting airway epithelial apoptosis and inflammation in asthma, suggesting its potential as a therapeutic target.
己糖激酶催化糖酵解的第一个限速步骤。然而，己糖激酶2（HK2）在哮喘中的作用仍未完全明确。本研究旨在探讨哮喘中的代谢改变，重点关注HK2的表达、功能及调控。在本研究中，对20例哮喘患者和15名健康对照进行非靶向代谢组学分析，确定了哮喘中的代谢改变，尤其是糖酵解途径中的改变。同样，在哮喘患者和过敏性气道炎症小鼠中，HK2表达均升高。气道上皮特异性HK2基因敲低以及用2-脱氧-D-葡萄糖（2-DG）进行药物抑制，可显著减轻卵清蛋白/脂多糖诱导的小鼠气道炎症和高反应性。机制分析表明，HK2通过与肽基脯氨酰异构酶F（PPIF）相互作用调节上皮细胞凋亡和炎症，独立于电压依赖性阴离子通道1（VDAC1）。哮喘与代谢重编程相关，其特征为脂质和葡萄糖代谢改变。这些发现表明HK2通过促进哮喘气道上皮细胞凋亡和炎症在哮喘发病机制中起关键作用，提示其作为治疗靶点的潜力。
