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.

Table 2 Biological information provided by intact and C-terminal fibroblast growth factor 23 measurements

Measurement	What the assay detects	Biological information	Main interpretive limitation
iFGF23	Full-length FGF23; antibodies recognize epitopes on opposite sides of the cleavage site	Circulating biologically active hormone available for receptor activation	May remain stable despite markedly increased production when cleavage rises in parallel[36,37]
cFGF23	Intact hormone plus C-terminal fragments; antibodies recognize epitopes downstream of the cleavage site	Composite signal influenced by both production and proteolytic processing	Does not measure C-terminal fragments selectively and should not be interpreted as intact hormone[36,37]
Paired iFGF23 and cFGF23	Both measurements obtained in the same clinical or experimental setting	Supports interpretation of discordant assay responses; does not directly quantify production, cleavage, or fragments	Assay methods are not standardized or interchangeable. Research interpretation, not a direct cleavage-rate measure[36,37]
C-terminal fragments	Not selectively quantified by current cFGF23 assays	Potential modulation of BMP-hepcidin signaling and iron availability	Biological activity remains supported mainly by experimental evidence. Mouse and cellular evidence[4]

BMP: Bone morphogenetic protein; cFGF23: C-terminal fibroblast growth factor 23 assay result; FGF23: Fibroblast growth factor 23; iFGF23: Intact fibroblast growth factor 23.

Table 3 Clinical contexts linking iron status and fibroblast growth factor 23 biology

Clinical setting	Typical FGF23 pattern	Potential relevance
Iron-deficiency anemia	High cFGF23 with relatively preserved iFGF23	Efficient cleavage may protect phosphate homeostasis despite increased production. Human observational and interventional evidence[9,42]
ADHR with iron deficiency	Increased iFGF23 because the mutant hormone resists cleavage	Hypophosphatemia and osteomalacia; oral iron may correct the biochemical phenotype. Small open-label human trial[48]
X-linked hypophosphatemia	Iron is associated mainly with variation in cFGF23	Iron-sensitive regulation persists in a primary FGF23-excess disorder. Human observational evidence[43]
Chronic inflammatory disorders	Variable FGF23 pattern influenced by cytokines, hepcidin and iron restriction	Clinical evidence remains limited and disease-specific. Small human studies; uncertain generalizability[77,78]
Heart failure	Iron deficiency and elevated FGF23 frequently coexist	Associations with congestion, remodeling, hospitalization and mortality; causality remains uncertain. Human observational evidence; causality unproven[21,79]
Chronic kidney disease	Elevated intact and C-terminal measurements; production, processing, clearance, and mineral metabolism contribute	Cardiovascular, heart-failure and mortality associations. Human observational evidence with experimental support; causal contribution uncertain[10,22]
General population	Higher FGF23 associated with incident heart failure and coronary events	May integrate iron status, erythropoietic drive, kidney function and inflammation. Human observational evidence; no established testing indication[15,20,80]

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

Table 4 Tissue context and receptor specificity of fibroblast growth factor 23 signaling

Receptor	Tissue	Alpha-Klotho context	Evidence and interpretation
FGFR1c	Renal tubular epithelium	Membrane-bound α-Klotho in canonical signaling	Structural, cellular, and animal evidence supports phosphate and vitamin D regulation[1,29,30]
FGFR4	Cardiomyocytes	Membrane α-Klotho not required in the cited models; soluble α-Klotho can modulate responses	Rodent/cell studies support hypertrophy and metabolic effects, with negative replication in other models; human benefit unproven[19,24,82,83]
FGFR4	Hepatocytes	Membrane α-Klotho-independent in the cited models	Cell and rodent evidence for inflammatory mediator production[3]
FGFR1	Erythroid progenitors	Requirement not established by the cited study	Mouse lineage deletion and progenitor culture support local inhibition of erythropoiesis[25]
FGFR1	Atrial fibroblasts and vascular smooth muscle	Do not infer independence without direct testing	Cell and animal evidence for proliferation or phenotype switching; these endpoints differ from calcification[88,93]
FGFR1	Coronary endothelial cells	Membrane α-Klotho detected; inhibition altered the response	Human cells in culture, not a clinical intervention: Context-dependent nitric oxide and redox effects[91]
FGFR2	Neutrophils	No α-Klotho requirement demonstrated here	Mouse and ex vivo human evidence for impaired integrin activation and recruitment[59]

These are selected experimentally implicated pathways, not an exhaustive receptor map. Human cells studied in culture are classified as cellular evidence. Absence of a demonstrated requirement is not proof of co-receptor independence. FGFR: Fibroblast growth factor receptor.

Table 5 Clinical trials informing iron treatment and fibroblast growth factor 23 modulation

Ref.	Design and population	Intervention	Findings and limits
FIRM[16]	Randomized double-blind trial; 1997 adults with iron-deficiency anemia; 185 in the physiological substudy; follow-up to week 5	Ferric carboxymaltose 750 mg vs ferumoxytol 510 mg, administered intravenously at baseline and week 1	Hypophosphatemia < 2.0 mg/dL: 50.8% vs 0.9% over 5 weeks. Intact FGF23 rose after ferric carboxymaltose. Biochemical and mechanistic outcomes; no cardiovascular efficacy inference
PHOSPHARE-IDA[17,99]	Two randomized open-label trials; 245 adults; reduced kidney function excluded; follow-up to day 35	Ferric derisomaltose 1000 mg once on day 0 vs ferric carboxymaltose 750 mg on days 0 and 7	Hypophosphatemia < 2.0 mg/dL through day 35: 7.9% vs 75.0% and 8.1% vs 73.7%. Severe or persistent hypophosphatemia occurred only with ferric carboxymaltose in the secondary analysis. Different total iron doses and short follow-up limit extrapolation
PHOSPHARE-IBD[100]	Randomized double-blind trial; 97 adults with inflammatory bowel disease and iron-deficiency anemia; follow-up to day 70; primary endpoint through day 35	Ferric derisomaltose vs ferric carboxymaltose: 1000 mg on day 0, followed by 500 or 1000 mg on day 35 according to calculated iron requirement	Hypophosphatemia < 2.0 mg/dL from baseline to day 35: 8.3% vs 51.0%; adjusted risk difference -42.8% (95%CI: -57.1% to -24.6%). Both corrected anemia. Longer-term clinical consequences remain uncertain
ExplorIRON-CKD[101]	Single-center randomized double-blind exploratory trial; 26 patients with CKD stages 3a-5; follow-up to 3 months	Ferric derisomaltose vs ferric carboxymaltose: 1000 mg at baseline, followed by 500-1000 mg at 1 month as required for iron repletion	Greater intact FGF23 rise and phosphate and calcitriol reduction with ferric carboxymaltose. Small mechanistic study, not powered for clinical events
AXLES-1[105]	Randomized double-blind placebo-controlled phase 3 trial; 134 adults with XLH; 24 weeks	Burosumab 1 mg/kg subcutaneously every 4 weeks vs placebo	Mean midpoint serum phosphate above the lower limit of normal: 94.1% vs 7.6%; fracture healing improved at week 24. Demonstrates efficacy in primary FGF23 excess, not CKD or cardiovascular disease
EVOLVE Biomarker analysis[107]	Secondary analysis of a randomized placebo-controlled trial in hemodialysis with secondary hyperparathyroidism; 2602 participants with paired baseline/week-20 samples	Cinacalcet 30-180 mg/day vs placebo, added to conventional treatment; dose titrated according to PTH and calcium	At least 30% FGF23 reduction by week 20: 68% vs 28%. Within the cinacalcet group, biomarker reduction was associated with fewer events; the secondary responder analysis does not establish causality

Trial acronyms identify the cited studies. Percentages are reported in the intervention order shown. Trials differ in eligibility, dosing, sampling, and endpoints and should not be compared as a pooled dataset. CI: Confidence interval; CKD: Chronic kidney disease; FGF23: Fibroblast growth factor 23; XLH: X-linked hypophosphatemia; PTH: Parathyroid hormone.