The PI3K-AKT signaling network plays a crucial role in cancer by disconnecting cell growth, survival, and metabolism from exogenous growth stimuli. This network regulates cellular metabolism through direct control of metabolic enzymes and transcription factors that influence key metabolic pathways. Aberrant activation of the PI3K-AKT pathway leads to dysregulation of these metabolic control points, promoting aerobic glycolysis, de novo lipid and nucleotide synthesis, and anabolic processes. The network also modulates redox homeostasis by influencing NADPH production and antioxidant responses. Understanding the molecular mechanisms underlying these metabolic changes can inform therapeutic strategies, particularly targeting metabolic enzymes and pathways. Clinical perspectives highlight the challenges and potential of PI3K-AKT inhibitors, including hyperglycemia and resistance, and the need for combination therapies and patient stratification. Future research aims to refine the molecular map of metabolic dependencies and vulnerabilities in cancer, offering new therapeutic opportunities.The PI3K-AKT signaling network plays a crucial role in cancer by disconnecting cell growth, survival, and metabolism from exogenous growth stimuli. This network regulates cellular metabolism through direct control of metabolic enzymes and transcription factors that influence key metabolic pathways. Aberrant activation of the PI3K-AKT pathway leads to dysregulation of these metabolic control points, promoting aerobic glycolysis, de novo lipid and nucleotide synthesis, and anabolic processes. The network also modulates redox homeostasis by influencing NADPH production and antioxidant responses. Understanding the molecular mechanisms underlying these metabolic changes can inform therapeutic strategies, particularly targeting metabolic enzymes and pathways. Clinical perspectives highlight the challenges and potential of PI3K-AKT inhibitors, including hyperglycemia and resistance, and the need for combination therapies and patient stratification. Future research aims to refine the molecular map of metabolic dependencies and vulnerabilities in cancer, offering new therapeutic opportunities.