Iron, inflammation, and fibroblast growth factor 23: Integrating molecular crosstalk, cardiovascular biology, and therapeutic perspectives

Table 1 Regulation of fibroblast growth factor 23 production and processing by iron status, inflammation, and erythropoietic signals

Stimulus	Effect on production	Effect on processing	Biological consequence
Iron deficiency	Stimulates FGF23 transcription through iron- and HIF-sensitive pathways	Increased cleavage usually limits iFGF23 accumulation	Predominant rise in the C-terminal signal with preserved phosphate homeostasis. Experimental and human evidence[8,9]
Iron deficiency with impaired cleavage (e.g., ADHR)	Stimulates FGF23 production	Cleavage-resistant FGF23 accumulates	Increased iFGF23, renal phosphate wasting and hypophosphatemia. Genetic and experimental evidence[8]
Inflammation	Cytokines directly stimulate FGF23 transcription and also restrict iron availability through hepcidin	Processing may increase in parallel, especially early in inflammation	The iFGF23 response depends on the balance between production and cleavage. Experimental evidence[10]
Blood loss and erythropoietic stress	EPO and marrow erythroid cells increase FGF23 production	Cleavage commonly increases	Links the response to anemia with FGF23 regulation. Mouse and human EPO studies[13,14]
Iron repletion	Removes the iron-deficiency stimulus	Cleavage rate is not directly quantified by the fall in cFGF23	Restores iron-dependent regulation. Human intervention evidence[9]
Some intravenous iron formulations	Correct iron deficiency but may transiently alter post-translational regulation	Intact hormone rises after some formulations; the molecular mechanism remains unresolved	Transient iFGF23 elevation, phosphate wasting and hypophosphatemia. Randomized human evidence[16,17]

cFGF23: C-terminal fibroblast growth factor 23 assay result; ADHR: Autosomal dominant hypophosphatemic rickets; EPO: Erythropoietin; FGF23: Fibroblast growth factor 23; HIF: Hypoxia-inducible factor; iFGF23: Intact fibroblast growth factor 23.