High glucose uptake by cancer cells is one of the most widely recognized features of tumor metabolism and provides an important biological basis for positron emission tomography/computed tomography (PET/CT) imaging. Although this phenotype is commonly attributed to the energetic and biosynthetic demands of rapid proliferation, glucose-derived carbon is also distributed among multiple downstream pathways. A research team led by Prof. Ying Xu at the SUSTech Homeostatic Medicine Institute, School of Medicine, Southern University of Science and Technology, China, in collaboration with Prof. Ye Zhang’s team at The First Hospital of China Medical University, therefore performed a systems-level analysis of glucose allocation across 19 cancer types using transcriptomic data from The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) project. The researchers reconstructed a glucose-centered metabolic network covering eight major destinations and integrated tumor-specific expression, estimated catalytic efficiency parameters (), and stoichiometric constraints in a two-step flux-balance and quadratic-programming framework. Across the 19 cancer types, de novo nucleotide synthesis received the largest mean proportion of glucose-derived flux (28.27%), followed by lactate production (26.87%) and lipid synthesis (16.20%); together, these three pathways accounted for approximately 71% of the model-allocated glucose flux, indicating that tumor glucose avidity cannot be equated solely with increased lactate metabolism.
Building on the team’s previous studies of cytosolic Fenton reactions in cancer cells, the authors further propose a testable interpretation in which Fenton-reaction-associated intracellular alkaline stress may favor proton-producing glucose metabolism and thereby contribute to intracellular pH homeostasis; the conceptual framework is summarized in Figure 1. According to the stoichiometric model, nucleotide synthesis contributed an average of 25.81% of the estimated total proton production across the eight downstream glucose pathways, followed by lactate metabolism at 23.69% and ganglioside/sialic acid-related metabolism at 23.26%. Expression-based regression models showed substantial explanatory power between the integrated signal of the eight acidifying metabolic programs and the Fenton-reaction-related signal (R² = 0.844–0.978 across cancer types). Structural causal analyses in breast invasive carcinoma and colon adenocarcinoma yielded adjusted average treatment effects of 0.541 and 0.312, respectively, with permutation p < 0.0001, supporting a possible link between nucleotide-synthesis activity and proliferative intensity under the model assumptions. Cell-based experiments in HGC27, AGS, LM3, and Huh7 cancer cells and the corresponding non-malignant GES-1 and THLE-2 cells further showed greater cancer-cell sensitivity to glucose restriction after induction of Fenton-reaction-associated alkaline stress. Together, these findings provide a quantitative systems biology framework for examining whether homeostatic stress contributes to cancer-associated glucose dependence.