Journal of Energy Bioscience 2025, Vol.16, No.5, 227-237 http://bioscipublisher.com/index.php/jeb 231 glyceraldehyde 3-phosphate dehydrogenase (GAPD), are also subject to oxidative modification or allosteric regulation. These changes allow more carbon to enter PPP (Hurbain et al., 2022). The collaboration of multiple enzymes enables cells to flexibly adjust PPP activity as needed (Christodoulou et al., 2018; Hurbain et al., 2022). 5.2 Hormonal regulation Hormones can indirectly affect PPP by regulating gene expression and enzyme activity. Insulin can upregulate the expression of PPP-related enzymes such as G6PD, thereby promoting anabolic and antioxidant responses. This effect is particularly evident in the liver and adipose tissue. Glucocorticoids and growth hormones can also enhance PPP activity through transcriptional regulation to meet the requirements of cells for NADPH and synthetic substrates during growth, differentiation or stress states (Wu et al., 2018; TeSlaa et al., 2023). Furthermore, some transcription factors (such as YY1) can directly activate the transcription of the G6PD gene, further increase the flux of PPP, and support cell proliferation and antioxidant defense (Wu et al., 2018). 5.3 Cellular stress responses Under stressful conditions such as oxidative stress, PPP will be rapidly activated as the first line of defense. Oxidative stress will accelerate the consumption of NADPH, thereby relieving the inhibition of G6PD and promoting the entry of glucose into PPP in order to replenish NADPH rapidly (Kuehne et al., 2015; Christodoulou et al., 2018; Hurbain et al., 2022). Meanwhile, intermediate products such as 6-phosphogluconic acid (6PG) can also inhibit glycolysis, further promoting carbon flow into PPP (Dubreuil et al., 2020). Genomic and metabolomics studies have shown that the dynamic regulation of PPP not only affects the generation of NADPH, but also coordinates the overall antioxidant response by regulating the antioxidant system (such as glutathione, catalase, etc.) and gene expression (Kruger et al., 2011; Hambardikar et al., 2022). Furthermore, PPP has a certain reserve capacity and can rapidly increase NADPH supply during acute stress, thereby enhancing the viability of cells. 6 PPP in Physiology and Pathophysiology 6.1 Normal physiology The pentose phosphate pathway (PPP) plays many important roles under normal circumstances. It can generate ribose 5-phosphate, providing raw materials for the synthesis of nucleotides, thereby supporting cell division and the replication of genetic material. PPP also generates NADPH. These molecules not only provide reducing power for the synthesis of fatty acids and cholesterol, but also help maintain the REDOX balance of cells and enhance antioxidant capacity. NADPH participates in the glutathione and thioredoxin systems, eliminating reactive oxygen species (ROS) and reactive nitrogen species (RNS), and protecting cells from oxidative damage. In addition, PPP can also support the functions of immune cells. For instance, neutrophils and macrophages utilize NADPH oxidase to produce ROS, which is used to kill pathogens (TeSlaa et al., 2023). These functions are important for cell growth, differentiation, immune defense and overall metabolic balance (Ge et al., 2020). 6.2 Disease contexts In many diseases, the functions and regulation of PPP will undergo significant changes. In terms of genetic defects, glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common problem. This defect can reduce the antioxidant capacity of red blood cells, making them prone to hemolytic anemia. If the defect is severe, the oxidative burst of white blood cells will also be affected, resulting in a higher risk of infection (TeSlaa et al., 2023). In tumors, cancer cells often upregulate PPP to meet the demands of rapid proliferation for nucleotides and NADPH. In this way, they can not only support synthesis but also enhance antioxidant capacity to resist metabolic stress. Therefore, inhibiting PPP is regarded as a potential direction for anti-cancer treatment (Ge et al., 2020). In diabetes and metabolic syndrome, abnormal regulation of PPP can affect the REDOX balance and synthetic processes of cells. This is related to insulin resistance, chronic inflammation and the occurrence of complications (Ge et al., 2020).
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