Abstract
Inorganic polyphosphate (polyP) is a conserved linear polymer of orthophosphate units with emerging roles in mammalian cell biology. While extracellular platelet-derived polyP is well established as an enhancer of coagulation, inflammation, and thromboinflammation, the intracellular functions of polyP remain less clearly defined. Recent evidence suggests that intracellular polyP pools, particularly within mitochondria, may regulate bioenergetics, calcium handling, redox balance, and inflammatory readiness. However, much of this evidence is indirect, and causal relationships remain to be established. This review aims to synthesize current knowledge on intracellular polyP as a potential cell-intrinsic regulator of metabolism, inflammation, and thromboinflammatory signaling, and to highlight key mechanistic gaps and future research directions. A narrative review approach was used to integrate evidence from studies on mammalian polyP biology, mitochondrial function, immunometabolism, inflammatory signaling, thromboinflammation, and emerging single-cell and multi-omic methodologies. Particular attention was given to intracellular polyP localization, physicochemical regulation, experimental detection strategies, and causal perturbation approaches. Current evidence is consistent with the presence of dynamic intracellular polyP pools in mammalian cells, including cytosolic, granular, and mitochondrial compartments. Mitochondrial polyP has been associated with oxidative phosphorylation, ATP homeostasis, calcium buffering, mitochondrial permeability transition, reactive oxygen species production, and cellular stress tolerance. These observations support the hypothesis that intracellular polyP functions as a potential regulator of inflammatory activation thresholds rather than a classical receptor-mediated signaling molecule. In thromboinflammatory contexts, intracellular polyP may prime endothelial cells, immune cells, and platelets for exaggerated inflammatory and procoagulant responses, while extracellular polyP amplifies downstream coagulation–inflammation cascades. However, major uncertainties remain regarding mammalian polyP biosynthesis, compartment-specific regulation, chain-length-dependent effects, and single-cell heterogeneity. Intracellular polyP represents a potentially important but underexplored candidate linking metabolic dysfunction to inflammation and thrombosis. Rather than functioning solely as an extracellular procoagulant mediator, polyP may act as a cell-intrinsic rheostat that tunes mitochondrial resilience, inflammatory priming, and thromboinflammatory susceptibility—though this model remains provisional and requires causal validation. Future studies using improved detection tools, compartment-specific perturbation, and single-cell multi-omic approaches are needed to establish causal mechanisms and assess the therapeutic potential of targeting intracellular polyP biology.