Dysregulation of glycolysis is a hallmark of non-small cell lung cancer (NSCLC), with hexokinases (HKs) playing a critical role in cancer metabolism. Among them, HK2 is particularly involved in tumor energy homeostasis and has emerged as a potential therapeutic target. This study explores the impact of HK2 targeting on NSCLC cell growth and metabolism through a comprehensive analysis of transcriptomic and metabolomic data. Data from The Cancer Genome Atlas (TCGA) were used to examine the correlation between the expression of different HK isoforms (HK1, HK2, HK3) and patient prognosis in NSCLC. siRNA-mediated knockdown of HK2 was performed in NCI-H1975 cells, which exhibit relatively high HK2 expression based on CCLE datasets. The effects on cell proliferation, cell cycle progression, and apoptosis were evaluated using CCK-8 assays, EdU incorporation, and flow cytometry. Integrated transcriptomic and metabolomic analyses were conducted to identify key metabolic pathways influencing cell growth and progression. Elevated expression of HK2 in NSCLC was associated with poor prognosis. Knockdown of HK2 led to a significant reduction in both HK1 and HK2 levels, resulting in decreased cell proliferation and a marked shift in the cell cycle to the G0/G1 phase. Integrated omics analyses revealed that HK2 depletion disrupted nucleotide metabolism, specifically impairing the pentose phosphate pathway (PPP), which is vital for ribonucleotide synthesis. Targeting HK2 disrupts NSCLC cell growth and cell cycle progression by modulating nucleotide metabolism under conditions of inhibited glycolysis, highlighting its potential as a therapeutic target in cancer metabolism.
Zhou et al. (Thu,) studied this question.