## 4 Role of Ap4A: Functions in Normal and Cancer Cells
### Metabolic Adaption  
One of the primary ways Ap4A contributes to metabolic adaptation is by regulating cellular energy homeostasis. Ap4A interacts with various enzymes involved in ATP synthesis and degradation, ensuring that cells maintain an adequate energy supply while preventing excessive energy expenditure. This regulation is particularly important in cancer, where energy demands are elevated due to increased cell division and biosynthesis. Ap4A's involvement in managing ATP levels helps cancer cells adapt to the high-energy requirements of rapid proliferation and growth [27].  
Ap4A accumulates under stress conditions such as oxidative stress, heat shock, and DNA damage. So, indirectly, increased Ap4A may promote AMPK activation if it contributes to a stress response, elevates intracellular calcium, or causes mitochondrial dysfunction leading to ATP depletion.  
Moreover, Ap4A affects several metabolic pathways by modulating key enzymes and regulatory proteins. For instance, Ap4A can influence the activity of AMP-activated protein kinase (AMPK), a central regulator of cellular energy balance. AMPK activation, in turn, affects pathways involved in glucose uptake, fatty acid oxidation, and protein synthesis, all of which are critical for supporting cancer cell metabolism and growth [28]. Ap4A's role in modulating AMPK activity underscores its importance in maintaining energy balance and supporting the anabolic processes required for tumor expansion.  
In addition to its role in regulating apoptosis, the PI3K/AKT pathway is also critically involved in metabolic adaptation. Notably, Ap4A has been shown to influence the PI3K/AKT signaling cascade, which governs key cellular processes such as glucose metabolism, lipid synthesis, and cell growth. Although the precise molecular mechanism by which Ap4A affects PI3K/AKT signaling remains to be fully elucidated, emerging evidence suggests that Ap4A may indirectly influence this cascade by modulating upstream purinergic receptors or cellular stress responses. For instance, Ap4A interaction with purinergic receptors such as P2X7 can lead to downstream activation of PI3K, promoting AKT phosphorylation and supporting oncogenic signaling. Given that dysregulation of this pathway is a hallmark of many cancers, Ap4A's ability to modulate PI3K/AKT signaling may play a significant role in driving the metabolic reprogramming characteristic of tumor cells [29]. High Ap4A levels can promote metabolic adaptations that favour tumorigenesis, including increased glucose uptake, enhanced mitochondrial function, and altered lipid metabolism. These adaptations enable cancer cells to thrive in challenging conditions and continue proliferating despite metabolic stress.  
In the context of nutrient deprivation, Ap4A facilitates metabolic adaptation by modulating cellular responses to low glucose or other essential nutrients. During such conditions, Ap4A can influence signaling pathways related to autophagy, a process through which cells degrade and recycle their own components to maintain energy levels and remove damaged organelles. By promoting autophagy, Ap4A helps cancer cells adapt to nutrient scarcity, ensuring their survival and continued proliferation even in nutrient-limited environments [27]. This adaptation is crucial for tumor growth, especially in the nutrient-poor microenvironments often found within solid tumors. The ability of Ap4A to regulate these processes highlights its potential as a therapeutic target for disrupting the metabolic advantages of cancer cells.