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

Abstract

Inorganic phosphate (Pi) is a fundamental cellular metabolite whose excess triggers active signalling cascades that drive pathological remodelling across multiple organ systems. This review synthesises evidence from vascular, renal and oncological research to reveal how hyperphosphataemia deregulates eight conserved signalling pathways-AMPK, ERK1/2, HIF-1α, JAK-STAT, KEAP1/NRF2/p62, NF-κB, TGF-β1 and Wnt/β-catenin-and how these converge on shared regulatory hubs to produce vascular calcification, renal fibrosis and tumour progression. Phosphate overload suppresses the cytoprotective kinase AMPK while simultaneously activating the ERK1/2 cascade, forcing vascular smooth muscle cells towards an osteogenic phenotype and driving endothelial apoptosis. Oxidative stress generated by elevated Pi stabilises HIF-1α under normoxic conditions and activates JAK-STAT3 signalling, sustaining a pro-inflammatory tumour microenvironment. Chronic activation of NF-κB links phosphate toxicity to secondary hyperparathyroidism, hepatic iron dysregulation and epithelial-mesenchymal transition in cancer cells. TGF-β1 and Wnt/β-catenin pathways orchestrate extracellular matrix remodelling across vascular and renal compartments. The mechanistic convergence of these pathways on AMPK, ERK1/2 and NF-κB identifies these kinases as priority therapeutic nodes. Restoring AMPK activity or attenuating the ERK1/2 and NF-κB cascades may represent tractable strategies to limit systemic phosphate toxicity across disease contexts.

Key Findings

• Excess inorganic phosphate (Pi) triggers multiple conserved signalling pathways including KEAP1/NRF2/p62, contributing to pathological remodelling in vascular, renal, and cancer contexts.
• Phosphate overload suppresses cytoprotective AMPK kinase and activates ERK1/2, promoting vascular smooth muscle osteogenic transformation and endothelial apoptosis.
• Elevated Pi-induced oxidative stress stabilizes HIF-1α and activates JAK-STAT3, sustaining a pro-inflammatory tumor microenvironment, while chronic NF-κB activation links phosphate toxicity to secondary hyperparathyroidism and cancer epithelial-mesenchymal transition.

Clinical Significance

Citation

Silva Amanda Lima, da Silva Freitas Beatriz Bereda, Oliveira Pedro Henrique Silvaet al.. Inorganic phosphate beyond a mineral: Signal transduction in multi-organ pathology. Cellular signalling. 2026-Jul-10.