Journal of Energy Bioscience 2025, Vol.16, No.5, 227-237 http://bioscipublisher.com/index.php/jeb 232 In terms of immunity and infection, the NADPH produced by PPP can not only assist in antioxidant defense but also enable immune cells to generate ROS to kill bacteria. Those with G6PD deficiency are not only prone to hemolysis, but also more susceptible to infection due to the decline in immune cell function. 7 Case Study: PPP in Cancer Metabolism 7.1 Background The metabolism of tumor cells is often reprogrammed, which is an important characteristic of cancer. Unlike normal cells that mainly rely on mitochondrial oxidative phosphorylation, cancer cells prefer to obtain energy and synthesize necessary substances through glycolysis and the pentose phosphate pathway (PPP) even under aerobic conditions. This is known as the Warburg effect. PPP can not only provide ribo5-phosphoric acid to meet the nucleotide demand during the rapid proliferation of tumor cells, but also generate NADPH to support reductic metabolism and antioxidant defense (Jiang et al., 2014; Nagao et al., 2019; Ghanem et al., 2021; Qiao et al., 2025). 7.2 PPP upregulation In many cancers, the expression and activity of key enzymes of PPP (such as G6PD, 6PGD, TKT) will significantly increase, leading to an increase in the flux of PPP. The reasons for this upregulation include the activation of some tumor-related signaling pathways, such as PI3K/AKT, STAT3, HIF-1α, NRF2, etc. These pathways promote the transcription, translation or modification of enzymes such as G6PD, thereby increasing the supply of NADPH and nucleotides, helping tumor cells resist oxidative stress, maintain growth, and may also enhance drug resistance (Rao et al., 2015; Sarfraz et al., 2020; Cheng et al., 2020). 7.3 Illustrative example In hepatocellular carcinoma and lung adenocarcinoma, studies have found that PPP enzymes such as G6PD and 6PGD are highly expressed in tumor tissues, promoting cell proliferation, migration and anti-apoptosis (Sarfraz et al., 2020; Bai et al., 2024; Wu et al., 2024). In gastrointestinal tumors, PPP not only regulates the REDOX balance of the tumor microenvironment, but also supports continuous tumor growth and drug resistance development by providing raw materials for nucleotide and lipid synthesis (Qiao et al., 2025). In addition, some molecules such as TIGAR can promote more glucose to enter PPP, thereby increasing NADPH production, reducing ROS levels, and further protecting tumor cells (AlMaazmi et al., 2025) (Figure 2). Figure 2 The role of TIGAR protein (Adopted from AlMaazmi et al., 2025) 7.4 Therapeutic implications The high activity of PPP has brought new targets for tumor treatment. If the key enzymes of PPP (such as G6PD, 6PGD, TKT) are inhibited, it can significantly reduce the proliferation and drug resistance of tumor cells, and also
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