Upregulated Hexokinase-2 in Airway Epithelium Regulates Apoptosis and Drives Inflammation in Asthma via peptidylprolyl isomerase F

Hexokinase catalyzes the initial rate-limiting step in glucose metabolism by transforming glucose into glucose-6-phosphate. 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. Analysis of non-targeted metabolomics revealed metabolic alterations in asthma, particularly in glycolysis pathway. HK2 expression was elevated in both asthma individuals and murine models. Airway epithelium–specific-HK2-knockdown alleviated airway inflammation and hyperresponsiveness in asthmatic murine models. Moreover, HK2 regulated epithelial apoptosis and inflammation interacting with peptidyl-prolyl cis-trans isomerase (PPIF) but not voltage-dependent anion channel 1(VDAC1). Moreover, inhibiting HK2 with 2-DG significantly alleviated airway inflammation and hyperresponsiveness. Asthma is associated with metabolic reprogramming, characterized by alterations in lipid and glucose metabolism. HK2 plays a crucial role in asthma pathogenesis by promoting airway epithelial apoptosis and inflammation via PPIF. Targeting HK2 represents a promising therapeutic strategy for asthma treatment.