The PI3K/AKT signaling networks in cancer glucose metabolism: mechanisms and therapeutic implications

The PI3K/AKT axis is frequently dysregulated and serves as a central regulator in cancer glucose metabolism. This review outlines the composition and activation mechanisms of the PI3K/AKT pathway, its interactions with core metabolic enzymes (hexokinase, pyruvate kinase, phosphofructokinase, aldolase, lactate dehydrogenase) and their non-canonical roles in cancer metabolism. We also dissect crosstalk between PI3K/AKT, the AMPK energy sensor, and major metabolic pathways (pentose phosphate pathway, oxidative phosphorylation, de novo lipogenesis). Further, we summarize latest advances in targeting metabolic enzymes and combined therapies, discuss challenges in targeting PI3K/AKT-mediated metabolic reprogramming, and propose future directions. Collectively, this review provides a theoretical framework for cancer metabolism mechanisms and identifies novel targets for cancer therapies.