Inorganic phosphate beyond a mineral: Signal transduction in multi-organ pathology

Area of Science:

• Cellular Metabolism and Signalling
• Pathophysiology of Hyperphosphatemia
• Multi-organ Systemic Effects

Background:

• Inorganic phosphate (Pi) is essential but excess levels (hyperphosphatemia) induce pathological cellular signalling.
• Hyperphosphatemia drives detrimental remodelling in vascular, renal, and oncological systems.
• Eight conserved signalling pathways are implicated in Pi-induced pathology.

Purpose of the Study:

• To review and synthesize evidence on how hyperphosphatemia deregulates key signalling pathways.
• To elucidate the convergence of these pathways on shared regulatory hubs.
• To identify potential therapeutic targets for mitigating systemic phosphate toxicity.

Main Methods:

• Literature review synthesizing evidence from vascular, renal, and oncological research.
• Analysis of the deregulation of eight conserved signalling pathways: AMPK, ERK1/2, HIF-1α, JAK-STAT, KEAP1/NRF2/p62, NF-κB, TGF-β1, and Wnt/β-catenin.
• Identification of shared regulatory hubs and convergence points.

Main Results:

• Phosphate overload suppresses AMPK and activates ERK1/2, promoting vascular calcification and endothelial apoptosis.
• Elevated Pi induces oxidative stress, stabilizing HIF-1α and activating JAK-STAT3, fostering a pro-inflammatory tumor microenvironment.
• Chronic NF-κB activation links phosphate toxicity to secondary hyperparathyroidism, hepatic iron dysregulation, and epithelial-mesenchymal transition.

Conclusions:

• The convergence of deregulated pathways on AMPK, ERK1/2, and NF-κB highlights them as critical therapeutic nodes.
• Restoring AMPK activity or inhibiting ERK1/2 and NF-κB pathways offers potential strategies.
• Targeting these nodes may limit systemic phosphate toxicity across diverse disease contexts.