Pentose Phosphate Pathway Regulation in Cancer Metabolism

The pentose phosphate pathway (PPP) is a critical metabolic route branching from glucose 6-phosphate that fulfils two central roles in proliferating cells: generation of nicotinamide adenine dinucleotide phosphate (NADPH) for reductive biosynthesis and antioxidant defence, and provision of ribose-5-phosphate for nucleotide synthesis. The pathway divides into an oxidative branch, which irreversibly produces NADPH and ribulose-5-phosphate, and a non-oxidative branch, which interconverts sugar phosphates to balance biosynthetic demands or feed back into glycolysis. In cancer, dysregulated PPP flux supports anabolic growth, maintains redox homeostasis under oxidative stress and contributes to chemoresistance. Oncogenic signals—including mutations in KRAS, LKB1, androgen receptor and mTOR pathways—converge on key enzymes to fine-tune carbon allocation between glycolysis and the PPP. Emerging evidence highlights context-dependent flux control, adaptive rerouting to one-carbon metabolism and post-translational modifications of glucose-6-phosphate dehydrogenase (G6PD) as pivotal mechanisms. Therapeutic targeting of PPP regulators offers a translational avenue to disrupt tumour metabolism and enhance treatment response.

Research from Nature Portfolio

Genetically engineered lung cancer models harbouring co-occurring KRAS and LKB1 mutations demonstrate strict dependence on G6PD: deletion of G6PD markedly reduces NADPH generation, impairs redox balance and inhibits tumour growth, whereas parallel engagement of serine-driven one-carbon metabolism emerges as a compensatory NADPH source. In breast cancer, elevated Rac1 signalling activates aldolase A and ERK, selectively up‐regulating non-oxidative PPP flux to bolster nucleotide synthesis and confer multi-drug resistance; nanoparticle-mediated delivery of Rac1-targeting siRNA restores chemosensitivity in patient-derived xenografts. Under hypoxia, dynamic O-GlcNAcylation of G6PD has been shown to enhance its catalytic activity, increasing oxidative PPP throughput to supply nucleotide precursors and antioxidant capacity, thereby promoting tumour proliferation in vivo.

Pentose Phosphate Pathway Regulation in Cancer Metabolism publication trend

The graph below shows the total number of articles in pentose phosphate pathway regulation in cancer metabolism across all publications each year (not limited to Nature Index journals).

Technical terms

Pentose phosphate pathway (PPP): A metabolic network branching from glucose 6-phosphate that generates NADPH and ribose-5-phosphate through oxidative and non-oxidative reactions.

Oxidative branch: The irreversible segment of the PPP that produces NADPH and ribulose-5-phosphate from glucose 6-phosphate.

Non-oxidative branch: The reversible segment of the PPP that interconverts sugar phosphates to balance nucleotide synthesis and glycolytic intermediates.

Glucose-6-phosphate dehydrogenase (G6PD): The rate-limiting enzyme of the oxidative PPP, controlling NADPH production and redox homeostasis.

NADPH: A reducing cofactor generated by the oxidative PPP essential for anabolic reactions and detoxification of reactive oxygen species.

Reactive oxygen species (ROS): Chemically reactive molecules derived from oxygen that can damage cellular components unless neutralised by antioxidant systems.

References

1. Glucose-6-phosphate dehydrogenase maintains redox homeostasis and biosynthesis in LKB1-deficient KRAS-driven lung cancer. Nature Communications (2024).
2. Rac1 activates non-oxidative pentose phosphate pathway to induce chemoresistance of breast cancer. Nature Communications (2020).
3. O-GlcNAcylation of G6PD promotes the pentose phosphate pathway and tumor growth. Nature Communications (2015).
4. Metabolic classification suggests the GLUT1/ALDOB/G6PD axis as a therapeutic target in chemotherapy-resistant pancreatic cancer. Cell Reports Medicine (2023).
5. Disrupting G6PD-mediated Redox homeostasis enhances chemosensitivity in colorectal cancer. Oncogene (2017).
6. Regulation of the pentose phosphate pathway by an androgen receptor–mTOR-mediated mechanism and its role in prostate cancer cell growth. Oncogenesis (2014).