Inositol hexaphosphate (IP6), a natural polyphosphorylated carbohydrate widely present in grains, legumes, and mammalian cells, has been increasingly recognized as a key regulator of cellular metabolism. This review examines how IP6 modulates metabolic reprogramming and plasticity in stem cells and disease states and discusses the implications of these mechanisms for translational medicine. IP6 influences central metabolic circuits, including glycolysis, mitochondrial oxidative phosphorylation, and redox balance. In stem cells, IP6 modulates energy utilization, enhances antioxidant defenses, and stabilizes pluripotency networks, thereby helping maintain self-renewal and delay premature differentiation. In pathological settings, such as cancer, IP6 acts as a metabolic checkpoint by attenuating aerobic glycolysis, modulating the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mechanistic target of rapamycin (mTOR) signaling pathway, and restoring mitochondrial integrity, which leads to growth arrest and apoptosis. These cancer-associated metabolic effects provide a framework for interpreting the IP6-mediated regulation of metabolic thresholds in stem and progenitor cells. Emerging evidence further suggests that IP6 can influence epigenetic landscapes through metabolite-dependent chromatin remodeling, thereby establishing a link between metabolic state and the transcriptional regulation of stemness and lineage commitment. In summary, IP6 is a versatile metabolic rheostat that preserves stem cell function while counteracting maladaptive metabolic reprogramming in disease states. Its pleiotropic effects are also implicated in neurodegeneration, hearing loss, and metabolic syndromes. Future studies should focus on defining IP6-regulated metabolic checkpoints, identifying direct molecular targets, and addressing pharmacokinetic and delivery challenges to help translate IP6-based strategies into regenerative and disease-modifying applications.
Lin et al. (Fri,) studied this question.