The PI3K-AKT pathway is the most commonly activated signaling pathway in human cancers. Under normal conditions, it regulates key metabolic processes, including glucose metabolism, biosynthesis of macromolecules, and redox balance. In cancer cells, oncogenic activation of this pathway reprograms cellular metabolism by enhancing nutrient transporters and metabolic enzymes, supporting the anabolic demands of aberrantly growing cells. The PI3K-AKT pathway is activated downstream of receptor tyrosine kinases, cytokine receptors, integrins, and G protein-coupled receptors, playing a central role in promoting cell survival and growth. Class Ia PI3K exists as heterodimers of a catalytic subunit (p110α, β, or δ) associated with a regulatory subunit (p85α or p85β), while class Ib is comprised of the catalytic subunit p110γ associated with the regulatory subunit p101. Activation of PI3K at the plasma membrane stimulates phosphorylation of its phospholipid substrate phosphatidylinositol 4,5-bisphosphate (PIP2) to produce the second messenger phosphatidylinositol 3,4,5-trisphosphate (PIP3). PI3K signaling is attenuated by phosphatase and tensin homolog (PTEN), which dephosphorylates PIP3 to regenerate PIP2. PIP3 accumulation at the plasma membrane creates docking sites to recruit downstream effector proteins that contain a subclass of pleckstrin homology (PH) domain that specifically engage this lipid species. One such protein is the serine-threonine kinase AKT, which upon PIP3 binding is phosphorylated by phosphoinositide-dependent protein kinase 1 (PDK1) at T308 and by mechanistic target of rapamycin (mTOR) complex 2 (mTORC2) at S473, further increasing the activity of AKT. AKT-mediated phosphorylation of downstream substrates influences a variety of cell biological functions, including cell growth, proliferation, survival, and metabolism. Genetic events leading to growth factor-independent activation of the PI3K-AKT pathway are among the most frequently occurring drivers of human cancer. Common alterations include activating mutations in PIK3CA, loss of function mutations and deletions in PTEN, amplification and activation of specific PI3K-activating RTKs, and amplification and gain-of-function missense mutations in one of the three isoforms of AKT. The PI3K-AKT pathway controls several aspects of this metabolic program, including glucose metabolism, lipid synthesis, nucleotide synthesis, and protein synthesis. AKT activation promotes aerobic glycolysis, which is characterized by increased glucose uptake and glycolytic conversion to lactate even under oxygen-rich conditions. AKT promotes glucose uptake through both GLUT1 and GLUT4The PI3K-AKT pathway is the most commonly activated signaling pathway in human cancers. Under normal conditions, it regulates key metabolic processes, including glucose metabolism, biosynthesis of macromolecules, and redox balance. In cancer cells, oncogenic activation of this pathway reprograms cellular metabolism by enhancing nutrient transporters and metabolic enzymes, supporting the anabolic demands of aberrantly growing cells. The PI3K-AKT pathway is activated downstream of receptor tyrosine kinases, cytokine receptors, integrins, and G protein-coupled receptors, playing a central role in promoting cell survival and growth. Class Ia PI3K exists as heterodimers of a catalytic subunit (p110α, β, or δ) associated with a regulatory subunit (p85α or p85β), while class Ib is comprised of the catalytic subunit p110γ associated with the regulatory subunit p101. Activation of PI3K at the plasma membrane stimulates phosphorylation of its phospholipid substrate phosphatidylinositol 4,5-bisphosphate (PIP2) to produce the second messenger phosphatidylinositol 3,4,5-trisphosphate (PIP3). PI3K signaling is attenuated by phosphatase and tensin homolog (PTEN), which dephosphorylates PIP3 to regenerate PIP2. PIP3 accumulation at the plasma membrane creates docking sites to recruit downstream effector proteins that contain a subclass of pleckstrin homology (PH) domain that specifically engage this lipid species. One such protein is the serine-threonine kinase AKT, which upon PIP3 binding is phosphorylated by phosphoinositide-dependent protein kinase 1 (PDK1) at T308 and by mechanistic target of rapamycin (mTOR) complex 2 (mTORC2) at S473, further increasing the activity of AKT. AKT-mediated phosphorylation of downstream substrates influences a variety of cell biological functions, including cell growth, proliferation, survival, and metabolism. Genetic events leading to growth factor-independent activation of the PI3K-AKT pathway are among the most frequently occurring drivers of human cancer. Common alterations include activating mutations in PIK3CA, loss of function mutations and deletions in PTEN, amplification and activation of specific PI3K-activating RTKs, and amplification and gain-of-function missense mutations in one of the three isoforms of AKT. The PI3K-AKT pathway controls several aspects of this metabolic program, including glucose metabolism, lipid synthesis, nucleotide synthesis, and protein synthesis. AKT activation promotes aerobic glycolysis, which is characterized by increased glucose uptake and glycolytic conversion to lactate even under oxygen-rich conditions. AKT promotes glucose uptake through both GLUT1 and GLUT4